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To obtain preliminary evidence on the safety and efficacy of high dose nicotine patch therapy among smokeless tobacco (ST) users who consume ≥ 3 cans of ST per week, we conducted a randomized, placebo-controlled clinical trial with 42 ST users randomized to nicotine patch doses of 21, 42, and 63 mg/day or placebo. Serum nicotine concentrations were measured during ad libitum ST use and nicotine replacement therapy, and percentages of nicotine replacement were calculated. We observed substantial inter-subject variability in nicotine concentrations with ad lib ST use. The mean percentage replacement of ad lib ST use serum nicotine concentrations approximated 100% with the 42 mg/day patch dose (mean±SD, 98.4%±45%). Dosing with the 21 mg/day nicotine patch was associated with mean “under-replacement” (53.2%±17.1%), and the 63 mg/day nicotine was associated with mean “over-replacement” (159.2%±121.9%). We observed symptoms of nausea consistent with nicotine toxicity in two subjects in the 63 mg/d group while no subjects in the 42 mg/d reported toxicity symptoms. We conclude that the use of 42 mg/day nicotine patch therapy is safe and should be considered as initial therapy in the clinical setting among ST users who use ≥ 3 cans per week.
Smokeless tobacco (ST) produced in the United States is estimated to be the greatest exogenous source of human exposure to carcinogenic nitrosamines. ST use has been reported to be associated with active periodontal disease (Fisher et al., 2005) and death from cardiovascular disease, cerebrovascular disease and cancer (Henley et al., 2005). However, the risks associated with ST may vary depending upon the type of ST used, such as snuff and chewing tobacco in the United States, snus in Sweden, and other oral tobacco preparations in India and Africa (Critchley and Unal, 2003; Foulds et al., 2003). A need for efficacious interventions exists as 64% of ST users in the U.S. report the desire to quit (Severson, 1992).
Previous research with cigarette smokers has suggested that moderate and heavy smokers experience nicotine “under-replacement” with standard dose nicotine patch therapy (up to 22 mg/day) (Lawson et al., 1998). Nicotine “under-replacement” with standard dose nicotine patch therapy may also occur among ST users. Clinical trials assessing the efficacy of the nicotine patch for ST users in doses of 15-mg/day (Howard-Pitney et al., 1999) and 21-mg/day (Hatsukami et al., 2000) have failed to increase long-term (≥ 6 months) tobacco abstinence rates in ST users despite the fact that it has been shown to decrease craving and nicotine withdrawal symptoms. “Under-replacement” of serum nicotine concentrations among ST users receiving standard doses of nicotine patches may explain the disappointing treatment efficacy results.
We conducted a randomized, double-blinded placebo-controlled clinical trial in order to obtain preliminary evidence of safety and efficacy of higher dose nicotine patch therapy among ST users consuming ≥ 3 cans (1 can equals ~ 34 grams of moist ground tobacco) per week. We randomized 42 ST users to nicotine patch doses of 21, 42, or 63 mg/d or placebo. We evaluated whether standard dose nicotine patch therapy resulted in “under-replacement” of serum nicotine concentrations and if higher doses of nicotine patches would increase the percentage replacement of serum nicotine concentrations. The overall study design and findings from the efficacy analyses have been reported (Ebbert et al., In press). In the current report we present the serum nicotine concentrations and percentage replacement achieved with varying doses of nicotine patch therapy among ST users.
The Mayo Foundation Institutional Review Board (IRB) and the U.S. Food and Drug Administration reviewed and approved the study protocol prior to recruitment and enrollment. Subjects were recruited from the community surrounding the Mayo Clinic in Rochester, MN between November 2003 and October 2004. Individuals interested in stopping ST were recruited through press releases and local advertisements.
Eligible subjects were required to be ≥ 18 years of age, in good general health, have used ST daily for the past year, and be using ≥ 3 cans/pouches per week at the time of enrollment. The cutoff of at least 3 cans/pouches per week was selected to ensure subject safety considering that the use of nicotine patch doses up to 63 mg/day in ST users had only been previously reported in a case series (Ebbert et al., 2004b).
Details of the study have been previously reported (Ebbert et al., In press). This study was divided into three phases: an outpatient preadmission phase (phase I), an inpatient General Clinical Research Center (GCRC) phase (phase II), and an outpatient treatment and follow-up phase (phase III). We are reporting the serum nicotine data and patient experience during the inpatient phase (phase II).
Phase II consisted of a 3-day hospital stay at the Mayo GCRC. The purpose of this phase was to ensure subject safety and to allow close monitoring. Patients were admitted the evening before GCRC Day #1.
On GCRC Day #1, subjects used ST ad libitum and blood was drawn for serum tobacco alkaloids at 0800 and 1600 hours. On GCRC Day #2, subjects were randomly assigned to 1 of 4 groups in a blinded fashion to nicotine patch doses of 21, 42, or 63 mg/day or placebo. Each subject wore three patches simultaneously allowing for blinded removal of nicotine patches if nicotine toxicity developed. We used a nicotine toxicity questionnaire used in previous trials (Dale et al., 1995) modified for ST users collected every evening on an electronic diary. Subjects experiencing symptoms of severe nicotine toxicity removed patches which were replaced later if tolerated.
On GCRC Days #2 and #3, blood samples were obtained before patch application which occurred at 0800 hours. A blood sample was also obtained at 1600 hours. Patients were dismissed after the afternoon blood draw on GCRC Day #3. Tobacco alkaloid concentrations in blood serum were quantified using tandem mass spectrometry (Moyer et al., 2002).
Serum nicotine concentrations obtained at 1600 hours during ad lib ST use on GCRC Day#1 were used as the denominator for the calculation of percentage replacement. This timing is based upon the half-life of nicotine (2 hours) and the observations that steady-state serum nicotine concentrations are achieved by this time of day in regular tobacco ST users (Benowitz et al., 1989).
The serum nicotine concentrations obtained during nicotine patch use at 1600 hours on GCRC Day#3 were used to represent steady-state concentrations for the given patch dose. The 1600 hour time point was selected based upon the pharmacokinetics of the nicotine patch and observations that peak serum nicotine concentrations are generally achieved within 9 hours with repeated patch administration, although substantial inter-individual variability exists (Gupta et al., 1995).
We used the serum nicotine concentrations rather than cotinine to calculate percentage replacement based upon our previous work suggesting that cotinine concentrations correlate with the frequency of swallowing tobacco juice in ST users and, therefore, should not be used when guiding treatment decisions such as nicotine replacement therapy (Ebbert et al., 2004a). Percentage nicotine replacement with the nicotine patch is a percentage determined by calculating the ratio of the serum nicotine concentrations achieved with the nicotine patch and the concentration observed with ad lib ST use (serum nicotine concentrations on nicotine patch ÷ serum nicotine concentration with ad lib ST use × 100%) Data are summarized separately for each patch dose using mean±SD and median (25th, 75th percentile).
All of the 42 enrolled subjects were male with a mean age (±SD) of 35.7 ± 7.5 (range 20–56) years who used an average of 5.9 ± 2.9 cans per week for 17.0 ± 7.3 years. All subjects used snuff (loose, moist ground tobacco) at an average rate of 12.5 ± 7.3 dips per day which they kept in their mouths for an average of 52.1 ± 33.1 minutes. The mean body mass index (BMI) was 30.4 (SD 5.2; median 31.1; range 19.9 to 41). Eighty-three percent (N = 35) had made one or more serious quit attempts prior to study entry. Forty-one were Caucasian, one was of Asian descent, and 76% were married.
Serum nicotine concentrations measured at 0800 hours during ad lib ST use during GCRC Day#1were lower compared to those measured at 1600 (paired t-test, p<0.001). Serum nicotine concentrations in the morning (0800 hours) had a mean±SD of 22.3±16.2 ng/mL (median 20.5, range 2.6–80.0, N = 42) and in the evening (1600 hours) 37.9±17.6 ng/mL (median 37.0, range 8.1–95.0, N = 40).
During the nicotine patch phase (GCRC Day #2 and Day #3), serum nicotine concentrations were correlated with patch dose, with higher nicotine patch dose associated with higher median serum nicotine concentration (Figure 1).
Nicotine concentrations measured during ad lib ST use were comparable across the 3 dose groups (Table). The mean percentage of nicotine replacement increased with higher patch dose. Notably, the 42 mg/d nicotine patch dose achieved a mean percentage replacement approximating 100%.
Figure 2 shows the serum nicotine concentrations achieved with the nicotine patch dose versus the serum nicotine concentration with ad lib ST use. The line of identity (representing 100% replacement) is included as a reference. Points above the reference line indicate patients achieving >100% replacement (i.e., “over-replacement”) of serum nicotine concentrations using the given patch dose and points below the line indicate patients achieving <100% replacement (i.e., “under-replacement”) using the given dose.
There were two subjects in the 63 mg/day group and one subject in the 21 mg/day group who reported moderate or severe nausea during the nicotine patch phase of the GCRC stay. Of these, one subject in the 63 mg/day group also had vomiting. The percentage replacement for the subject experiencing vomiting was found to be 191%. Other nicotine toxicity symptoms reported as moderate or severe by more than one subject during the patch phase of the GCRC stay included headache (reported by one subject in each of the 21, 42, and 63 mg/day groups) and exhaustion (reported by one subject in the 21 mg/day group and one subject in the 42 mg/day group).
In this study, we observed that among ST users who used 3 cans/week, standard dose (21 mg/day) nicotine patch therapy resulted in a mean “under-replacement” of serum nicotine concentrations achieved during ad lib ST use. We also found that the 63 mg/day dose of the nicotine patch frequently resulted in “over-replacement” of nicotine and that subjects receiving this dose had more reports of toxicity. The 42 mg/day dose achieved nearly 100% replacement of the ad lib steady-state serum nicotine concentrations and was associated with minimal toxicity.
Nicotine concentrations observed in the current study at 1600 hours with the nicotine patch were similar to steady-state nicotine concentrations achieved in abstinent cigarette smokers receiving similar nicotine patch doses in previous studies (Lawson et al., 1998). Higher doses of nicotine patch therapy for smokers have been observed to increase the percentage of cotinine replacement, decrease withdrawal symptoms (Dale et al., 1995) and increase tobacco abstinence rates (Silagy et al., 2002). We were underpowered in this study for an assessment of increased treatment efficacy with higher nicotine patch doses in ST users.
Several strengths to our study exist. First, the inpatient GCRC setting for this study provided the ability to obtain frequent blood samples among ST users wearing different nicotine patch doses in a controlled research environment designed to eliminate the chances for concomitant tobacco use. Second, the randomized, placebo-controlled trial design may have prevented early subject discontinuation of the nicotine patch therapy resulting from knowledge of treatment assignment. Third, the design allowed us to collect serum nicotine measurements during ad lid ST use. Fourth, our study provides novel information on the percentage replacement of serum nicotine concentrations among ST users using ≥ 3 cans/week and the use of nicotine patch doses up to 63 mg/day. Finally, our findings have important implications for the treatment of ST users seeking treatment who, in previously published studies, have a reported average ST use rate of over 3 cans per week (Dale et al., 2002; Hatsukami et al., 2000; Hatsukami et al., 1996; Howard-Pitney et al., 1999).
The major weakness of this study relates to the fact that enrolled ST users were required to be using ≥ 3 cans/pouches per week. While this was necessary in order to ensure subject safety with the doses of nicotine patch therapy, the results do not apply to all ST users. Another weakness of this study is the small sample size as only 42 patients were enrolled. The small sample-size precludes drawing any definitive conclusions regarding the association between the use of 63 mg/day and nicotine toxicity.
Nicotine replacement therapy should be guided by the principles of maximization of symptom relief and minimization of toxicity. We have observed that higher doses of nicotine patch therapy resulted in improved relief of withdrawal symptoms (Ebbert et al., In press). Since we identified clinical adverse events associated with “over-replacement” of serum nicotine concentrations in the 63 mg/day patch dose, we submit that this may not be the optimal starting dose for ST users who consume ≥ 3 cans/week. Our data support the initial dose of nicotine patch for heavier ST users should be 42 mg/day. We conclude that in a clinical setting in which serum tobacco alkaloids are not typically measured, heavier ST users (≥ 3 cans/week) can safely be treated with nicotine patch doses of 42 mg/day with dose-titration based upon clinical response. Careful clinical monitoring of response is recommended due to the wide inter-individual variation in serum nicotine concentrations between ST users.
This project was supported by the National Cancer Institute R01 CA96881 (J.O.E).
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