Published online September 1, 2008
PEDIATRICS
Vol. 122
No. 3
September 2008, pp.
e595-e600
(doi:10.1542/peds.2008-0501)
A Randomized Trial of Nicotine Nasal Spray in Adolescent Smokers
Mark L. Rubinstein, MDa,
Neal L. Benowitz, MDb,
Glenna M. Auerback, MPHa and
Anna-Barbara Moscicki, MDa
Division of a Adolescent Medicine, Department of Pediatrics
b Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California, San Francisco, California
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ABSTRACT
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OBJECTIVES. Nicotine nasal spray has been 1 of the most successful forms of nicotine-replacement therapy in adult populations. The nasal sprayer has not been studied in adolescent smokers. The objective of this pilot study was to determine the feasibility and utility of using nicotine nasal spray for adolescent smokers who wanted to quit smoking.
METHODS. Forty adolescent smokers who were between 15 and 18 years of age and smoked 
5 cigarettes daily for at least 6 months were recruited from several San Francisco Bay area schools from 2005 to 2007. Using a randomized, open-label, 12-week trial, adolescent smokers were assigned to receive either weekly counseling alone (control) for 8 weeks or 8 weeks of counseling along with 6 weeks of nicotine nasal spray. Self-reported smoking abstinence was verified by both expired-air carbon monoxide and salivary cotinine.
RESULTS. There was no difference in cessation rates, the numbers of cigarettes smoked per day, or cotinine levels at 12 weeks. Fifty-seven percent of participants stopped using their spray after only 1 week. The most commonly reported adverse effect was nasal irritation and burning (34.8%) followed by complaints about the taste and smell (13%).
CONCLUSIONS. The unpleasant adverse effects, poor adherence, and consequent lack of efficacy observed in our pilot study do not support the use of nicotine nasal spray as an adjunct to counseling for adolescent smokers who wish to quit.
Key Words: smoking cessation • adolescent • nicotine nasal spray
Abbreviations: NRT—nicotine-replacement therapy • NNS—nicotine nasal spray • cpd—cigarettes per day • CO—expired-air carbon monoxide
Most adolescent smokers who are daily smokers are addicted to nicotine and want to quit but find it difficult to do so.1,2 Rates of quitting smoking among adolescents who do not participate in structured cessation programs range from 0% to 11%.3,4 The role of nicotine replacement as an effective means of augmenting success rates among smokers who wish to quit has already been well established among adults.5 Quit rates nearly double when nicotine-replacement therapy (NRT) is used for adults.6 To date, only a few studies have examined the efficacy of NRT for adolescent smoking cessation.7–10 Moreover, the only forms of NRT that have been evaluated in adolescents are the transdermal patch and the nicotine gum, and those trials demonstrated limited success.11
Although not studied previously in adolescent populations, nicotine nasal spray (NNS) might be more useful than other types of NRT for adolescents for a number of reasons. First, the nasal spray uses a relatively fast system for delivering nicotine that is expected to speed relief of withdrawal and craving, which adolescents are likely to value. Second, compared with the transdermal delivery of the patch, self-administration of the nasal spray allows for greater self-control of relief from withdrawal symptoms, and self-control may play a large role in strategies for adolescents who seek to quit. In addition, among the different types of NRT, NNS seems to be 1 of the most efficacious in adults.6,12–14 The aim of this pilot study was to explore the feasibility and utility of using NNS for adolescent smokers who wished to quit.
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METHODS
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Study Population
The research design and procedures were reviewed and approved by the institutional review board at the University of California, San Francisco. In 2005–2006, adolescent smokers were recruited from 5 San Francisco Bay area high schools using fliers and posters. Study staff also recruited directly from smoking cessation classes situated in each of the schools. Participants were required to be between 15 and 18 years of age, smoke 5 cigarettes per day (cpd) for at least 6 months, and want to quit smoking. The cutoff of 5 cpd was chosen on the basis of estimates that the daily intake of 
5 mg of nicotine (roughly corresponding to 5 cpd) is the threshold level that can readily establish and maintain addiction in adults.15 Adolescents who were using or had used nicotine replacement in the previous week were excluded. Those who used bupropion (Zyban [GlaxoSmithKline, King of Prussia, PA]) within the past 30 days were also excluded.
Informed written consent was obtained from the adolescent and from 1 parent or legal guardian before data collection. Participants were randomly assigned in a 1:1.5 ratio to receive either weekly counseling alone for 8 weeks or 8 weeks of counseling in conjunction with 6 weeks of NNS by using a computer-generated randomization list. The randomization sequence was generated by Dr Rubinstein and concealed until interventions were assigned. Participants were provided with remuneration for their participation in this open-label trial.
NNS Group
Participants who were assigned to use the nasal spray were given training on proper usage and were instructed to begin using the sprayer after the second week of counseling. Nicotrol nasal spray (Pfizer, New York, NY) delivers a metered dose spray of 
0.5 mg of nicotine. One dose (2 sprays, 1 in each nostril) is considered to deliver a dosage of 1 mg of nicotine. Participants were advised to use their sprayer whenever they had strong cravings for a cigarette but not to exceed 40 doses per day. Participants were instructed to stop using the spray by their last visit (at 8 weeks) if possible. To achieve this, participants were instructed to begin using the spray less frequently during the weeks before the final visit. Empty sprayers were collected before new ones were distributed, and participants were instructed not to share their sprayer with anyone.
Counseling and Follow-up
Group counseling was based on the American Lung Association's Not On Tobacco curriculum,16 a smoking cessation program designed specifically for teen smokers. Each group counseling session was run by a trained facilitator from the American Lung Association, was composed of between 6 and 12 participants, and lasted 45 to 60 minutes. Participants returned weekly for a total of 8 counseling sessions. Quit dates were arranged to follow the second counseling session, at which time the first weeks' supply of nasal sprayers was distributed to participants who were randomly assigned to the NNS group. Postcounseling follow-up visits were conducted after the last counseling session and 4 weeks later (at 8 and 12 weeks).
Measures
Baseline Characteristics
At baseline, participants completed a self-administered questionnaire that included demographics and baseline smoking characteristics (eg, frequency and quantity of cigarette smoking, depth of inhalation, amount of each cigarette smoked). Number of cigarettes smoked each day was calculated by averaging the number of cigarettes smoked that they reported for each day of the last week during which they smoked. Participants were asked how much of each cigarette they smoked (100% = down to the filter to 0% = none) and how deeply they inhaled ("very deeply" to "no smoke at all"). Nicotine dependence was assessed by using the Fagerström Tolerance Questionnaire modified for use in adolescents.17 Participants were also asked to describe the degree to which they felt addicted to tobacco by using a scale from 0 = "not at all addicted" to 100 = "totally addicted." The participants' motivations for quitting were assessed using the Reason for Quitting scale,18 which includes subscales that measure self-concept issues, health concerns, and social influence.
Craving and Withdrawal
Nicotine craving and withdrawal were assessed at all visits. Craving was assessed using the following question: "How soon after you wake up do you crave your first cigarette?" Possible responses ranged from 1 = "<15 minutes" to 7 = "I don't crave cigarettes." This question was chosen to measure craving best on the basis of recent literature suggesting that responses were highly correlated with addiction among smokers.19 Nicotine withdrawal symptoms were measured by using the Minnesota Withdrawal Scale.20
Determination of Smoking Status
A salivette (Sarstedt Ltd, Newton, NC) was used to collect saliva for measurement of cotinine levels at baseline and 12 week follow-up. The salivette is a cotton swab within a plastic container, designed for collection of saliva samples for drug analysis. Adolescents were asked to open the salivette tube, place the cotton swab into their cheek for 2 minutes, remove the swab, place it immediately into the salivette container, and secure the cap tightly on the tube. Cotinine was measured using liquid chromatography–tandem mass spectrometry with a lower limit of detection of 0.1 ng/mL.21 Adequate saliva samples for cotinine measurement were obtained from 31 (78%) of the 40 smokers. Participants also had expired-air carbon monoxide (CO) measured by using the Vitalograph breath CO monitor (Vitalograph, Inc, Lenexa, KS) at baseline and each follow-up visit. All procedures were performed under the supervision of research staff. The principle criterion used for determination of abstinence was self-reported continuous abstinence for at least 7 days, validated by a CO concentration of <4 ppm.22
Attitudes About the Nasal Spray
At the 8-week follow-up, participants who were assigned to use the nasal spray were asked to rate their experiences with regard to ease of use, efficacy, and adverse effects using a 5-point Likert type scale (1 = "strongly agree" to 5 = "strongly disagree"). We also collected spontaneous qualitative data by asking participants to list 3 things that they liked and 3 things that they disliked about the spray.
Spray Use
Use of the spray was determined by self-report of the number of sprays administered each day. In addition, open-ended questions were asked regarding potential adverse effects of the sprayer at each visit.
Data Analysis
The original power calculation for the NNS trial was based on standard assumptions (
= .05, β = .80) for an efficacy study and would have required a sample size of 144. These estimates proved to be unrealistic given difficulties in recruitment (eg, negative word of mouth regarding the burning associated with the spray); therefore, we truncated the study for a feasibility study. Power levels in the final sample size (n = 40) were sufficient for exploratory analysis of effects. Descriptive univariate analyses of all of the variables were performed, and means and SDs were calculated. 
2 tests were used to compare abstinence rates. Independent t tests were used to compare the change in cigarettes smoked per day, withdrawal symptoms, and craving between groups and from baseline to follow-up. In all cases P < .05 was considered to be significant. An intention-to-treat analysis was used to determine abstinence such that participants who did not complete the study were considered still to be smoking. Correlation coefficients were calculated to assess the relationship between sprays per day and cigarettes smoked per day. In addition, associations between cotinine and self-reported smoking were assessed by using bivariate correlation.
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RESULTS
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Demographic and Smoking Characteristics
Forty adolescents aged 15 to 18 (mean: 16.7; SD: 0.99) were recruited (Fig 1). As the main group of interest, the NNS-plus-counseling group was overrepresented such that 23 participants were randomly assigned to receive the NNS plus counseling and 17 were randomly assigned to receive counseling alone (Table 1). The sample was racially diverse with less than half being white; 54% were female. Mean baseline smoking rate was 9.9 cpd (SD: 6.4), and mean baseline cotinine was 123 ng/mL (SD = 79). Baseline cotinine was correlated with the reported number of cigarettes smoked per day at baseline (r = 0.40, P = .02). Forty percent reported that their father or male guardian smoked, 43% reported that a mother or female guardian smoked, and 90% reported that their best friend smoked. Seventy-seven percent of participants reported having tried to quit in the past. When asked how confident they were that they could "quit smoking for good" this time, 77% reported that they were "fairly or very confident." Eleven (28%) participants reported having used a nicotine patch, and 9 (23%) reported using nicotine gum during a previous, unsuccessful quit attempt. None had used the nasal spray.
The proportions of randomly assigned participants who completed the 8-week study were similar between both groups (83% and 76% for the NNS-plus-counseling and counseling-only groups, respectively; P = .62). At the 12-week follow-up, 65% of participants in the NNS-plus-counseling group and 70% of participants in the counseling-only group completed questionnaires (P = .39). Participants who withdrew from the study before completion had higher levels of salivary cotinine at baseline compared with participants who completed the study (169 vs 104 ng/mL; P = .04). There were no differences at baseline for age, cigarettes smoked per day, score on the modified Fagerström Tolerance Questionnaire, self-described level of addiction, score on the Reason for Quitting scale, or number of previous quit attempts between those who withdrew before completion of the study and those who completed the study (P = .29–.74).
Nasal Spray Use
During the first week of spray use, only 6 (26%) participants who were assigned to the NNS-plus-counseling group used their spray every day. Median use was reported at 1.14 sprays per day (range: 0.14–3.00 sprays per day). Ten (43%) participants who were assigned to the NNS-plus-counseling group were still using their spray by end of treatment (week 6 of NRT/week 8 of counseling) with a median of 0.64 sprays per day (range: 0.29–2.00 sprays per day). The other 13 (57%) participants stopped using their spray after only 1 week.
Abstinence
All participants who withdrew from the study before completion were considered still to be smoking. There was no difference in cessation rates between groups: 2 (11.8%) participants from the counseling-only group quit smoking at 8 weeks, and none of the participants in the NNS-plus-counseling group quit (P = .16). At 8 weeks, both groups had decreased their smoking rates from baseline, with participants in the NNS-plus-counseling group reporting a 50% drop versus 28% among participants in the counseling only group (P = .10). The self-reported drop in cpd among the NNS users was highly correlated with the number of sprays administered in the preceding week such that the greater number of sprays used was associated with a greater reduction in the number of cigarettes smoked (r = 0.55, P = .03). At 12-week of follow-up, participants in the NNS-plus-counseling group reported a 42% reduction in cigarettes smoked per day versus 32% for the counseling-only group (P = .61). Teens also reported inhaling less deeply (P = .02) and smoking less of the cigarette (P = .03) at 12 weeks compared with baseline. Although the number of cigarettes smoked per day was correlated with cotinine at baseline, self-reported cigarettes per day was not correlated with cotinine level at 12-week of follow-up in either group (r = –0.06, P = .84).
Tobacco-Withdrawal Symptoms and Craving
Scores on the withdrawal scale were not different between the NNS-plus-counseling group and the counseling-only group at the 8-week follow-up (8.84 vs 9.58; P = .26; Table 2). Similarly, after controlling for current cigarettes smoked per day, there were no significant differences in craving between participants in the NNS-plus-counseling and counseling-only groups at the 8-week follow-up (3.47 vs 2.75; P = .20).
Adverse Effects
Of the participants assigned to use the spray, 38.9% agreed or strongly agreed that the spray had "lots of side effects" (Table 3). The most commonly reported adverse effect was nasal irritation and burning (34.8%) followed by complaints about the taste and smell (13%).
Attitudes About the Spray
Seventy-one percent of participants either "agreed or strongly agreed" that the spray "is good for preventing smoking" (Table 3). Eighty-three percent of participants who were assigned to use the spray "agreed or strongly agreed" that the spray made their "urge to smoke" less, and 69% "agreed or strongly agreed" that the spray "controls my cravings." Only 39% of participants "agreed or strongly agreed" that they would recommend the spray to friends.
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DISCUSSION
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This study evaluated the utility and feasibility of using NNS for adolescent smokers who are attempting to quit smoking. Although our total sample was small, this is the first study to evaluate the use of this mode of nicotine replacement for adolescent smokers. Despite 8 weeks of formal smoking cessation counseling and the addition of nicotine replacement for some participants, only 2 participants were able to quit smoking by the end of the trial. One of the reasons that might explain the low overall quit rates was the infrequent use of the nasal spray. Although participants who were assigned to use NNS were advised to use their spray whenever they had cravings, mean daily use was minimal (1.5–0.5 sprays per day). This low rate may have been attributable to the nasal irritation frequently reported by the participants. We did observe that the number of sprays used each day was highly correlated with the subsequent reduction in cigarettes smoked per day reported among participants who were assigned to the NNS-plus-counseling group. This might suggest that NNS may have been alleviating craving even with far fewer sprays than reported for adults. Unfortunately, we suspect that the reduction in cigarettes smoked per day may have been a result of underreporting because the reduction in cigarettes smoked per day was not associated with the expected decrease in saliva cotinine levels. Alternatively, teenagers may offset the decrease in cigarettes smoked per day by a compensatory increase in smoking vigor (eg, greater depth of inhalation), thereby taking in more nicotine per cigarette; however, at follow-up, participants reported a decrease in the amount of each cigarette smoked (P = .02) as well as lower volumes of inhalation (P = .03), although the self-reporting of depth of inhalation may not be reliable for adolescents.
Overall cessation rates that were obtained in our study were below those reported previously for samples of adolescent smokers.7,9,10,23–25 One possible explanation for this discrepancy is that our participants were less motivated to quit and more interested in the monetary compensation. There are several limitations of our study in addition to the small sample size. First, we used a school-based sample, which may not be generalizable to the office practice. Second, the lack of a placebo spray arm along with the interval lack of association between self-reported smoking and cotinine levels at follow-up may point to a possible measurement bias. Participants who were assigned to the NNS-plus-counseling group may have been more inclined to report what they thought to be a more socially desirable response (eg, having cut down their smoking).
Nasal burning, especially during the first week of treatment, was the most common complaint offered by participants in the NNS-plus-counseling group and was the reason most often given for poor adherence. Ironically, most participants viewed the spray positively; however, only one third would recommend it to friends to help with smoking cessation, suggesting that the adverse effects are clearly an obstacle to its use. What is more, participants with severe nasal burning were so vocal in their complaints that many potential participants were reluctant to try the spray, a factor that clearly interfered with recruitment efforts (data not shown).
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CONCLUSIONS
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On the basis of our small, open-label trial, use of NNS was not well tolerated, resulting in poor adherence and a failure to promote quitting. Although a larger, blinded study of NNS is needed to determine definitively its efficacy for use in adolescent smokers, our pilot study does not support the use of NNS as an adjunct to counseling for adolescent smokers who wish to quit.
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ACKNOWLEDGMENTS
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This study was supported by Dr Rubinstein's grants from National Institutes of Health K23 RR018471 and Tobacco-Related Disease Research Program TRDRP 11FT-0233. Dr Benowitz's effort and the laboratory were supported by DA02277.
We acknowledge the invaluable contributions from Nancy Eagan, Minda Concepcion, Becky Sha, and all of the study participants.
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FOOTNOTES
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Accepted May 14, 2008.
Address correspondence to Mark L. Rubinstein, MD, University of California, Division of Adolescent Medicine, 3333 California St, Suite 245, San Francisco, CA 94118. E-mail: rubinsteinm{at}peds.ucsf.edu
This trial has been registered at www.clinicaltrials.gov (identifier NCT00625794).
Financial Disclosure: Dr Benowitz has been a paid expert witness in litigation against the tobacco industry, including providing testimony on adolescent tobacco addiction; Drs Rubinstein, Auerback, and Moscicki have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject
NNS has been 1 of the most successful forms of NRT in adult populations. Unfortunately, the nasal sprayer has not been studied in adolescent smokers.
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| What This Study Adds
The unpleasant adverse effects, poor adherence, and consequent lack of efficacy observed in our pilot study do not support the use of NNS as an adjunct to counseling for adolescent smokers who wish to quit.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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ABSTRACT
METHODS
