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Despite tremendous potential public health impact, little work has focused on development of evidence-based smoking cessation treatments for adolescents, including pharmacotherapies. No prior studies have explored the feasibility and safety of varenicline and bupropion XL, 2 potentially promising pharmacotherapies, as smoking cessation treatments in adolescents.
Treatment-seeking older adolescent smokers (ages 15–20) were randomized (double-blind) to varenicline (n = 15) or bupropion XL (n = 14), with 1-week titration and active treatment for 7 weeks. Structured safety, tolerability, and efficacy assessments (cotinine-confirmed 7-day point prevalence abstinence) were conducted weekly.
There were no serious adverse events. Two participants discontinued bupropion XL due to adverse effects, and none discontinued varenicline. Over the course of treatment, participants receiving varenicline reduced from 14.1 ± 6.3 (mean ± SD) to 0.9 ± 2.1 cigarettes/day (CPD, 4 achieved abstinence), while those receiving bupropion XL reduced from 15.8 ± 4.4 to 3.1 ± 4.0 CPD (2 achieved abstinence).
These preliminary results support the feasibility and safety of conducting adequately powered, placebo-controlled efficacy studies of varenicline and bupropion XL for adolescent smoking cessation.
Almost all adult smokers began smoking during adolescence, and youth smoking rates range, in steadily increasing numbers, from 6% of 14-year olds to 37% of 21-year olds (Backinger, Fagan, Matthews, & Grana, 2003; Substance Abuse and Mental Health Services Administration, 2008). Daily smoking, a particularly concerning predictor of long-term smoking and adverse health outcomes, is uncommon in younger adolescents (3% of 8th graders, 7% of 10th graders), but increasingly prevalent as older adolescents transition into adulthood (11% of 12th graders and 17% of 21-year olds; Johnston, O’Malley, Bachman, & Schulenberg, 2011; Substance Abuse and Mental Health Services Administration, 2008). Nearly two-thirds of young smokers may be interested in quitting, but only 4%–6% of unassisted quit attempts are successful (Chassin, Presson, Pitts, & Sherman, 2000; Stanton, McClelland, Elwood, Ferry, & Silva, 1996; Zhu, Sun, Billings, Choi, & Malarcher, 1999).
Surprisingly, few controlled studies have evaluated adolescent smoking cessation programs, and almost all have exclusively focused on psychosocial treatments, yielding generally discouraging results. For example, a meta-analysis of 48 studies showed a mean quit rate of 9.1%, compared with 6.2% among control groups (Sussman, Sun, & Dent, 2006). In the interest of enhancing these modest quit rates, and in light of clear evidence that adolescent smokers experience nicotine withdrawal and craving (Jacobsen et al., 2005; Killen et al., 2001; Prokhorov et al., 2001), a handful of recent studies have explored the potential impact of pharmacotherapy for adolescent smokers. Only six controlled cessation trials to date, most enrolling predominantly older adolescents, have investigated bupropion SR (Gray et al., 2011 [mean age 18]; Killen et al., 2004 [mean age 17]; Muramoto, Leischow, Sherrill, Matthews, & Strayer, 2007 [mean age 16]) and/or nicotine replacement therapy (Hanson, Allen, Jensen, & Hatsukami, 2003 [mean age 17]; Moolchan et al., 2005 [mean age 15]; Rubinstein, Benowitz, Auerback, & Moscicki, 2008 [mean age 17]). Results, while mixed, suggest that some pharmacotherapies may complement psychosocial treatment and enhance cessation outcomes.
Bupropion SR trials in adolescents support the efficacy of the 300 mg/day dose, but not the 150-mg dose (Gray et al., 2011; Killen et al., 2004; Muramoto et al., 2007). Twice daily dosing, which is necessary for 300 mg/day of bupropion SR, introduces concerns about multidose medication adherence, a common issue among adolescents (McGuinness & Worley, 2010) that may diminish efficacy (Charach, Volpe, Boydell, & Gearing, 2008). Bupropion XL, administered once daily (300 mg), may allow for improved adherence and persistence with treatment (McLaughlin, Hogue, & Stang, 2007; Stang, Suppapanaya, Hogue, Park, & Rigney, 2007; Stang, Young, & Hogue, 2007). However, there have been no previous published smoking cessation studies of bupropion XL in adolescents or adults.
Varenicline has demonstrated superior efficacy in adults compared with bupropion SR and nicotine patch (Aubin et al., 2008; Eisenberg et al., 2008; Gonzales et al., 2006; Jorenby et al., 2006; Nides et al., 2006), but each of these trials was based on a sample of adult smokers (e.g., mean age ≥42 for each trial). The only prior study of varenicline for adolescent smokers was limited in scope (Faessel, Ravva, & Williams, 2009). This 2-week pharmacokinetic study supported the short-term safety of varenicline and provided guidance on dosing in adolescents, but did not evaluate its smoking cessation efficacy and safety.
Given the shortage of prior smoking cessation pharmacotherapy trials focused on young smokers, and the potential promise of varenicline and bupropion XL, the present study sought to evaluate, via a double-blind randomized design, the feasibility and safety of both within an older adolescent population.
To enroll in the study, adolescents were required to (a) be 14–20 years old; (b) smoke at least five cigarettes/day (CPD; but not use other tobacco products); (c) express interest in quitting, including at least one prior unsuccessful quit attempt; (d) not be pregnant and use birth control to avoid pregnancy; (e) lack current non-nicotine substance use disorders; (f) have no unstable psychiatric or medical illness; (g) have no history of suicidal, homicidal, or aggressive behavior; (h) have no history of seizures or eating disorders; and (i) not be taking current pharmacotherapy for smoking cessation treatment or medications metabolized by CYP2B6 or CYP2D6. Recruitment occurred primarily through community media advertisements (e.g., flyers, newspaper advertisements, etc.). If an initial telephone screen suggested potential eligibility, adolescents were scheduled for an informed consent and baseline assessment visit. Participant consent was obtained for all adolescents aged 18 years or older, whereas parental consent and participant assent were obtained for those less than 18 years old. The U.S. Food and Drug Administration (FDA) approved the Investigational New Drug application for the conduct of this study. The procedures followed were approved by the university institutional review board and were in accord with the Helsinki Declaration of 1975.
Comprehensive psychiatric assessment (Sheehan et al., 1998, 2010), physical examination, laboratory testing (complete blood count, comprehensive metabolic panel, urine pregnancy test, and urine drug screen), and electrocardiogram were performed. A thorough smoking history was obtained, and baseline nicotine dependence was assessed using the Modified Fagerström Tolerance Questionnaire (Prokhorov et al., 2000) and the Hooked on Nicotine Checklist (DiFranza et al., 2002).
Eligible participants in both groups were given quit smoking brochures, instructed to set a quit date within 2 weeks of medication initiation, and randomized to receive an 8-week double-blind course of varenicline or bupropion XL. Varenicline participants ≥55 kg received 0.5 mg daily for 3 days, 0.5 mg twice daily for 4 days, and then 1 mg twice daily thereafter. Those <55 kg received 0.5 mg daily for 7 days and then 0.5 mg twice daily thereafter (Faessel et al., 2009). Bupropion XL participants received 150 mg daily for 7 days and then 300 mg daily thereafter. The university investigational drug service encased medications in identical-appearing capsules and dispensed them in weekly blister packs with specific instructions on day/time for each dose. Placebo capsules were used at times when no active medication was scheduled (i.e., evening dose for participants randomized to bupropion XL, to match evening dose of varenicline). We recognize that this design element undermined the potential adherence advantage of bupropion XL once daily dosing, but judged that maintenance of the treatment blind was of primary importance.
Participants were seen weekly during the 8-week medication trial and returned for posttreatment follow-up assessment at Week 12. At all visits, the study physician provided brief individual cessation counseling (≤10 min) and structured safety assessment.
A thorough safety evaluation was conducted at each visit (weekly during active treatment): (a) physician evaluation of physical and neuropsychiatric adverse events via open-ended interview and comprehensive, structured review of systems (Kalachnik, 2001), (b) Columbia Suicide Severity Rating Scale (Meyer et al., 2010; Posner et al., 2007) and the Beck Depression Inventory II (BDI; Beck, Steer, & Brown, 1996; Subramaniam, Harell, Huntley, & Tracy, 2009) to assess neuropsychiatric events, (c) urine pregnancy testing (females only), and (d) vital sign measurement.
Medication diaries and weekly pill counts (inspection of blister packs and documentation of missed doses) were used to measure adherence.
Participants completed a 30-day cigarette timeline followback at the assessment visit and daily cigarette diaries (collected weekly) throughout treatment (Harris et al., 2009; Sobell, Sobell, Leo, & Cancilla, 1988). Carbon monoxide breathalyzer and urine cotinine testing (NicAlert, Nymox Pharmaceuticals) were used to biologically verify smoking status.
Urine cotinine-verified 7-day point prevalence abstinence was assessed at each study visit beyond the scheduled quit date.
The pilot nature of the protocol precluded powered statistical analyses of safety or efficacy. Results are thus generally descriptive in nature. Nonetheless, generalized estimating equations (GEE) were used to assess for time effects on secondary outcomes of smoking behavior (CPD, abstinence). Given (a) the study’s small sample, (b) our secondary focus on efficacy, and (c) no placebo control group, we did not anticipate any medication effects or time × medication interactions. CPD and medication adherence were calculated only among participants retained in the study at each corresponding time point.
Twenty-nine participants (age range 15–20 years) enrolled over an 8-month recruitment period and were randomized to treatment (15 to varenicline and 14 to bupropion XL). Sample characteristics are detailed in Table 1. There were no significant differences between treatment groups among these variables.
There were no FDA-defined serious adverse events in either treatment group. None of the varenicline participants discontinued medication. One participant randomized to bupropion XL discontinued medication due to increased anxiety and another discontinued due to “feeling too focused.” Adverse events occurring in more than one varenicline participant included insomnia (4), nausea (3), and headache (2). Adverse events occurring in more than one bupropion XL participant included vivid dreams (5), insomnia (2), nausea (2), and chest discomfort (2). No suicidal behavior or ideation was observed in either treatment group, and no participants reported clinically significant depressive symptoms on BDI.
Varenicline participants took 80% of dispensed doses, and bupropion XL participants took 79% of dispensed doses.
Smoking outcomes (CPD, abstinence by week) are detailed in Table 2. GEE analysis revealed significant (p < .01) time effects for both outcomes over the course of treatment and as expected no significant treatment (varenicline vs. bupropion XL) effects or interactions.
Results of this preliminary pilot trial support the feasibility and safety of conducting older adolescent smoking cessation trials with varenicline and bupropion XL. While both medications carry FDA “black box warnings” related to potential neuropsychiatric adverse effects, they were generally well tolerated and were not associated with depressive symptoms or suicidality as assessed by comprehensive, validated evaluation methods. Additionally, smoking outcomes (detailed in Table 2), while preliminary, are encouraging, and though our design did not include a placebo control, suggest that both medications could be efficacious. We believe these findings warrant larger, adequately powered (and controlled) clinical trials within older adolescent smokers.
Interpretation of findings should be tempered by study limitations, most notably the lack of power within the small sample to comprehensively assess safety, tolerability, and efficacy of these medications. While the double-blind nature of the randomized treatment was a methodological strength, inclusion of a placebo treatment group would have allowed for additional comparisons. Another concern is poor participant retention, a pervasive challenge in adolescent smoking cessation studies that undermines the ability to detect effects over time. For this reason, we caution readers not to over-interpret abstinence outcomes (Table 2), which are provided for descriptive purposes only. To address attrition, future studies should incorporate innovative techniques, such as retention-targeted contingency management (Carroll et al., 2006; Festinger, Marlowe, Dugosh, Croft, & Arabia, 2008; Ledgerwood, Alessi, Hanson, Godley, & Petry, 2008; Sinha, Easton, Renee-Aubin, & Caroll, 2003), and should be conservatively powered in anticipation of elevated dropout rates compared with adult studies.
Despite these limitations, findings provide a novel addition to the nascent older adolescent smoking cessation pharmacotherapy literature. Varenicline and bupropion XL, never before investigated as cessation treatments in young smokers, appear to be viable candidates for further study based on the present results. Future studies to comprehensively evaluate their safety, tolerability, and efficacy in older adolescents should incorporate a fully powered sample, a longer course of treatment (12 weeks), and posttreatment follow-up over several months to allow for more direct comparison with the well-established adult smoking cessation pharmacotherapy literature. One would expect, based on findings to date, lower absolute rates of abstinence among older adolescents versus adults, but it is unclear how effect sizes (odds ratios) would compare between these two age groups. What is clear is that, given the prevalence and significant public health impact of older adolescent smoking, as well as the limits of the current cessation evidence base, further studies of pharmacotherapy for older adolescent smoking cessation will be critical contributions to the field.
Medical University of South Carolina Hollings Cancer Center Pilot Research Program and the National Institutes of Health (K12DA000357, K23DA020482, R25DA020537, and UL1RR029882).
Dr. Upadhyaya is an employee and stockholder of Eli Lilly and Company. The other authors do not have potential conflicts to declare.
The authors would like to thank participants and their families and gratefully acknowledge the efforts of the Medical University of South Carolina (MUSC) Investigational Drug Service and the MUSC Clinical and Translational Research Center clinical support staff.