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Efficacy and Safety of an Over-the-counter Transdermal Nicotine Patch as an Aid for Smoking Cessation
Michael Davidson, MD;
Michael Epstein, MD;
Robert Burt, FRCA, FRCPE;
Connie Schaefer;
Gene Whitworth, PhD;
Arline McDonald, PhD
Arch Fam Med. 1998;7:569-574.
ABSTRACT
Objective To evaluate the efficacy and safety of a transdermal nicotine patch as an aid for smoking cessation in an over-the-counter setting.
Design Multicenter, double-blind, randomized, placebo-controlled trial of 6-week duration with 18 weeks of follow-up.
Setting Four shopping mall precincts.
Participants The randomized sample consisted of 802 adults (mean age, 39 years) and was 89% white and 54% female. A smoking history of at least 20 cigarettes per day for 1 year and a score of 5 (on a 10-point scale) on a motivational assessment questionnaire were required for enrollment. Poststudy follow-up was limited to those who had quit smoking at the end of 6 weeks.
Intervention Nicotine patches were provided at the shopping mall. Guidance consisted only of package instructions and a smoking cessation self-help booklet.
Main Outcome Measures Quit rates were defined as total abstinence from smoking for 4 consecutive weeks (treatment weeks 3-6), point prevalence smoking status at week 6, or nonsmoker at week 6 and week 24 (6-month postquit date). Smoking status was assessed by diaries, and verification for the first 2 quit rates was obtained by confirmation of carbon monoxide of 8 ppm or less in expired breath. Safety was evaluated by self-reported adverse events.
Results Quit rate was 12% for the active treatment group and 5.5% for the placebo group, based on total abstinence for 4 consecutive weeks (P = .001) compared with quit rates of 19.5% and 7.5% for active treatment and placebo groups, respectively, based on point prevalence data at week 6. At 24 weeks, 8.2% of nonsmokers in the active treatment group and 4.0% in the placebo group remained nonsmokers. At least 1 adverse event was reported by 57% receiving the nicotine patch and 39% receiving placebo (P<.001).
Conclusions When the nicotine patch was used in an over-the-counter setting, quit rates were comparable to those reported for medical settings. A 2:1 quit rate advantage was achieved at week 6 and was maintained at 24 weeks.
INTRODUCTION
SMOKING REMAINS a major public health problem in the United States, contributing to approximately 20% of total mortality each year.1 An estimated 28% of adults are currently smoking, down from a high of 40% in 1964, but still well above the goal of 15% targeted by national public health policy for the year 2000.1-3 Several interventions, including behavioral therapy, goal setting, advice from a health care professional, self-help approaches, group counseling, filtration devices, hypnosis, and acupuncture, have been widely used with varying degrees of success to assist individuals in quitting their smoking habit.4 However, the success of these interventional approaches in changing smoking behavior over the long-term has generally been poor, with more than 90% of smokers who quit relapsing by 1 year.4
Based on a meta-analysis of data from 17 randomized, double-blind, placebo-controlled trials, nicotine transdermal patches coupled with professional advice and follow-up have an efficacy of 27% at the end of 6 weeks and 22% after 6 months, which is more than twice the success rate of placebo in achieving and maintaining nonsmoking status.5 The quit rate diminishes after a 12-month period but the ratio between patch and placebo treatment groups is maintained.6-11
Nicotine transdermal patches have been available without prescription in the United States since the middle of 1996. A few studies9, 12 have suggested that the effectiveness of the transdermal patch may be improved by concomitant behavioral therapy. However, many smokers may find the need for a learned intermediary such as a physician or other health care provider a barrier to seeking assistance to quit smoking. The primary objective of the present study was to evaluate the efficacy and safety of a nicotine transdermal patch as a smoking cessation aid in free-living adults receiving limited information regarding use. A second objective was to evaluate the consumer ability to interpret package label and other self-help information to judge whether, for safety precautions, the patch would be suitable for them to use.
SUBJECTS AND METHODS
STUDY DESIGN
The study was conducted as a multicenter trial using a double-blind, randomized, placebo-controlled, parallel-group design to evaluate the efficacy and safety of nicotine transdermal patches in an over-the-counter (OTC) setting. The study was designed to mimic the environment associated with securing and using a nonprescription item with no office visits or contact with a physician or other learned intermediary. However, complete reproducibility of the OTC setting was impossible because of the requirement for consent forms, description of the study, follow-up contacts, and free distribution of study drugs.
Study sites were identified at 4 shopping malls: 3 in the Annapolis, Md, area and 1 in the Chicago, Ill, area. An enrollment booth for providing general consumer information was established at each mall. Interested individuals were referred to a market research center also located at each mall for screening. The market research center was also the site where study participants returned for data collection on a weekly basis throughout the treatment period and follow-up. The study protocol, self-screening questionnaire, package labels, consent form, and radio and newspaper advertising were reviewed and approved by the Essex institutional review board, Lebanon, NJ.
Recruitment
Potential participants were recruited through local radio and newspaper advertisements that encouraged smokers who wanted to quit to visit the local shopping mall. Individuals who had not heard or seen the advertisements but who stopped at the enrollment booth at the mall were also eligible to participate in the study. Interested individuals were directed to the market research center where they were given a mock-up box of patches, asked to read the label, and instructed to answer the self-screening questionnaire to determine whether they qualified for the study. Educational level was not recorded or evaluated in this study, and participants received no payment for the study.
Motivational Assessment
One of the questions on the self-screening questionnaire asked individuals to rate their motivation to stop smoking on a 10-point scale (1 = little interest and 10 = extremely motivated). No visual analog scale was used. The motivational assessment questionnaire was modified from the Pretreatment Confidence Questionnaire described by Best and Hakstian13 and validated by Condiotte and Lichtenstein.14 Only individuals scoring 5 or more on the questionnaire were eligible for enrollment. This level was selected only to rule out the casual passerby who might not have been serious about quitting, or those attracted only because the patches were provided at no cost.
Inclusion and Exclusion Criteria
All smokers older than 18 years who scored at least 5 or more on the motivational assessment questionnaire were eligible to participate regardless of medical illness or concomitant medication. Only those who were currently pregnant or had sustained a myocardial infarction during the past month were excluded. A smoking history of at least 1 year and at least 20 cigarettes per day was required.
Screening
Individuals meeting the inclusion and exclusion criteria signed the screening log book and provided photographic identification. They were asked to decide on a "quit date" within 7 days of the screening visit when all use of cigarettes would stop. A consent form was read and signed. A brief medical history, list of concomitant medications, and a smoking history were obtained. A quantitative assessment of carbon monoxide (CO) in expired breath was made by means of a Bedfont EC350 device (Keison Products, Chelmsford, England).
Randomization
Eligible individuals were assigned to receive either nicotine patches or placebo patches according to a computer-generated randomization schedule provided by Pharmaco LSR, Austin, Tex, before initiation of the study. To ensure even distribution between men and women, only 60% of either sex could enroll at each center.
Treatment Period
Participants meeting eligibility requirements were given a box containing either 7 nicotine patches or 7 placebo patches and instructed to apply 1 patch daily at the same time each day for 1 week and then to return to the market research center. ProStep (Transdermal Nicotine System) patches were provided by Elan Pharmaceutical Research Corp, Gainesville, Ga. Each nicotine patch contained 30 mg of nicotine to release 22 mg every 24 hours. An extra 7-day supply of patches was also given to permit some flexibility in scheduling visits. Instructions on patch application were provided and the participants applied the first patch under supervision. Participants were asked to keep a record of their smoking behavior on a diary card and were given the name of someone to contact in the event of an emergency. A smoking cessation self-help booklet was provided.
At each of the 6 weekly visits during the period of patch application, smoking behavior was evaluated, diary cards reviewed, information collected on changes in concomitant medications and adverse events, and CO levels monitored. Participants self-rated the severity of adverse events without reference to rating scale or medical input. Drug accountability was maintained at the study site and audited during site visits and on completion of the study. Participants were asked to return the empty boxes at each visit. Each visit was verified by photographic identification and signature in the log book. A new box of patches was dispensed for the next week of treatment.
Follow-up Visits
At the end of the 6-week treatment period, participants who had quit smoking were scheduled for follow-up visits at 16 weeks (from the screening visit) and at 24 weeks. Those who were continuing to smoke completed an "end of patch" form and an "end of study" form and were not required to return for further follow-up.
Withdrawal
Participants were withdrawn from the study if an adverse event occurred that justified withdrawal, there was a protocol violation, the participant requested to be withdrawn, or the sponsor decided the participant should be withdrawn. Participants who withdrew from the study or who were lost to follow-up, including those who failed to return for any visits, were counted as smokers and thus treatment failures.
STATISTICAL METHODS
Sample Size
Based on previously published results,4-8 it was expected that the quit rate for the active treatment group compared with the placebo group would be a ratio of 20% to 12.5%, or approximately 2. With this expectation, 800 participants would be needed to declare statistical significance at  = 0.05 with a power of 80%.
Outcome Measures
The primary efficacy variable was the proportion of participants who quit smoking. The quit rate was based on the definition of the Food and Drug Administration and required total abstinence from smoking to be achieved starting after the first 2 weeks of the study and maintained for 4 consecutive treatment weeks (weeks 3-6). The point prevalence quit rate at week 6 was also obtained. This calculation included all participants who reported not smoking at week 6, regardless of the length of abstinence, and who returned for at least 1 postbaseline visit. After completion of patch therapy at week 6, those who met the Food and Drug Administration definition of nonsmoker were followed up to 18 additional weeks (week 24) and the number of nonsmokers were assessed at that time.
Classification as a nonsmoker was based on participant reports and diary data. Where possible, diary data were verified by measurement of expired CO (CO concentration minus background CO), and a value of 8 ppm or less provided confirmation of nonsmoking status. Verification of CO was obtained to confirm quit rates based on consecutive weeks of abstinence and on point prevalence data at week 6. At each visit, the diary card was reviewed and the participant asked if he or she had smoked since the previous visit. If the answer was no, that visit and any previously scheduled visits that had been missed were classified as "no." Anyone who missed visit 7 and could not be contacted by telephone was assumed to be smoking.
The primary safety variable was the comparison of participant-reported adverse events between the 2 treatment groups.
Statistical Analyses
The proportion of participants who quit smoking was summarized and tested for overall treatment group differences using the Pearson  2 test. Comparison of treatment groups stratified by site, sex, age, and smoking history was performed using the Cochran-Mantel-Haenszel test.
Incidence rates of each adverse event were summarized for all body systems combined, by body system, and by event type. The incidence rates by body system as well as the rate for all body systems combined were tested for significant treatment group differences using the 2 test. Only P values of .10 or less were reported in the summary tables.
RESULTS
BASELINE CHARACTERISTICS
A total of 1844 adults between the ages of 18 and 78 years were screened for study participation. After exclusions for ineligibility, 802 adults were enrolled: 371 men and 431 women. Table 1 shows the distribution of the total number of individuals screened and randomized at each of the 4 study sites. Of the 802 individuals randomized, 541 withdrew prematurely from the study. All 802 participants were included in the intent-to-treat analysis.
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Table 1. Numbers of Participants Screened, Randomized, and Discontinued by Study Site
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The demographic characteristics of the 802 adults randomized into the study are given in Table 2. The treatment groups were similar in race and sex composition. Each group was composed of 89% whites and 54% women. Mean age of participants in each group was 39 years. Baseline smoking habits were similar with a mean smoking history of 21 years in each group. There were no significant differences between the treatment groups in any of the baseline demographic characteristics assessed.
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Table 2. Baseline Demographic Characteristics of Randomized Participants by Treatment Group
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Almost all participants reported at least 1 underlying illness at randomization; many of them reported several. The most common of the illnesses reported were allergies, which afflicted 38% of total participants. Cardiovascular-related illnesses were reported by 16% and pulmonary illnesses by 20% of participants.
Because there were no statistically significant or clinically relevant differences in the baseline characteristics of the participants by group or site, the results from all 4 sites were combined for analysis of efficacy and safety.
EVALUATION OF EFFICACY AND SAFETY
Premature Withdrawal
Of the 802 participants randomized into the study, 541 (67.5%) withdrew before the study was completed. A greater number of participants from the placebo group withdrew prematurely than from the active treatment group (297 vs 244, respectively). The most frequent reason given for early withdrawal was "lost to follow up," which was recorded for 32% (173/541) and usually indicated continued smoking. Of the 14% (76/541) who withdrew prematurely because of an adverse event, 18% (44/244) had used the nicotine patch and 10.8% (32/297) had used the placebo patch. None of the differences between treatment groups in reasons given for withdrawal was statistically significant.
Quit Rates
Quit rates expressed as total abstinence from smoking during treatment weeks 3 to 6 and point prevalence at week 6 are compared in Table 3. The number of nonsmokers at week 6, based on total abstinence from smoking during weeks 3 to 6, who were also nonsmokers at week 24 is also shown. Based on diary data alone, the quit rate based on total abstinence from smoking for 4 consecutive weeks was 12% (48/401) for participants who received the nicotine patch and 5.5% (22/401) for participants who received placebo (P = .001). The quit rate ratio between the nicotine group and placebo group was 2.2:1. Of the total of 70 participants from both groups who claimed to have successfully quit smoking, CO verification was obtained from 54 (77%). These measurements provided positive confirmation for 97% (34/35) of the active treatment group and 95% (18/19) of the placebo group from whom CO data were collected. Only 1 participant in each group who claimed to have quit smoking had a CO concentration of greater than 8 ppm in expired breath.
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Table 3. Quit Rates Assessed by Diary Data (N = 802)
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The point prevalence quit rate at week 6 was 19.5% (78/401) for the active treatment group and 7.5% (30/401) for the placebo group based on diary data alone. Verification of CO was obtained from 98 of the 108 participants from both groups who identified themselves as nonsmokers. Nonsmoking status was confirmed in 91% (71/78) of the active treatment group and in 90% (27/30) of the placebo group. The quit rate ratio between the active treatment group and placebo group based on the point prevalence quit rate was 2.6 (Table 4). The difference in quit rates between active treatment and placebo using data only for the 692 participants who had at least 1 postbaseline visit was statistically significant (P = .01).
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Table 4. Nonsmoking Status During Follow-up Based on Diary Data Alone
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The quit rate at week 24 was determined from the nonsmokers identified at week 6 using the criterion of total abstinence for 4 consecutive weeks who were no longer receiving patch therapy for the 18 weeks of follow-up. Of 70 nonsmokers at week 6, 48 had been randomized to active treatment and 22 to placebo. At week 24, 8.2% (33/401) in the active treatment group again report nonsmoking status compared with 4.0% (16/401) in the placebo group. The quit rate ratio was 2.1(Table 4). The difference in quit rates between active treatment and placebo groups at week 24 was statistically significant (P = .01).
Point Prevalence
Point prevalence data were also collected at every week throughout the 6 weeks of the study. These data for nonsmokers in each group at each week verified by CO measures are displayed in the Figure 1. At any given week, 15% (60/401) to 21% (83/401) of the actively treated participants were classified as nonsmokers based on diary data alone compared with 7.2% to 7.7% (29-31/401) of placebo-treated participants. The proportion of nonsmokers was 2 to 3 times greater for active treatment than for placebo. Upon verification of smoking status by CO measurements, the overall proportions classified as nonsmokers decreased to 14.2% to 19% (57-76/401) for active treatment and 6% to 7% (24-28/401) for placebo, but the ratio of nonsmokers in the active treatment and placebo groups at each week did not change.
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Percentage of nonsmokers at each week by treatment group (point prevalence) diary data and carbon monoxide (CO)-verified diary data.
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Adverse Events
Adverse events were the reason given for premature withdrawal from the study for 44 participants in the active treatment group and 32 in the placebo group (Table 5). The most frequently reported event leading to withdrawal was an application site reaction (ASR). The ASR was defined by a cluster of signs and symptoms at the site where the patch was applied. To be classified as an ASR, 1 or more of the following signs or symptoms had to be reported: erythema (redness), pruritus (itching), burning (irritation), and local swelling or edema.
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Table 5. Numbers of Participants Reporting Adverse Events by Treatment Group
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Adverse events were reported during the follow-up phase for 22% of the 81 participants from the active treatment group and 16% of the 31 from the placebo group. The most common of these events was an ASR with 25% of the active treatment group and 13% of the placebo group reporting 1 or more of the associated signs and symptoms. Since the last patch had been applied at 6 weeks, these events were considered to be a carryover from the treatment phase.
COMMENT
Previous comparisons of nicotine transdermal patches with placebo to aid in smoking cessation have shown a consistent 2:1 ratio in favor of the nicotine patch, regardless of the level of counseling offered.5 The results of this study demonstrate that a similar ratio in favor of the nicotine patch can be achieved in an OTC setting with no support other than published self-help material. This 2:1 ratio was also maintained for 18 weeks following the last application of the patch.
In actual percentages, the quit rates of 12% in the active treatment group and 5.5% in the placebo group at the end of 6 weeks, and 8% for active treatment and 4% for placebo at 24 weeks are lower than values reported for nicotine patches in a medical setting.5-10 These differences may reflect the stringent definition of nonsmoking status used in this study compared with the point prevalence quit rate that has been used in most studies. For the purposes of the present study, participants were classified as nonsmokers only if they had remained a nonsmoker for 4 consecutive weeks (weeks 3-6 of patch application). Other studies have presented their quit rates based on numbers of participants classified as nonsmokers at the end of the study regardless of when they quit or for how long.5
When quit rates were estimated from the point prevalence data collected at week 6, the values of 19.5% for active treatment and 7.5% for placebo were more comparable to previously reported values.5
Smoking status was verified in the determination of 2 of the quit rates by use of a monitoring device that measured end-expiratory CO. The CO monitor is a useful clinical instrument for assessing smoking behavior because it is objective, noninvasive, and inexpensive, and provides immediate accurate results. The specificity of the CO monitor has been demonstrated to be 100%, which is identical to that of measurement of blood carboxyhemoglobin, but better than the specificity of measurement of serum thiocyanate at 70%.15 Sensitivity of the CO monitor was 60% compared with 80% to 90% for the other methods.15
Cutaneous reactions at the site of application were the most commonly reported complaints associated with use of the transdermal patch experienced by 38% of participants using the nicotine patch in this study. Some of the discomfort may have been associated with the adhesive used in the patch since similar reactions were also reported by 17% of the placebo group. The finding that allergies were the most common of the concomitant illnesses reported by participants of both groups in this study also may partly explain the frequency of occurrence of ASR. Despite the occurrence of these adverse events, only 11% of participants using the nicotine patch felt uncomfortable enough to withdraw from the study because of them. This percentage is in agreement with the 10% of participants described by Gourlay8 who reported symptoms sufficient enough to discontinue use of the patch.
The finding that consumers can effectively use a nicotine transdermal patch in an OTC setting with minimal safety concerns has important significance for public health. Larger numbers of smokers may be reached through ease of accessibility to this smoking cessation aid. Barriers are fewer and costs lower than are usually associated with prescription items.
The availability of a smoking cessation aid with documented safety and efficacy to a larger number of smokers may expand the opportunity to change smoking behavior in this country. The poor long-term success rates of most interventions for smoking cessation underscores the difficulty of making this behavioral change.4 The more highly motivated, self-referred smokers who smoke an average of 10 to15 cigarettes per day appear to benefit most from nicotine replacement therapy.8, 11 The excellent response to media advertisements for recruiting participants into this study suggests that the nicotine transdermal system is attractive to many smokers who want to quit. Confirmation of efficacy and safety of the nicotine patch in an OTC setting should increase the confidence of physicians to recommend nicotine transdermal systems for patients who are motivated to quit smoking. However, the quit rates recorded at 24 weeks show that maintaining the smoke-free status remains a continuing challenge.
In conclusion, the results of this study show that in an OTC setting, in the absence of counseling or group support that are available in a medical setting, the quit rate was lower than documented by previous investigations. However, the previously reported 2:1 advantage of nicotine transdermal patches over placebo treatment in quit rate was maintained as long as 18 weeks after patch use had been discontinued.
AUTHOR INFORMATION
Accepted for publication September 2, 1997.
This research was supported by Elan Pharmaceutical Research Corporation, Gainesville, Ga.
Reprints: Michael Davidson, MD, Chicago Center for Clinical Research, 515 N State St, Suite 2700, Chicago, IL 60610-4324 (e-mail: mdavidson{at}protocare.com).
From Chicago Center for Clinical Research, Chicago, Ill (Drs Davidson and McDonald), AMMSYS Inc, Annapolis, Md (Dr Epstein), Elan Pharmaceutical Research Corporation, Gainesville, Ga (Dr Burt), Pharmaco:LSR, Columbia, Md (Ms Schaefer), and Pharmaco LSR, Austin, Tex (Dr Whitworth).
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