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Short communication
Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial Charlotte S. Scherphof a,∗ , Regina J.J.M. van den Eijnden a , Rutger C.M.E. Engels b , Wilma A.M. Vollebergh a a b
Child and Adolescent Studies, Utrecht University, P.O. Box 80.140, 3508 TC Utrecht, The Netherlands Behavioural Science Institute, Radboud University Nijmegen, P.O. Box 9104, 6500 HE Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history: Received 21 October 2013 Received in revised form 4 April 2014 Accepted 5 April 2014 Available online xxx Keywords: RCT Adolescents Nicotine replacement therapy Nicotine patch Efficacy Smoking
a b s t r a c t Background: A double-blind RCT on the short-term efficacy of nicotine patches compared to placebo patches among Dutch adolescents was conducted. The findings demonstrated that nicotine patches are efficacious for smoking cessation at end-of-treatment; however, only in highly compliant participants. We tested whether the effects of NRT also held in 6- (T7) and 12-month (T8) follow-up assessments. Methods: Adolescents aged 12–18 years, who smoked at least seven cigarettes a day and who were motivated to quit smoking were recruited at school yards and randomly assigned to either a nicotine patch (n = 182) or a placebo patch (n = 180) condition according to a computer generated list. Participants (N = 257, age: 16.7 ± 1.13 years) attended an information meeting followed by a 6- or 9-week treatment. Smoking cessation, compliance, and potential covariates were measured by means of online questionnaires. Smoking cessation at T8 was biochemically validated by saliva cotinine. Results: At T7, 8.1% and 5.7% of participants were abstinent in the nicotine and placebo patch groups, respectively. At T8, abstinence was 4.4% and 6.6%, respectively. Intention-to-treat analyses showed no significant effects of NRT on abstinence rates at T7 (OR = 1.54, 95% CI = 0.57, 4.16) and validated abstinence rates at T8 (OR = 0.64, 95% CI = 0.21, 1.93) neither after considering compliance nor after adjusting for covariates. Conclusions: NRT fails in helping adolescents quit smoking at 6- and 12-month follow-ups. This finding suggests that a more intensive approach is needed to assist youngsters in their quit attempts. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Considering the negative health consequences (NHS, 1998), the high prevalence of adolescent smoking (11% daily smokers aged 11–19; STIVORO, 2012), and the low success rates of (self-aided) quitting among adolescent smokers (12.2%; Centers for Disease Control and Preventions [CDC], 2009), a strong need exists for evidence-based intervention programs to help young people quit smoking. Because research has found that nicotine dependence is an important factor that hampers smoking cessation among youngsters (e.g., Kleinjan et al., 2009; Prokhorov et al., 2001), nicotine replacement therapy (NRT) may help. Nicotine replacement therapy acts mainly by reducing withdrawal symptoms in regular smokers who quit (Molyneux et al., 2006).
∗ Corresponding author. Tel.: +31 30 253 3056; fax: +31 30 253 4733. E-mail address: [email protected] (C.S. Scherphof).
While NRT has been shown to facilitate smoking cessation in adults (Lemmens et al., 2008; Stead et al., 2012; Willemsen et al., 2003), evidence for the efficacy of NRT among adolescents is not as straightforward. Recently a meta-analysis (Kim et al., 2011) and a review (Bailey et al., 2012) focused on the effectiveness of pharmacotherapy (NRT + bupropion) in adolescents. These studies showed some evidence for short-term efficacy (≤12 weeks; Bailey et al., 2012); however, no mid-term (26 weeks) efficacy was found (Kim et al., 2011). Recently, the short-term efficacy of nicotine patches, compared to placebo patches, was tested among Dutch adolescents (Scherphof et al., 2014). The results indicated that nicotine patches were efficacious in predicting abstinence 2 weeks after participants’ quit dates. At end-of-treatment (after 6 or 9 weeks), nicotine patches increased abstinence rates significantly, but only in highcompliant, compared to low-compliant, participants (22.4% versus 7.4%, respectively). The percentages of quitters in the placebo patch group were quite similar among high- and low-compliant participants (14.5% and 11.7% respectively). The current study was
http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007 0376-8716/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
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conducted as a continuation of the study by Scherphof et al. (2014) on the short-term efficacy of NRT and the same sample was used. We examined whether NRT enhances adolescents’ mid-term (6month follow-up) and long-term (12-month follow-up) quit rates, thereby including the possible moderating role of compliance.
Compliance was measured with the first six online questionnaires. Respondents were asked how many days since the previous online questionnaire they had used the patches. The total number of days a participant used the patches was calculated by summing the answers from T1 to T6. Therefore, the compliance score for all participants ranged from 0 to 42 days. 2.3. Data analyses
2. Methods 2.1. Procedure The recruitment of participants was conducted by visiting schools. Individuals interested in participating were required to fill out an online screening questionnaire to define eligibility (12–18 years old, not having major physical health problems, smoking ≥7 cigarettes per day, parent awareness of smoking behaviors, and motivated to quit smoking). Excluded from participation were those (1) who were using nicotine replacement therapy or other smoking cessation medication at the time of participant recruiting, (2) who were pregnant or lactating, and (3) who reported being allergic to patches in general or any ingredients in the patches. Both participants and parents (if participants were 17 years or younger) were required to sign informed consent. Participants began the intervention with a 75-min information meeting that consisted of a pre-treatment questionnaire (T0), information about the study, a short behavioral intervention aimed at quitting smoking (e.g., preparations and expectations), and instructions on using NRT that emphasized the relevance of using the patch during the whole treatment period as described. The treatment period with the patches started the Monday after the meeting (Day 1), and participants were asked to quit smoking from that day on. The duration of treatment with nicotine (or placebo) patches was 6 or 9 weeks, depending on the number of cigarettes participants smoked at T0. Participants were asked to fill out eight online questionnaires; six were administered during treatment and the other two were administered 6 months (T7) and 12 months (T8) after the start of treatment. To assess the validity of smoking cessation, participants who self-reported being abstinent at T8 were contacted for biochemical analyses. Research assistants visited participants at their homes to collect salivary samples for a cotinine assay. Study participants were compensated a maximum of D 90 for participating in all study phases. This study is registered at TrialRegister.nl (NTR3031), and was approved in September 2010 by the Medical Ethical Committee of the Utrecht Medical Center. For a detailed description of the procedures, we refer to our short-term efficacy article (Scherphof et al., 2014).
Data were analyzed (SPSS version 20) in accordance with the intention-to-treat principle and with the completers-only framework. Missing data on all other variables were handled by the Expectation–Maximization algorithm (Schafer, 1999). Logistic regression analyses were used to explore the effect of NRT (1) versus placebo (0) on smoking cessation (0 = abstinence after 6 or 12 months; 1 = smoking). We followed the same procedure as in our previous article (Scherphof et al., 2014). In the first step, the sole effect of NRT was examined; the interaction between treatment condition and compliance was added in the second step. Both steps were tested in two models, one in which we adjusted for gender (Model 1) as this variable was associated with treatment group assignment, and one in which we adjusted for other variables that that were correlated significantly with the outcome measure of smoking cessation (Model 2).
3. Results 3.1. Loss to follow-up The final sample consisted of 257 participants (for a flow diagram and participant characteristics we refer to our previous study: Scherphof et al., 2014). Participants who did not complete the seventh (n = 19, 7.4%) or eighth (n = 26, 10.1%) online questionnaire were slightly younger when they started smoking on a daily basis (T8: t = −1.98, p = .049) and more likely to have a lower educational level (T7: 2 (1) = 4.72, p = .049; T8: 2 (1) = 10.55, p = .002). No significant differences were found for treatment condition, gender, age, self-efficacy to quit smoking, motivation, alcohol consumption, or drug use as assessed at baseline. 3.2. Smoking cessation
2.2. Measures At T7, the 30-day point prevalence abstinence rate was measured using two items. Participants were asked to report which of the following statements suited them best: “In the period between the previous questionnaire until now (1) I have not smoked at all; (2) I have smoked, but now I quit; (3) I quit for a while, but now I smoke again; or (4) I have smoked the whole period.” Respondents who answered (1) or (2) were presented with the following question: “How long ago did you smoke your last cigarette?” Participants who answered “4 weeks ago or longer” to the latter question were considered to be abstinent. At T8, the same self-report measure was used and included biochemical verification of smoking cessation using the NicAlert saliva strip (Nymox). The NicAlert test yields a semi-quantitative measure of cotinine based on a colorimetric immunoassay reaction. The test strip displays seven zones that represent saliva cotinine levels ranging from 0 (0–10 ng/ml) to 6 (>1000 ng/ml). Results were recorded as values from 0 to 6; the cutoff for smoker versus nonsmoker was 1; however, a level of 1 could also indicate passive exposure to tobacco. Preceding the cotinine test, participants filled out a short paper questionnaire that examined smoking behaviors in the period between T8 and the cotinine test. Thus, at T7 and T8, self-reported smoking cessation was measured using a 30-day point prevalence abstinence based on the answers given in the questionnaire. At T8, we used the additional criterion of a self-reported 30-day point prevalence abstinence validated by a cotinine level ≤1 to determine smoking cessation.
In total, 18 adolescents self-reported to be abstinent at T7 and 21 at T8. The biochemically validated smoking cessation rate at T8 resulted in 14 abstinent adolescents (see Table 1). Reasons for these differences were (1) participants resumed smoking between the online questionnaire and the cotinine measurement (n = 5), (2) participants could not be contacted for the cotinine test (n = 1), and (3) the cotinine test was not valid (n = 1). Point prevalence validated abstinence results were discordant between outcome time points; only seven adolescents were abstinent after 6 and 12 months. Table 2 showed no significant effects for both the main effect of NRT and the interaction between NRT and compliance regardless of the inclusion of covariates. The analyses using self-reported abstinence yielded similar results except for the significant effect of alcohol consumption in Step 1 of Model 2 (see Supplementary Table S1). Additionally, the intention-to-treat analyses and completers-only analyses showed similar results for both self-reported abstinence and validated abstinence measures (statistics available upon request from the corresponding author).
Table 1 30-day point prevalence abstinence rates after 6 and 12 months. No./total no. (%) of subjects abstinent Validated self-reporta
Self-report
6 Months 12 Months
Nicotine patch
Placebo patch
Nicotine patch
Placebo patch
11/135 (8.1) 11/135 (8.1)
7/122 (5.7) 10/122 (8.2)
– 6/135 (4.4)
– 8/122 (6.6)
Note: Numbers are based on intent-to-treat analyses. a Biochemically verified in participants who self-reported to be abstinent at T8, using the NicAlert saliva strip.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
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Table 2 Predictors of self-reported abstinence after 6 and 12 months for two models (intention-to-treat analyses, N = 257). Model 1
Model 2
Step 1
Abstinence after 6 months Condition Gender Compliance Compliance × condition Self-efficacy Alcohol consumption Drug use Abstinence after 12 months Condition Gender Compliance Compliance × condition Self-efficacya Alcohol consumptionb Drug usec
Step 2
Step 1
Step 2
OR
CI
OR
CI
OR
CI
OR
CI
1.54 0.66
[0.57, 4.16] [0.25, 1.73]
1.86 0.66 1.02 0.99
[0.19, 17.92] [0.25, 1.76] [0.96, 1.09] [0.92, 1.07]
1.63 0.60
[0.59, 4.47] [0.22, 1.67]
1.67 0.98 0.98
[0.90, 3.11] [0.88, 1.09] [0.95, 1.01]
2.09 0.61 1.02 0.99 1.64 0.98 0.98
[0.20, 22.07] [0.22, 1.68] [0.96, 1.09] [0.91, 1.07] [0.88, 3.09] [0.88, 1.09] [0.95, 1.01]
1.00 0.81
[0.40, 2.52] [0.32, 2.07]
1.39 0.90† 1.00
[0.80, 2.41] [0.80, 1.00] [0.97, 1.03]
1.13 0.79 0.99 0.99 1.41 0.90† 1.00
[0.17, 7.44] [0.31, 2.03] [0.94, 1.05] [0.92, 1.07] [0.81, 2.45] [0.80, 1.00] [0.97, 1.03]
1.00 0.98
[0.40, 2.46] [0.40, 2.41]
1.28 0.96 1.00 0.99
[0.21, 7.94] [0.39, 2.38] [0.95, 1.05] [0.92, 1.06]
Note: OR = odds ratio, CI = 95% confidence interval. Model 1 tested the effects of condition, compliance, and the interaction between these two variables on smoking cessation, controlling for initial differences between treatment conditions. Model 2 tested the same effect as in model 1, but adjusted for variables that were significantly correlated with smoking cessation in our sample. a Self-efficacy was measured on a scale ranging from 1 (=not confident at all) to 5 (=very confident). b Alcohol use during weekend days was transformed from a scale ranging from 0 (=0 glasses) to 11 (=20 glasses or more) to a mean number of glasses alcohol. c Drug use in the past year was transformed from a scale ranging from 1 (=0 times) to 7 (=40 times or more) to a mean number of joints smoked. † p ≤ .10.
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.drugalcdep. 2014.04.007. 4. Discussion The short-term effects of the nicotine patch on end-of-treatment abstinence among high-compliant participants (Scherphof et al., 2014) were not confirmed in the extended follow-up assessments. This finding indicates that nicotine patches fail to help adolescents remain abstinent. Little research exists on the mid- and long-term effects of NRT among adolescents. Only one previously conducted RCT among adolescents has examined the influence of the nicotine patch on abstinence rates after 6 months. Moolchan et al. (2005) found verified abstinence rates of 20.6% in the nicotine patch condition, 8.7% in the nicotine gum condition, and 5% in the placebo condition, with a trend toward significance for the effects of the patch compared to those of the placebo. The substantially larger percentage of quitters in the nicotine condition, compared to our results, might be attributed to a combination of the following aspects of that study: weekly cognitive-behavioral group therapy sessions, relatively high compliance rates (78.4%), and a high amount of compensation for participation ($225). The difference in efficaciousness of NRT between adolescents and adults suggests the existence of essential differences in the process of smoking cessation between the two groups. For example, compared to adults, adolescents show a lack of self-regulation skills needed to anticipate problem situations and develop plans to handle difficult times (Mermelstein, 2003); they are also more susceptible to peer pressure (Rubin et al., 1998). These factors might have hampered the process of smoking cessation among adolescents despite their NRT use. In the Netherlands, NRT is available from drugstores or pharmacies without a prescription; however, minors are discouraged to use NRT without preceding medical advice because of limited evidence for efficacy in this age group. Elaborating on the results of previous research on NRT among adolescents (i.e., little evidence for efficacy,
but low addictive potential and well tolerated), the present study aimed to contribute to the development of an effective accessible smoking cessation intervention for this age group. Despite its strengths, including a large sample size, low dropout, and figures on long-term abstinence rates, the current study had some limitations. First, although self-reported cessation was biochemically validated at T8, at T7, we were unable to validate self-reported cessation. Under or over reporting may have occurred because adolescents’ self-reports were accepted without biochemical validation (Patrick et al., 1994). On the other hand, several studies among adolescents have found that self-reported smoking and quitting behaviors are as valid and reliable as are more objective methods such as biochemical verification (Dolcini et al., 1996; Hunter et al., 1980). Second, NRT compliance was assessed using six online selfreport measures, which may have elicited socially desirable answering tendencies. However, we decided to use these selfreport measures because a previous study showed that more objective measures of compliance (i.e., collecting used and unused patches) were unreliable because participants often failed to return their patches (Hanson et al., 2003). Finally, treatment durations and concentrations of the patches were based on the manufacturer’s instructions leaflet of the nicotine patches (in which 3 phases of 3 weeks for each concentration are recommended). However, we cannot rule out that the effects might have been different if other treatment durations or NRT concentrations had been used. Our results suggest that merely offering NRT is not advisable for adolescents. From our results, we suggest that additional therapeutic conditions be fulfilled in combination with NRT to establish significant long-term effects of smoking cessation. Such interventions could offer a more intensive approach. For example, this could be accomplished by including the adolescents’ social environments such as peers and parents and by improving self-regulation skills such as well-structured cognitive behavioral intervention programs over a substantial period of time as such programs are especially sensitive to the cognitive developmental variations among adolescents.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
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Role of funding source This study was financed by ZonMw – The Netherlands Organization for Health Research and Development. ZonMw had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors Regina van den Eijnden and Wilma Vollebergh designed the longitudinal study and wrote the protocol. Charlotte Scherphof coordinated and performed the data collection. Regina van den Eijnden, Wilma Vollebergh and Charlotte Scherphof developed the specific research questions discussed in the manuscript. Charlotte Scherphof managed the literature searches and summaries of previous related work. Charlotte Scherphof and Regina van den Eijnden carried out the statistical analysis. Charlotte Scherphof wrote the first draft of the manuscript and all authors were involved in the critical revision of the first draft. All authors contributed to and have approved the final manuscript. Conflict of interest No conflict declared. Acknowledgements We thank Novartis for providing the study medication (Nicotinell, 21 mg, 14 mg, and 7 mg, and identical appearing placebo). References Bailey, S.R., Crew, E.E., Riske, E.C., Ammerman, S., Robinson, T.N., Killen, J.D., 2012. Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents. Paediatr. Drugs 14, 91–108. Centers for Disease Control and Prevention, 2009. High school students who tried to quit smoking cigarettes – United States, 2007. MMWR 58, 428–431.
Dolcini, M.M., Adler, N.E., Ginsberg, D., 1996. Factors influencing agreement between self-reports and biological measures of smoking among adolescents. J. Res. Adolesc. 6, 515–542. Hanson, K., Allen, S., Jensen, S., Hatsukami, D., 2003. Treatment of adolescent smokers with the nicotine patch. Nicotine Tob. Res. 4, 515–526. Hunter, S.M., Webber, L.S., Berenson, G.S., 1980. Cigarette smoking and tobacco usage behavior in children with adolescents: Bogalusa heart study. Prev. Med. 9, 701–712. Kim, Y., Myung, S.K., Jeon, Y.J., Lee, E.H., Park, C.H., Seo, H.G., Huh, B.Y., 2011. Effectiveness of pharmacologic therapy for smoking cessation in adolescent smokers: meta-analysis of randomized controlled trials. Am. J. Health Syst. Pharm. 68, 219–226. Kleinjan, M., van den Eijnden, R.J.J.M., Engels, R.C.M.E., 2009. Adolescents’ rationalizations to continue smoking: the role of disengagement beliefs and nicotine dependence in smoking cessation. Addict. Behav. 34, 440–445. Lemmens, V., Oenema, A., Klepp Knut, I., Brug, J., 2008. Effectiveness of smoking cessation interventions among adults: a systematic review of reviews. Eur. J. Cancer Prev. 17, 535–544. Mermelstein, R., 2003. Teen smoking cessation. Tob. Control 12, i25–i34. Molyneux, A., Lewis, S., Coleman, T., McNeill, A., Godfrey, C., Madely, R., Britton, J., 2006. Designing smoking cessation services for school-age smokers: a survey and qualitative study. Nicotine Tob. Res. 4, 539–546. Moolchan, E.T., Robinson, M.L., Ernst, M., Cadet, J.L., Pickworth, W.B., Heishman, S.J., Schroeder, J.R., 2005. Safety and efficacy of the nicotine patch and gum for the treatment of adolescent tobacco addiction. Pediatrics 115, e407–e414. NHS Centre for Reviews and Dissemination, 1998. Smoking cessation: what the health service can do. Effectiveness Matters 3, 1–4. Patrick, D.L., Cheadle, A., Thompson, D.C., Diehr, P., Koepsell, T., Kinne, S., 1994. The validity of self-reported smoking: a review and meta-analysis. Am. J. Public Health 84, 1086–1093. Prokhorov, A.V., Hudmon, K.S., de Moor, C.A., Kelder, S.H., Conroy, J.L., Ordway, N., 2001. Nicotine dependence, withdrawal symptoms, and adolescents’ readiness to quit smoking. Nicotine Tob. Res. 3, 151–155. Rubin, K.H., Bukowski, W.M., Parker, J.G., 1998. Peer interactions, relationships, and groups. In: Damon, W., Lerner, R.M., Eisenberg, N. (Eds.), Handbook of Child Psychology. Social, Emotional, and Personality Development, vol. 3, 5th ed. Wiley, New York, pp. 619–700. Schafer, J.L., 1999. Multiple imputation: a primer. Stat. Methods Med. Res. 8, 3–15. Scherphof, C.S., van den Eijnden, R.J.J.M., Engels, R.C.M.E., Vollebergh, W.A.M., 2014. Short-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: a randomized controlled trial. J. Subst. Abuse Treat. 46, 120–127. Stead, L.F., Perera, R., Bullen, C., Mant, D., Hartmann-Boyce, J., Cahill, K., Lancaster, T., 2012. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst. Rev. 11, CD000146. STIVORO, 2012. Roken, de harde feiten: jeugd 2012 (Smoking, The Harsh Facts: Youth 2013). STIVORO–voor een rookvrije toekomst, The Hague. Willemsen, M.C., Wagena, E.J., van Schayck, C.P., 2003. De effectiviteit van stoppenmet-rokenmethoden die in Nederland beschikbaar zijn: Een systematische review op basis van Cochrane-gegevens. Ned. Tijschr. Geneeskd. 147, 922–927.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
ARTICLE IN PRESS Drug and Alcohol Dependence xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep
Short communication
Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial Charlotte S. Scherphof a,∗ , Regina J.J.M. van den Eijnden a , Rutger C.M.E. Engels b , Wilma A.M. Vollebergh a a b
Child and Adolescent Studies, Utrecht University, P.O. Box 80.140, 3508 TC Utrecht, The Netherlands Behavioural Science Institute, Radboud University Nijmegen, P.O. Box 9104, 6500 HE Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history: Received 21 October 2013 Received in revised form 4 April 2014 Accepted 5 April 2014 Available online xxx Keywords: RCT Adolescents Nicotine replacement therapy Nicotine patch Efficacy Smoking
a b s t r a c t Background: A double-blind RCT on the short-term efficacy of nicotine patches compared to placebo patches among Dutch adolescents was conducted. The findings demonstrated that nicotine patches are efficacious for smoking cessation at end-of-treatment; however, only in highly compliant participants. We tested whether the effects of NRT also held in 6- (T7) and 12-month (T8) follow-up assessments. Methods: Adolescents aged 12–18 years, who smoked at least seven cigarettes a day and who were motivated to quit smoking were recruited at school yards and randomly assigned to either a nicotine patch (n = 182) or a placebo patch (n = 180) condition according to a computer generated list. Participants (N = 257, age: 16.7 ± 1.13 years) attended an information meeting followed by a 6- or 9-week treatment. Smoking cessation, compliance, and potential covariates were measured by means of online questionnaires. Smoking cessation at T8 was biochemically validated by saliva cotinine. Results: At T7, 8.1% and 5.7% of participants were abstinent in the nicotine and placebo patch groups, respectively. At T8, abstinence was 4.4% and 6.6%, respectively. Intention-to-treat analyses showed no significant effects of NRT on abstinence rates at T7 (OR = 1.54, 95% CI = 0.57, 4.16) and validated abstinence rates at T8 (OR = 0.64, 95% CI = 0.21, 1.93) neither after considering compliance nor after adjusting for covariates. Conclusions: NRT fails in helping adolescents quit smoking at 6- and 12-month follow-ups. This finding suggests that a more intensive approach is needed to assist youngsters in their quit attempts. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Considering the negative health consequences (NHS, 1998), the high prevalence of adolescent smoking (11% daily smokers aged 11–19; STIVORO, 2012), and the low success rates of (self-aided) quitting among adolescent smokers (12.2%; Centers for Disease Control and Preventions [CDC], 2009), a strong need exists for evidence-based intervention programs to help young people quit smoking. Because research has found that nicotine dependence is an important factor that hampers smoking cessation among youngsters (e.g., Kleinjan et al., 2009; Prokhorov et al., 2001), nicotine replacement therapy (NRT) may help. Nicotine replacement therapy acts mainly by reducing withdrawal symptoms in regular smokers who quit (Molyneux et al., 2006).
∗ Corresponding author. Tel.: +31 30 253 3056; fax: +31 30 253 4733. E-mail address: [email protected] (C.S. Scherphof).
While NRT has been shown to facilitate smoking cessation in adults (Lemmens et al., 2008; Stead et al., 2012; Willemsen et al., 2003), evidence for the efficacy of NRT among adolescents is not as straightforward. Recently a meta-analysis (Kim et al., 2011) and a review (Bailey et al., 2012) focused on the effectiveness of pharmacotherapy (NRT + bupropion) in adolescents. These studies showed some evidence for short-term efficacy (≤12 weeks; Bailey et al., 2012); however, no mid-term (26 weeks) efficacy was found (Kim et al., 2011). Recently, the short-term efficacy of nicotine patches, compared to placebo patches, was tested among Dutch adolescents (Scherphof et al., 2014). The results indicated that nicotine patches were efficacious in predicting abstinence 2 weeks after participants’ quit dates. At end-of-treatment (after 6 or 9 weeks), nicotine patches increased abstinence rates significantly, but only in highcompliant, compared to low-compliant, participants (22.4% versus 7.4%, respectively). The percentages of quitters in the placebo patch group were quite similar among high- and low-compliant participants (14.5% and 11.7% respectively). The current study was
http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007 0376-8716/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
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conducted as a continuation of the study by Scherphof et al. (2014) on the short-term efficacy of NRT and the same sample was used. We examined whether NRT enhances adolescents’ mid-term (6month follow-up) and long-term (12-month follow-up) quit rates, thereby including the possible moderating role of compliance.
Compliance was measured with the first six online questionnaires. Respondents were asked how many days since the previous online questionnaire they had used the patches. The total number of days a participant used the patches was calculated by summing the answers from T1 to T6. Therefore, the compliance score for all participants ranged from 0 to 42 days. 2.3. Data analyses
2. Methods 2.1. Procedure The recruitment of participants was conducted by visiting schools. Individuals interested in participating were required to fill out an online screening questionnaire to define eligibility (12–18 years old, not having major physical health problems, smoking ≥7 cigarettes per day, parent awareness of smoking behaviors, and motivated to quit smoking). Excluded from participation were those (1) who were using nicotine replacement therapy or other smoking cessation medication at the time of participant recruiting, (2) who were pregnant or lactating, and (3) who reported being allergic to patches in general or any ingredients in the patches. Both participants and parents (if participants were 17 years or younger) were required to sign informed consent. Participants began the intervention with a 75-min information meeting that consisted of a pre-treatment questionnaire (T0), information about the study, a short behavioral intervention aimed at quitting smoking (e.g., preparations and expectations), and instructions on using NRT that emphasized the relevance of using the patch during the whole treatment period as described. The treatment period with the patches started the Monday after the meeting (Day 1), and participants were asked to quit smoking from that day on. The duration of treatment with nicotine (or placebo) patches was 6 or 9 weeks, depending on the number of cigarettes participants smoked at T0. Participants were asked to fill out eight online questionnaires; six were administered during treatment and the other two were administered 6 months (T7) and 12 months (T8) after the start of treatment. To assess the validity of smoking cessation, participants who self-reported being abstinent at T8 were contacted for biochemical analyses. Research assistants visited participants at their homes to collect salivary samples for a cotinine assay. Study participants were compensated a maximum of D 90 for participating in all study phases. This study is registered at TrialRegister.nl (NTR3031), and was approved in September 2010 by the Medical Ethical Committee of the Utrecht Medical Center. For a detailed description of the procedures, we refer to our short-term efficacy article (Scherphof et al., 2014).
Data were analyzed (SPSS version 20) in accordance with the intention-to-treat principle and with the completers-only framework. Missing data on all other variables were handled by the Expectation–Maximization algorithm (Schafer, 1999). Logistic regression analyses were used to explore the effect of NRT (1) versus placebo (0) on smoking cessation (0 = abstinence after 6 or 12 months; 1 = smoking). We followed the same procedure as in our previous article (Scherphof et al., 2014). In the first step, the sole effect of NRT was examined; the interaction between treatment condition and compliance was added in the second step. Both steps were tested in two models, one in which we adjusted for gender (Model 1) as this variable was associated with treatment group assignment, and one in which we adjusted for other variables that that were correlated significantly with the outcome measure of smoking cessation (Model 2).
3. Results 3.1. Loss to follow-up The final sample consisted of 257 participants (for a flow diagram and participant characteristics we refer to our previous study: Scherphof et al., 2014). Participants who did not complete the seventh (n = 19, 7.4%) or eighth (n = 26, 10.1%) online questionnaire were slightly younger when they started smoking on a daily basis (T8: t = −1.98, p = .049) and more likely to have a lower educational level (T7: 2 (1) = 4.72, p = .049; T8: 2 (1) = 10.55, p = .002). No significant differences were found for treatment condition, gender, age, self-efficacy to quit smoking, motivation, alcohol consumption, or drug use as assessed at baseline. 3.2. Smoking cessation
2.2. Measures At T7, the 30-day point prevalence abstinence rate was measured using two items. Participants were asked to report which of the following statements suited them best: “In the period between the previous questionnaire until now (1) I have not smoked at all; (2) I have smoked, but now I quit; (3) I quit for a while, but now I smoke again; or (4) I have smoked the whole period.” Respondents who answered (1) or (2) were presented with the following question: “How long ago did you smoke your last cigarette?” Participants who answered “4 weeks ago or longer” to the latter question were considered to be abstinent. At T8, the same self-report measure was used and included biochemical verification of smoking cessation using the NicAlert saliva strip (Nymox). The NicAlert test yields a semi-quantitative measure of cotinine based on a colorimetric immunoassay reaction. The test strip displays seven zones that represent saliva cotinine levels ranging from 0 (0–10 ng/ml) to 6 (>1000 ng/ml). Results were recorded as values from 0 to 6; the cutoff for smoker versus nonsmoker was 1; however, a level of 1 could also indicate passive exposure to tobacco. Preceding the cotinine test, participants filled out a short paper questionnaire that examined smoking behaviors in the period between T8 and the cotinine test. Thus, at T7 and T8, self-reported smoking cessation was measured using a 30-day point prevalence abstinence based on the answers given in the questionnaire. At T8, we used the additional criterion of a self-reported 30-day point prevalence abstinence validated by a cotinine level ≤1 to determine smoking cessation.
In total, 18 adolescents self-reported to be abstinent at T7 and 21 at T8. The biochemically validated smoking cessation rate at T8 resulted in 14 abstinent adolescents (see Table 1). Reasons for these differences were (1) participants resumed smoking between the online questionnaire and the cotinine measurement (n = 5), (2) participants could not be contacted for the cotinine test (n = 1), and (3) the cotinine test was not valid (n = 1). Point prevalence validated abstinence results were discordant between outcome time points; only seven adolescents were abstinent after 6 and 12 months. Table 2 showed no significant effects for both the main effect of NRT and the interaction between NRT and compliance regardless of the inclusion of covariates. The analyses using self-reported abstinence yielded similar results except for the significant effect of alcohol consumption in Step 1 of Model 2 (see Supplementary Table S1). Additionally, the intention-to-treat analyses and completers-only analyses showed similar results for both self-reported abstinence and validated abstinence measures (statistics available upon request from the corresponding author).
Table 1 30-day point prevalence abstinence rates after 6 and 12 months. No./total no. (%) of subjects abstinent Validated self-reporta
Self-report
6 Months 12 Months
Nicotine patch
Placebo patch
Nicotine patch
Placebo patch
11/135 (8.1) 11/135 (8.1)
7/122 (5.7) 10/122 (8.2)
– 6/135 (4.4)
– 8/122 (6.6)
Note: Numbers are based on intent-to-treat analyses. a Biochemically verified in participants who self-reported to be abstinent at T8, using the NicAlert saliva strip.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
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Table 2 Predictors of self-reported abstinence after 6 and 12 months for two models (intention-to-treat analyses, N = 257). Model 1
Model 2
Step 1
Abstinence after 6 months Condition Gender Compliance Compliance × condition Self-efficacy Alcohol consumption Drug use Abstinence after 12 months Condition Gender Compliance Compliance × condition Self-efficacya Alcohol consumptionb Drug usec
Step 2
Step 1
Step 2
OR
CI
OR
CI
OR
CI
OR
CI
1.54 0.66
[0.57, 4.16] [0.25, 1.73]
1.86 0.66 1.02 0.99
[0.19, 17.92] [0.25, 1.76] [0.96, 1.09] [0.92, 1.07]
1.63 0.60
[0.59, 4.47] [0.22, 1.67]
1.67 0.98 0.98
[0.90, 3.11] [0.88, 1.09] [0.95, 1.01]
2.09 0.61 1.02 0.99 1.64 0.98 0.98
[0.20, 22.07] [0.22, 1.68] [0.96, 1.09] [0.91, 1.07] [0.88, 3.09] [0.88, 1.09] [0.95, 1.01]
1.00 0.81
[0.40, 2.52] [0.32, 2.07]
1.39 0.90† 1.00
[0.80, 2.41] [0.80, 1.00] [0.97, 1.03]
1.13 0.79 0.99 0.99 1.41 0.90† 1.00
[0.17, 7.44] [0.31, 2.03] [0.94, 1.05] [0.92, 1.07] [0.81, 2.45] [0.80, 1.00] [0.97, 1.03]
1.00 0.98
[0.40, 2.46] [0.40, 2.41]
1.28 0.96 1.00 0.99
[0.21, 7.94] [0.39, 2.38] [0.95, 1.05] [0.92, 1.06]
Note: OR = odds ratio, CI = 95% confidence interval. Model 1 tested the effects of condition, compliance, and the interaction between these two variables on smoking cessation, controlling for initial differences between treatment conditions. Model 2 tested the same effect as in model 1, but adjusted for variables that were significantly correlated with smoking cessation in our sample. a Self-efficacy was measured on a scale ranging from 1 (=not confident at all) to 5 (=very confident). b Alcohol use during weekend days was transformed from a scale ranging from 0 (=0 glasses) to 11 (=20 glasses or more) to a mean number of glasses alcohol. c Drug use in the past year was transformed from a scale ranging from 1 (=0 times) to 7 (=40 times or more) to a mean number of joints smoked. † p ≤ .10.
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.drugalcdep. 2014.04.007. 4. Discussion The short-term effects of the nicotine patch on end-of-treatment abstinence among high-compliant participants (Scherphof et al., 2014) were not confirmed in the extended follow-up assessments. This finding indicates that nicotine patches fail to help adolescents remain abstinent. Little research exists on the mid- and long-term effects of NRT among adolescents. Only one previously conducted RCT among adolescents has examined the influence of the nicotine patch on abstinence rates after 6 months. Moolchan et al. (2005) found verified abstinence rates of 20.6% in the nicotine patch condition, 8.7% in the nicotine gum condition, and 5% in the placebo condition, with a trend toward significance for the effects of the patch compared to those of the placebo. The substantially larger percentage of quitters in the nicotine condition, compared to our results, might be attributed to a combination of the following aspects of that study: weekly cognitive-behavioral group therapy sessions, relatively high compliance rates (78.4%), and a high amount of compensation for participation ($225). The difference in efficaciousness of NRT between adolescents and adults suggests the existence of essential differences in the process of smoking cessation between the two groups. For example, compared to adults, adolescents show a lack of self-regulation skills needed to anticipate problem situations and develop plans to handle difficult times (Mermelstein, 2003); they are also more susceptible to peer pressure (Rubin et al., 1998). These factors might have hampered the process of smoking cessation among adolescents despite their NRT use. In the Netherlands, NRT is available from drugstores or pharmacies without a prescription; however, minors are discouraged to use NRT without preceding medical advice because of limited evidence for efficacy in this age group. Elaborating on the results of previous research on NRT among adolescents (i.e., little evidence for efficacy,
but low addictive potential and well tolerated), the present study aimed to contribute to the development of an effective accessible smoking cessation intervention for this age group. Despite its strengths, including a large sample size, low dropout, and figures on long-term abstinence rates, the current study had some limitations. First, although self-reported cessation was biochemically validated at T8, at T7, we were unable to validate self-reported cessation. Under or over reporting may have occurred because adolescents’ self-reports were accepted without biochemical validation (Patrick et al., 1994). On the other hand, several studies among adolescents have found that self-reported smoking and quitting behaviors are as valid and reliable as are more objective methods such as biochemical verification (Dolcini et al., 1996; Hunter et al., 1980). Second, NRT compliance was assessed using six online selfreport measures, which may have elicited socially desirable answering tendencies. However, we decided to use these selfreport measures because a previous study showed that more objective measures of compliance (i.e., collecting used and unused patches) were unreliable because participants often failed to return their patches (Hanson et al., 2003). Finally, treatment durations and concentrations of the patches were based on the manufacturer’s instructions leaflet of the nicotine patches (in which 3 phases of 3 weeks for each concentration are recommended). However, we cannot rule out that the effects might have been different if other treatment durations or NRT concentrations had been used. Our results suggest that merely offering NRT is not advisable for adolescents. From our results, we suggest that additional therapeutic conditions be fulfilled in combination with NRT to establish significant long-term effects of smoking cessation. Such interventions could offer a more intensive approach. For example, this could be accomplished by including the adolescents’ social environments such as peers and parents and by improving self-regulation skills such as well-structured cognitive behavioral intervention programs over a substantial period of time as such programs are especially sensitive to the cognitive developmental variations among adolescents.
Please cite this article in press as: Scherphof, C.S., et al., Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug Alcohol Depend. (2014), http://dx.doi.org/10.1016/j.drugalcdep.2014.04.007
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Role of funding source This study was financed by ZonMw – The Netherlands Organization for Health Research and Development. ZonMw had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors Regina van den Eijnden and Wilma Vollebergh designed the longitudinal study and wrote the protocol. Charlotte Scherphof coordinated and performed the data collection. Regina van den Eijnden, Wilma Vollebergh and Charlotte Scherphof developed the specific research questions discussed in the manuscript. Charlotte Scherphof managed the literature searches and summaries of previous related work. Charlotte Scherphof and Regina van den Eijnden carried out the statistical analysis. Charlotte Scherphof wrote the first draft of the manuscript and all authors were involved in the critical revision of the first draft. All authors contributed to and have approved the final manuscript. Conflict of interest No conflict declared. Acknowledgements We thank Novartis for providing the study medication (Nicotinell, 21 mg, 14 mg, and 7 mg, and identical appearing placebo). References Bailey, S.R., Crew, E.E., Riske, E.C., Ammerman, S., Robinson, T.N., Killen, J.D., 2012. Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents. Paediatr. Drugs 14, 91–108. Centers for Disease Control and Prevention, 2009. High school students who tried to quit smoking cigarettes – United States, 2007. MMWR 58, 428–431.
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