Individualizing Nicotine Replacement Therapy for the Treatment of Tobacco Dependence

Context Do certain forms of nicotine replacement therapy work better than others and, if so, in whom? Contribution This randomized trial of 299 treatment-seeking smokers found similar 6-month abstinence rates between smokers receiving behavioral counseling and 8 weeks of therapy with either nicotine nasal spray (12%) or transdermal nicotine (15%). Subgroup analyses suggested that highly dependent, obese, and nonwhite smokers achieved higher abstinence rates with nasal spray. Low to moderately dependent, nonobese, and white smokers achieved higher abstinence rates with transdermal nicotine. Cautions Tailoring nicotine replacement therapy on the basis of characteristics of smokers is an intriguing strategy but has not yet been tested. The Editors Nicotine replacement therapy is recommended as a first-line treatment for tobacco dependence (1). Although use of nicotine replacement therapy can double a person's odds of quitting smoking, as many as 70% to 80% of smokers receiving treatment do not achieve long-term abstinence (2-5). Nicotine replacement therapy is widely used; however, empirical data are insufficient to guide practitioners in selecting a particular form of treatment for individual patients with tobacco dependence (1). In lieu of such evidence, the most rational approach has been to base the choice of pharmacotherapy on the patient's previous treatment experiences and preferences (6). However, recent data suggest that smokers' past experiences and preferences have little bearing on the outcome of nicotine replacement therapy (7). Our goal was to evaluate the comparative efficacy of transdermal nicotine and nicotine nasal spray and to identify pretreatment clinical characteristics that predict treatment outcome. In addition, to suggest factors that may be useful for individualizing nicotine replacement therapy, we examined predictors of treatment outcome by using subgroup analyses. These 2 forms of nicotine replacement therapy were selected on the basis of their differing pharmacokinetic and pharmacodynamic properties. After administration of transdermal nicotine, levels of nicotine rise slowly and then plateau within 4 to 6 hours (8). This profile is believed to be optimal for alleviating withdrawal symptoms and perhaps reducing positive reinforcement from nicotine when subsequent exposure to tobacco occurs (that is, a brief lapse or slip) (9, 10). In contrast, nicotine nasal spray produces rapid peak venous levels of nicotine, which lead to rewarding effects that more closely approximate those achieved from cigarette smoking (9, 11, 12). Methods Participants were enrolled at Georgetown University (Washington, DC) and the University of Pennsylvania (Philadelphia, Pennsylvania). The institutional review boards from both universities approved the research procedures. Figure 1 shows the flow of participants through the enrollment, treatment, and follow-up phases of the trial. Figure 1. Flow diagram of trial participation. Smokers responding to local media advertisements for free smoking cessation treatment and to physician referrals were screened for eligibility and recruited from February 2000 through March 2002. Eligible persons were current cigarette smokers 18 years of age or older who had smoked 10 or more cigarettes per day for the previous 12 months. Exclusion criteria were pregnancy or lactation, uncontrolled hypertension, unstable angina, heart attack or stroke within the previous 6 months, current treatment or recent diagnosis of cancer, drug or alcohol dependence, current diagnosis or history of a psychotic disorder, or current use of bupropion or nicotine-containing products other than cigarettes. Study Design and Treatment Procedures This was a randomized, open-label clinical trial of transdermal nicotine versus nicotine nasal spray for smoking cessation. Randomization was determined by using a computer-generated randomization scheme operated by a senior data manager; stratification was done by study site. Allocation to treatment could not be concealed from the counselors or the study assistants who delivered the medication to patients after preparation at the research pharmacy. All participants received 7 sessions of standardized behavioral group counseling that included instruction in the management of smoking triggers, relapse prevention, and stress management techniques. The behavioral counseling sessions, which occurred in the evening, lasted approximately 1.5 hours each and included approximately 10 to 14 members per group. As reported previously (13), 70% of participants completed all 7 sessions, and differences in completion rates by study site were not statistically significant. At each site, two counselors with master's degrees led an equal number of groups receiving either transdermal nicotine or nicotine nasal spray therapy and received weekly supervision to ensure protocol adherence. Nicotine nasal spray therapy (Nicotrol, Pharmacia and Upjohn, Helsingborg, Sweden) was initiated on the target quit date (week 3) and was delivered over an 8-week period. At the second counseling session (week 2), participants were shown how to deliver a 1.0-mg dose (0.5-mg spray in each nostril) and how to use nicotine nasal spray 8 to 40 times per day (with a maximum of 5 doses/h) beginning on the target quit date. After 4 weeks of use, participants were instructed to taper their nicotine nasal spray dose by one third for a 2-week period and then by another third for the final 2 weeks of treatment. Participants used transdermal nicotine (Nicoderm CQ, GlaxoSmithKline, Research Triangle Park, North Carolina) over an 8-week treatment period, beginning with the morning of the target quit date (week 3). A 24-hour, tapered-dose formulation was used: 4 weeks at 21 mg, 2 weeks at 14 mg, and 2 weeks at 7 mg. To assess smoking status, we conducted telephone interviews at the end of treatment (8 weeks after the target quit date) and 6 months after the target quit date; a standard timeline follow-back method was used (14). Interviewers were blinded to study group assignment. Participants who reported complete abstinence (not even a puff of a cigarette) for at least 7 days before the assessment were asked to complete an in-person visit for biochemical verification of abstinence within 1 to 2 weeks after the follow-up interview. Adverse events were self-reported by using a weekly checklist that queried the severity of 17 common side effects associated with nicotine replacement therapy (for example, rash with transdermal nicotine). Research assistants evaluated the completed checklist before each counseling visit and reviewed it with the study physicians and participants, as needed. Measurements Predictors On the basis of previous research and ease of assessment, we selected the following variables as predictors: sex, ethnicity, education, body mass index (BMI), nicotine dependence, and depression symptoms (15-18). We used the Fagerstrom Test for Nicotine Dependence (19) to measure tobacco dependence; a cutoff score of 7 or greater was used to classify participants as highly nicotine dependent (20). The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess the severity of depression symptoms; a score 16 or greater was used to identify clinical symptoms of depression (21). Height and weight were measured at the medical screening visit. Body mass index was calculated by dividing weight in kilograms by height in millimeters (squared), and obesity was defined according to recommendations of the National Institutes of Health (BMI 30 kg/m2) (22). Treatment Monitoring Participants recorded their daily use of nicotine replacement therapy. Those assigned to transdermal nicotine recorded their daily application of patches, and those assigned to nicotine nasal spray recorded the number of doses per day. Because use of nicotine replacement therapy may be confounded with smoking status (that is, participants may discontinue nicotine replacement therapy if they have relapses), we focused on average use during the first 2 weeks of treatment. We calculated the percentage of cotinine replacement from treatment by dividing participants' plasma cotinine levels after 1 week of treatment by their pretreatment plasma cotinine levels (23). These time points were selected to coincide with a period of regular smoking and with steady-state cotinine levels achieved after treatment (23). Cotinine levels were analyzed by using gas chromatography with nitrogen phosphorus detection, modified for analysis by using a capillary gas chromatography column (24). Outcomes We used prolonged abstinence as the primary outcome measure and point prevalence as the secondary measure (25). For prolonged abstinence, relapse was defined as 7 consecutive days of smoking at any time during the follow-up period. Because the prolonged abstinence measurement period extends from the target quit date to 6-month follow-up, biochemical verification for this period, by definition, is not possible. The point prevalence measure required 7 days of continuous abstinence immediately before the follow-up point, which was confirmed by a carbon monoxide reading of less than 10 parts per million (ppm) (26). (Of note, of the 65 participants who self-reported 7 days of abstinence and provided a carbon monoxide sample, 15 [23%] had a carbon monoxide level 10 ppm). Thus, for prolonged abstinence, brief relapses or slips (that is, any smoking at all, even a puff) were allowed, whereas the point prevalence measure allowed no lapses during the 7 days before each follow-up (25). For descriptive purposes, we also assessed rates of continuous abstinence under the most stringent criterion (not even a puff) from target quit date to 6-month follow-up (not biochemically verified). In intention-to-treat analyses, we presumed that those who dropped out or were otherwise lost to follow-up had had relapses. Statistical Analysis We calculated that a sample size of at least