Nicotine lozenges for the treatment of smokeless tobacco use

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1 Nicotine & Tobacco Research Volume 9, Number 2 (February 2007) Nicotine lozenges for the treatment of smokeless tobacco use Jon O. Ebbert, Lowell C. Dale, Herbert Severson, Ivana T. Croghan, Donna F. Rasmussen, Darrell R. Schroeder, Mark W. Vander Weg, Richard D. Hurt Received 11 November 2005; accepted 10 March 2006 Nicotine lozenges have been shown to increase tobacco abstinence rates in cigarette smokers, but they have not been evaluated in smokeless tobacco (ST) users. We conducted an open-label, one-arm, phase II clinical trial to evaluate the efficacy of the 4-mg nicotine lozenge for the treatment of withdrawal and craving associated with tobacco abstinence among ST users. Eligible subjects received 4-mg nicotine lozenges for 6 weeks followed by a 6- week taper. Subjects completed daily tobacco withdrawal diaries, and data on lozenge use, adverse events, and lozenge acceptability were collected. Urine anabasine was collected at 3 and 6 months for biochemical confirmation of self-reported tobacco abstinence. Participants were 30 ST users with a mean age of 35.4 years (SD56.5) using an average of 4.2 cans or pouches (SD53.2) of ST per week for a mean of 15.1 years (SD56.5). Among subjects continuously tobacco abstinent for the first 2 weeks, no significant increases in composite withdrawal symptoms were observed, compared with baseline symptoms, whereas craving decreased significantly. Biochemically confirmed 7-day point-prevalence tobacco abstinence was 53% (95% CI534% 72%) at 12 weeks (end of treatment) and 47% (95% CI528% 66%) at 6 months. Few adverse events attributable to the nicotine lozenge occurred, and the lozenge was perceived as helpful in assisting subjects quit ST. The use of the 4-mg nicotine lozenge appears promising for the clinical treatment of withdrawal symptoms and craving associated with tobacco abstinence in ST users. Future phase III clinical trials investigating the efficacy of nicotine lozenges are warranted. Introduction In the United States, approximately 7.2 million individuals older than 12 years of age report current (past month) use of smokeless tobacco (ST), which includes snuff and chewing tobacco (Substance Abuse and Mental Health Services Administration, 2005). Use of ST is estimated to be the greatest exogenous source of human exposure to carcinogenic nitrosamines (U.S. Department of Health and Human Services, 2005). ST use is known to increase the risk for periodontal disease (Offenbacher & Weathers, 1985), precancerous oral lesions (leukoplakia; Mattson & Winn, 1989; Silverman, Gorsky, & Lozada, 1984; Sinusas, Coroso, Sopher, & Crabtree, 1992), and oropharyngeal cancer Jon O. Ebbert, M.D., M.Sc., Lowell C. Dale, M.D., Ivana T. Croghan, Ph.D., Donna F. Rasmussen, R.N., Darrell R. Schroeder, M.S., Mark W. Vander Weg, Ph.D., Richard D. Hurt, M.D., Mayo Clinic College of Medicine, Rochester, MN; Herbert Severson, Ph.D., Oregon Research Institute, Eugene, OR. Correspondence: Jon O. Ebbert, M.D., M.Sc., Mayo Clinic College of Medicine, 200 1st Street SW, Rochester, MN 55905, USA. Tel: +1 (507) ; Fax: +1 (507) ; ebbert.jon@mayo.edu (Stockwell & Lyman, 1986; Winn, 1992; Winn et al., 1981). ST also has been associated with an increased risk for pancreatic cancer (Boffetta, Aagnes, Weiderpass, & Andersen, 2005) and death from heart disease and stroke (Henley, Thun, Connell, & Calle, 2005). Despite these increased risks, no pharmacotherapies have been shown to increase long-term (.6 months) tobacco abstinence rates in ST users compared with placebo (Ebbert et al., 2004). Lack of effective pharmacotherapies for ST users poses a significant challenge to health care providers attempting to decrease cancer risk in ST users. Effective interventions are needed given that longterm ST use leads to tobacco dependence (National Institutes of Health, 1986) and most ST users report the desire to stop ST use (Severson, 1992). Nicotine lozenges are the newest form of nicotine replacement therapy (NRT), are available over-thecounter, increase long-term tobacco abstinence rates in smokers (Shiffman et al., 2002), and may be an ideal nicotine replacement product for ST users. Like ISSN print/issn X online # 2007 Society for Research on Nicotine and Tobacco DOI: /

2 234 NICOTINE LOZENGES FOR SMOKELESS TOBACCO USE the nicotine gum, the nicotine lozenge provides active oral self-dosing that can be used in response to cravings (Shiffman et al., 2002; West & Shiffman, 2001), which would provide ST users with a sense of control over symptoms that occur with ST abstinence (Schneider, Olmstead, & Nilsson, 1996). However, whereas nicotine release from the nicotine gum depends on the force and frequency of chewing (Choi, Dresler, Norton, & Strahs, 2003), the nicotine lozenge disintegrates passively as it releases nicotine over approximately 30 min. Although the 2- and 4- mg nicotine lozenges were developed to approximate the nicotine delivery from the nicotine gum, the nicotine lozenge delivers 8% 10% higher maximal plasma concentrations and 25% 75% higher areaunder-the-curve (AUC) values in single-dose studies (Choi et al., 2003). Higher nicotine concentrations may increase the therapeutic efficacy of the nicotine lozenge compared with the nicotine gum, which has not been shown to increase tobacco abstinence rates among ST users (Boyle, 1992; Hatsukami, Jensen, Allen, Grillo, & Bliss, 1996). Furthermore, the nicotine lozenge provides a type of sensory oral stimulation (Muramoto, Ranger-Moore, & Leischow, 2003) to which ST users are accustomed. ST users typically park (i.e., orally retain) ST in their mouths (Glover & Glover, 1992); thus they may not be accustomed to the periodic chewing required for effective nicotine release from the nicotine gum. Finally, previous studies have observed that nonnicotine-product substitutes that are not chewed (i.e., herbal chew) are more effective for decreasing ST use compared with chewed non-nicotine-product substitutes (i.e., chewing gum; Chakravorty, 1992). To begin to explore the effectiveness of the nicotine lozenge in ST users, we conducted an open-label, one-arm, phase II clinical trial of the 4- mg nicotine lozenge for reducing the craving and withdrawal associated with ST abstinence. Method Subjects The Mayo Foundation Institutional Review Board reviewed and approved the study protocol prior to recruitment and enrollment. Individuals interested in stopping ST use were recruited through press releases and local advertisements from the community surrounding the Mayo Clinic in Rochester, Minnesota, between November 2004 and January Eligible subjects were required to be at least 18 years of age, in good general health, and have used ST daily for at least 6 months. Subjects were excluded if they (a) were currently using any other behavioral or pharmacological treatment program for ST use, (b) had used any medication in the setting of a clinical trial within 30 days prior to enrollment, (c) had unstable angina, myocardial infarction, or coronary angioplasty in the past 3 months or a severe cardiac dysrhythmia, (d) were pregnant or lactating, (e) had another member of their household participating in the study, or (f) currently used (within the past 5 days) another form of tobacco. As with previous studies of the nicotine lozenge, we did not include patients with phenylketonuria because nicotine lozenges contain aspartame, which is metabolized to phenylalanine (Shiffman et al., 2002); all subjects were determined not to have this disease by history. All female subjects of child-bearing potential had a negative pregnancy test prior to enrollment and agreed to use contraception during study participation. Procedures After initial screening by telephone, eligible subjects attended an information session at which details of the study were explained and informed consent was signed. After completion of the informed consent process, demographics information and tobacco use history were obtained. We assessed nicotine dependence at baseline with the Fagerström Test for Nicotine Dependence-Smokeless Tobacco (FTND- ST), which we have used in a previous trial and which has internal consistency reliability similar to other commonly used nicotine dependence measures (Ebbert, Patten, & Schroeder, 2006). Subjects then returned for the baseline session, during which they completed questionnaires and underwent screening oral and physical examinations by a physician. Subjects were instructed to stop all tobacco use following the baseline visit and begin using the nicotine lozenge. Enrolled subjects received enough study medication to last them until the next scheduled weekly visit. Subjects received an instructional sheet on the proper use of the nicotine lozenges. For weeks 1 6, the number of dispensed lozenges was based on a maximum of 20 per day; lozenges were recommended to be used every 1 2 hr. After 6 weeks, a tapering schedule was initiated. For weeks 7 9, distribution was 8 lozenges/day; lozenges were recommended to be used every 2 4 hr. For weeks 10 12, distribution was 4 lozenges/day; lozenges were recommended to be used every 4 8 hr. Subjects returned weekly for 12 weeks for a count of the number of lozenges used the previous week, based on the empty blister packs, as well as for assessment of tobacco use status and adverse events. Brief (10-min) behavioral counseling by a trained study assistant was completed at each study visit.

3 NICOTINE & TOBACCO RESEARCH 235 A urine specimen for anabasine was collected for biochemical confirmation of tobacco use status at 3 and 6 months after the quit date for those selfreporting tobacco abstinence. Measures Daily diary. The daily diary included the Minnesota Nicotine Withdrawal Scale (Hughes & Hatsukami, 1998). With this seven-item measure, subjects rated the following symptoms on a 5-point Likert scale ranging from 0 (not present) to 4 (severe): Anger, irritability, or frustration; anxiety or nervousness; difficulty concentrating; impatience or restlessness; hunger; awakening at night; and depression. In addition, the same 5-point Likert scale was used to assess the item desire to use tobacco (i.e., craving). Subjects were instructed to complete the diary at the end of each day. We have used this scale in previous studies with ST users (Dale et al., 2002). Subjects also used the diary to report the number of nicotine lozenges used each day. Nicotine toxicity questionnaire. We used a questionnaire measuring the type and severity of side-effects from NRT that we have used in previous clinical trials (Dale et al., 1995; Ellenhorn & Barceloux, 1995). We modified the scale for ST users. Adverse events. Adverse events were recorded in accordance with the World Health Organization Adverse Reaction Terms System. Lozenge acceptability. We used a questionnaire assessing various aspects of nicotine lozenge use including perceived efficacy and usefulness, ease of use, taste, and a general impression about the acceptability of this product for ST users. Perceptions were rated on a 5-point Likert scale. Biochemical confirmation. Cotinine is a specific major metabolite of nicotine that can be detected in body fluids for hr after use of any product containing nicotine. The specificity and relatively long half-life of cotinine make it the biological marker of choice for quantifying exposure to nicotine through tobacco products or medicinal nicotine. Cotinine can be measured in a variety of body fluids such as blood, urine, and saliva (Etzel, 1990; Haley, Axelrad, & Tilton, 1983; Lawson et al., 1998a, 1998b; Watts, Langone, Knight, & Lewtas, 1990). A value of less than 50 ng/ml consistently discriminates between tobacco users (.50 ng/ml) and individuals passively exposed to tobacco smoke (,50 ng/ml; Haufroid & Lison, 1998). For individuals reporting use of NRT, however, cotinine cannot be used to biochemically validate tobacco abstinence. Since nicotine replacement products do not contain the tobacco alkaloid anabasine, urinary anabasine has been proposed as a biomarker of tobacco consumption that could differentiate tobacco users and nonusers (Jacob, Yu, Shulgin, & Benowitz, 1999). We used a urine anabasine concentration of less than 2 ng/ml to indicate tobacco abstinence in subjects reporting no tobacco use but reporting the use of medicinal nicotine. A cut-off of 2 ng/ml for anabasine provides 100% sensitivity for the confirmation of tobacco abstinence within the past 7 days among subjects using NRT as well as 100% specificity (Moyer et al., 2002). Data analyses This protocol assessed the efficacy of nicotine lozenges in ST users using a one-stage phase II study design. Unless stated otherwise, data are summarized using means with standard deviations and select percentiles for continuous variables, and frequencies and percentages for categorical variables. The primary abstinence endpoint of this trial was the biochemically confirmed point-prevalence tobacco abstinence rate at week 12 (end of treatment; Hughes et al., 2003). Subjects who discontinued the study or had a missed visit for any reason were classified as using tobacco for that visit. We assessed 7-day point-prevalence abstinence using the question Have you used any tobacco products in the last 7 days? and biochemically confirmed subjects responses. Subjects who were biochemically confirmed abstinent at a given study visit were considered continuously abstinent if they self-reported not using any tobacco since their target quit date and had not failed a previous biochemical confirmation. Tobacco abstinence rates at week 12 (end of treatment) and at 6 months are summarized using point estimates and exact binomial 95% confidence intervals. Nicotine withdrawal was assessed using the composite withdrawal score computed as the mean of the seven items included in the Minnesota Nicotine Withdrawal Scale. In addition to the composite score, the individual item assessing desire to use tobacco (i.e., craving) was of specific interest. Subjects began using the daily diary after the information visit, which was a minimum of 1 week preceding the baseline visit. For each subject, a baseline withdrawal score was calculated as the average of the daily assessments for the week prior to the baseline visit. Withdrawal symptom scores obtained after the baseline visit were analyzed as change from baseline. Withdrawal data were summarized daily for the first 2 weeks following the start of medication for subjects who were continuously abstinent from tobacco for this interval; the mean

4 236 NICOTINE LOZENGES FOR SMOKELESS TOBACCO USE change from baseline was compared with zero using the one-sample t test with a two-tailed p value of.05 used to denote statistical significance. For these analyses no adjustments were made to account for multiple comparisons. Using the number of nicotine lozenges selfreported in the daily diary, we calculated average daily nicotine lozenge use for each subject for each week of the treatment phase. Lozenge use was summarized across subjects using a descriptive analysis. Results Subjects We conducted telephone screening on 38 ST users, of whom 35 (92%) were determined to be eligible and invited to a screening visit. Of those 35 potential subjects, 30 (86%) were enrolled. Of the 30 enrolled subjects, two withdrew consent at weeks 1 and 8 and were unable to complete the study but were included in the final analysis. Enrolled ST users were predominantly male snuff users (Table 1). Withdrawal and desire to use tobacco For the subjects enrolled in this investigation, the mean baseline composite withdrawal score was 0.6 (SD50.4) and the mean baseline score for the desire to use tobacco item was 2.8 (SD50.9). The reported number of cans or pouches of tobacco used per week at baseline was positively correlated with the baseline composite withdrawal score (r5.48, p5.010) but was not significantly associated with baseline for the desire to use tobacco item (r5.18, p5.368). Of the 30 enrolled subjects, 21 (70%) reported continuous abstinence for the first 2 weeks following the start of medication. For these subjects, the mean composite withdrawal score did not change significantly from baseline through the first 2 weeks, except for some evidence (p5.035) of an increase from baseline detected on day 3 (Figure 1). However, the individual item desire to use tobacco was significantly decreased relative to baseline throughout the first 2 weeks of tobacco abstinence (Figure 2). Abstinence At 12 weeks (end of treatment), the self-reported 7- day point-prevalence tobacco abstinence rate was 66% (95% CI547% 83%) and the biochemically confirmed 7-day point-prevalence tobacco abstinence rate was 53% (95% CI534% 72%). At 6 months, the self-reported 7-day point-prevalence abstinence rate was 60% (95% CI541% 77%) and the biochemically confirmed 7-day point-prevalence tobacco abstinence rate was 47% (95% CI528% 66%). Among subjects who self-reported tobacco abstinence and failed biochemical confirmation, the urinary anabasine concentrations ranged from 2.5 ng/ml to 53.0 ng/ml. Table 1. Baseline demographics of smokeless tobacco (ST) users in a phase II clinical trial of nicotine lozenges (N530). Characteristic Mean (SD) Range Number of subjects (%) Age, years 35.4 (6.5) Gender Male 29 (97) Female 1 (3) Type of ST used Chewing tobacco 1 (3) Oral snuff 29 (97) Average number of dips or chews per day 9.9 (4.8) 1 20 Average number of cans or pouches per week 4.2 (3.2) Years of regular ST use 15.1 (6.5) 2 30 Fagerström Test for Nicotine Dependence-ST score 6.7 (2.0) 3 11 Number of previous serious stop attempts None 3 (10) 1to2 13 (43) 3to4 6 (20) 5 or more 8 (27) Previous pharmacological aids for cessation a Bupropion 12 (40) Nicotine patch 12 (40) Nicotine gum 14 (47) Other nicotine replacement products 2 (7) Longest duration of tobacco abstinence Less than 24 hr 2 (7) 1 7 days 7 (23) 8 28 days 4 (13) 1 6 months 10 (33) More than 6 months 7 (23) Note. a A total of 22 subjects (73%) reported previous use of one or more pharmacological aids for tobacco cessation.

5 NICOTINE & TOBACCO RESEARCH 237 Figure 1. Composite withdrawal score change from baseline among smokeless tobacco users continuously abstinent in a phase II clinical trial of nicotine lozenges (n521). *p(.05. The percentage of subjects who self-reported continuous abstinence from all tobacco and had urinary anabasine concentrations of less than 2 ng/ml at each assessment was 47% (95% CI528% 66%) at 12 weeks and 30% (95% CI515% 49%) at 6 months. Lozenge use During the first 6 weeks, when the maximum recommended dose was 20 lozenges/day, all subjects used less than the maximum amount (Table 2). Once the tapering started, however, the majority of subjects used the maximum recommended doses. Adverse events A total of 11 subjects (37%) reported upper respiratory tract infections, which were judged not to be related to the nicotine lozenge. Among adverse effects possibly or probably attributable to the nicotine lozenge, five subjects (17%) reported diarrhea, four (13%) heartburn, and two (7%) fatigue. Single occurrences of the following effects were Figure 2. Desire to use tobacco change from baseline among smokeless tobacco users continuously abstinent in a phase II clinical trial of nicotine lozenges (n521); *p(.05, { p(.01, { p(.001.

6 238 NICOTINE LOZENGES FOR SMOKELESS TOBACCO USE Table 2. Average daily lozenge use according to study week a among smokeless tobacco users in a phase II clinical trial of nicotine lozenges (N530). Week Maximum recommended lozenges/day N /n Mean (SD) Percentiles 50 th 75 th 90 th Range (3.6) (3.4) (3.6) (3.5) (3.6) (3.3) (2.4) (2.1) (2.1) (1.7) (1.6) (1.8) Note. a The number of lozenges used was reported in the daily diary. From these data the average number of lozenges used per day was calculated for each week of the treatment phase for each study subject. b Number of study subjects with diary data available for the given study week. reported: Difficulty concentrating, flatulence, headache, impetigo, irritability, nausea, radiculopathy, and vivid dreams. The subject reporting increased flatulence had known Crohn s disease at study entry and discontinued the study because of this sideeffect. Acceptability Among all subjects, 79% rated the nicotine lozenge as extremely helpful in their attempts to quit ST; 79% reported that the nicotine lozenge was easy to use ; 59% reported that the taste of the nicotine lozenge didn t bother me ; and 86% commented that they thought that the lozenge would be broadly accepted among other ST users trying to quit. Discussion Among ST users using the nicotine lozenge, we observed no associated change in the composite tobacco withdrawal symptoms but a significant decrease in the desire to use tobacco (i.e., craving) for tobacco compared with baseline during the first 2 weeks of tobacco abstinence. The nicotine lozenge was well-tolerated and acceptable to ST users. To our knowledge, this is the first report of the use of the nicotine lozenge in ST users. Because the 4-mg lozenge results in a higher serum nicotine concentration than does the nicotine gum (Choi et al., 2003), the use of the 4-mg lozenge addresses the concern previously raised by investigators regarding nicotine under-replacement as a cause for the gum being ineffective in helping ST users quit tobacco (Hatsukami et al., 1996). A strength of the present study is that the population of enrolled ST users is similar to ST users enrolled in other clinical trials (Boyle, 1992; Dale et al., 2002; Hatsukami et al., 2000; Hatsukami et al., 1996; Howard-Pitney, Killen, & Fortmann, 1999). In previous studies of interventions for ST users, tobacco abstinence rates in those that incorporated an orally retained control (placebo gum or mint snuff) were higher than in those that used a control pill. The end-of-treatment rates for ST intervention studies with an orally retained product were 51% with mint snuff (Hatsukami et al., 2000), and 40% (Boyle, 1992) and 42.6% (Hatsukami et al., 1996) with placebo gum. These findings contrast with the end-of-treatment placebo abstinence rates with placebo bupropion SR of 26% in two studies (Dale et al., 2002; Glover, Glover, Sullivan, Cerullo, & Hobbs, 2002). The abstinence rates observed in the present study are similar to the previously observed rates with placebo orally retained products. Our current design, however, does not allow us to assess whether the 4-mg nicotine lozenge will increase abstinence rates compared with placebo; future randomized, placebo-controlled trials are needed. However, we are encouraged by our observed abstinence rates given that previous studies have incorporated more intensive behavioral interventions (Boyle, 1992; Hatsukami et al., 2000; Hatsukami et al., 1996), whereas we limited ours to a brief behavioral intervention used in previous studies (Dale et al., 2002). The present study has several limitations. First, because this was a pilot study, we did not have a control group with which to compare the outcomes of withdrawal, craving, adverse events, and abstinence. Based on the current study design, we can conclude only that in general the composite withdrawal score is not increased and craving is reduced relative to baseline for individual ST users during the first 2 weeks of abstinence. Although we did not observe a significant change in composite withdrawal symptoms from baseline, previous studies of ST users

7 NICOTINE & TOBACCO RESEARCH 239 randomized to tobacco deprivation and placebo gum observed a significant increase in tobacco withdrawal symptoms after discontinuing ST use (Hatsukami, Anton, Keenan, & Callies, 1992). The amount of nicotine delivered by the 4-mg nicotine lozenge may be effective for decreasing anticipated tobacco withdrawal symptoms during tobacco abstinence in individual ST users. Two additional considerations must be noted regarding the use of the 4-mg nicotine lozenge in ST users. First, the label instructions for the nicotine lozenge suggest that dosing should be selected based on time to first cigarette of the day (i.e.,,30 min54- mg dose;.30 min52-mg dose). For this study, we selected the 4-mg dose with the rationale that although maximal serum venous concentrations of nicotine are similar between cigarettes and ST, the overall nicotine exposure (i.e., area under the curve) may be twice as high in ST users as it is in cigarette smokers (Benowitz, Porchet, Sheiner, & Jacob, 1988). Second, nicotine lozenges are FDA indicated for smoking cessation assistance. The present study provides information that may be beneficial for continued development of effective pharmacotherapies for ST users. A strong theoretical rationale exists for the use of the 4-mg nicotine lozenge in ST users. However, even though an orally retained product such as the nicotine gum has been shown to be effective for increasing smoking abstinence rates among cigarette smokers (Silagy, Lancaster, Stead, Mant, & Fowler, 2002), previous clinical trials of nicotine gum, compared with placebo gum, failed to increase long-term (.6 months) tobacco abstinence rates in ST users (Boyle, 1992; Hatsukami et al., 1996). Standard dose (21-mg, 15-mg) nicotine patch therapy also has not been shown to be effective for increasing abstinence rates in ST users despite being shown to decrease craving and nicotine withdrawal symptoms (Hatsukami et al., 2000; Howard-Pitney et al., 1999). Given that overall nicotine exposure may be twice as high in ST users as it is in cigarette smokers (Benowitz et al., 1988), higher doses of NRT may be needed in ST users to increase efficacy. Until additional clinical trial data are available, the clinical use of the 4-mg nicotine lozenge shows promise for treating tobacco withdrawal symptoms and craving associated with tobacco abstinence in ST users attempting to quit. The 4-mg nicotine lozenge can be added to the armamentarium of nicotine replacement products shown to decrease withdrawal symptoms in ST users, such as the nicotine patch (Hatsukami et al., 2000; Howard-Pitney et al., 1999) and the nicotine gum (Hatsukami et al., 1996). Notably, the 4-mg nicotine lozenge and the 4-mg nicotine gum have comparable safety profiles in patients with heart disease, diabetes, and hypertension (Marsh et al., 2005). Future studies will focus on assessing the efficacy of the nicotine lozenge for increasing long-term tobacco abstinence rates in ST users. Acknowledgments This work was supported through the Mayo Clinic Cancer Center and the Fraternal Order of Eagles competitive pilot project program. 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