Abstract Adolescent smoking remains a public health problem. Despite concerns regarding adolescent nicotine dependence, few well-designed smoking cessation studies have been conducted with teen smokers. This is particularly true regarding pharmacological treatments for nicotine dependence. Currently, pharmacological aids are not recommended for treating adolescent nicotine dependence, as efficacy has not been shown in this population. This review includes studies that have examined the efficacy of pharmacotherapy for smoking abstinence and/or reduction in cigarette consumption among adolescent smokers who want to quit smoking, lab-based adolescent studies that have examined the effectiveness of these medications in reducing cravings and/or withdrawal symptoms, and/or studies that have assessed the tolerability of medications for smoking cessation in adolescent smokers. This review provides information on the pharmacologic action of each medication, the efficacy of each medication for adolescent smoking cessation, the tolerability of each medication based on reported adverse events, and compliance with the medication protocols. Thirteen relevant articles were identified and included in the review. Nicotine patch, nicotine gum, nicotine nasal spray, bupropion, and varenicline have been studied in adolescent smokers. The adverse events reported in the studies on pharmacology for adolescent smoking suggest that the side effect profiles for nicotine replacement therapy, bupropion, and varenicline are similar to those reported in adult studies. There is some evidence of efficacy of nicotine patch and bupropion at end of treatment (efficacy of varenicline has not been assessed), but none of the medications included in this review were efficacious in promoting long-term smoking cessation among adolescent smokers. It is noted that many of the study protocols did not follow the recommended dose or length of pharmacotherapy for adults, rendering it difficult to determine the true efficacy of medication for adolescent smoking cessation. Future efficacy studies are warranted before recommending pharmacotherapy for adolescent smoking cessation. Adolescent Smoking and Pharmacotherapy Adolescent smoking remains a high priority public health concern. The U.S. Department of Health and Human Services has retained the goal of reducing adolescent smoking rates in the Healthy People 2020 initiative. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Considering that over 80% of adult smokers begin smoking prior to age of 18, Relatively few well-designed smoking cessation studies have been conducted with teen smokers. This is particularly true regarding pharmacological treatments for nicotine dependence. To date, nicotine replacement, bupropion (Zyban), and varenicline have been approved as therapies for adult smokers and the recommended treatment for adult nicotine dependence is a combination of psychotherapy and pharmacotherapy. Methods Study Identification and Inclusion Searches were conducted through the PubMed and PsycINFO online databases (through May 2011) and were limited to "English Language" and "Human." The following keywords were used in the initial search "smoking cessation", "adolescent OR teen" and then limited by the separate use of the following terms: "bupropion", "Zyban", "nicotine replacement therapy", "varenicline", "Chantix", "nicotine patch", "nicotine gum", "nicotine nasal spray", and "pharmacotherapy." Only studies that targeted adolescent smokers for recruitment and enrollment were included. In addition, studies referenced in relevant review articles, metaanalyses, and all selected articles were examined. The searches yielded 14 relevant studies that included pharmacotherapy for adolescent nicotine dependence. One study was excluded from the review because the focus was on reduction of smoking among adolescents that did not want to quit and did not include data on adverse events. Nicotine replacement therapy This review focuses on nicotine replacement therapy (NRT) that has been evaluated for smoking cessation among adolescent smokers (nicotine patch, gum, and spray); however, there are other nicotine replacement products approved for smoking cessation, including a nicotine inhaler, a nicotine lozenge and, in some countries outside of the United States, a nicotine sublingual tablet. Nicotine replacement therapy (NRT) replaces the nicotine delivered while smoking to reduce craving and withdrawal symptoms and is available in different forms and dosages depending on the number of cigarettes smoked. Open-label studies- The earliest study to use NRT with adolescent smokers was conducted by Smith and colleagues in 1996. No adverse events were associated with discontinuation of patch therapy. Hurt et al. conducted a larger open-label study (n = 101) that coupled six weeks of 15 mg/ 16-hour NP therapy with an optional brief individual counseling session at the first clinic visit. Randomized clinical trials (RCT)- The first randomized, double-blind, placebocontrolled study of NRT was conducted by Hanson et al. in 2003. [16] Initial dose and titration schedules were based on the teens' level of cigarette consumption. Participants (n = 100) received 10 weeks of NP therapy and cognitive-behavioral therapy and a contingency management procedure. There were no significant differences between groups in biologically verified, 7-day point prevalence abstinence at end of treatment (Week 10) (28.0% NP vs. 24.0% placebo), 30-day point prevalence abstinence (20.0% NP vs. 18.0% placebo), or continuous abstinence from the quit date. Compared to the placebo patch group, the active NP group experienced a significantly lower craving score and overall withdrawal symptom score. Participants in the placebo patch group reported more headaches than those in the active NP group (75.6% vs. 56.3%, respectively). None reported dropping out as a result of an adverse event and no significant differences in dropout rates or medication compliance were observed across the treatment groups. A community-based, double-blind pilot RCT was conducted by Roddy and colleagues with 98 regular smokers (defined as > 1 cigarette per day or < 1 cigarette per day but reported past or anticipated withdrawal). Moolchan and colleagues Finally, Rubinstein et al. conducted a pilot randomized trial of nicotine nasal spray (NNS) in 40 adolescent smokers. Summary of efficacy See Safety/tolerability None of the studies reported any severe or life-threatening side effects. The adverse events reported by adolescents for NRT were similar to those reported by adult smokers. Of the NRT studies, only three reported discontinuation of study medication during treatment due to an adverse event. Special considerations for use in adolescent smokers Controversy remains over the use of NRT in adolescents. Studies with animals indicate that nicotine can elicit neuronal damage and long-term changes in synaptic function, suggesting that there could be long-term adverse consequences of nicotine exposure in adolescence. Bupropion Bupropion was initially marketed as an atypical antidepressant and was approved in 1997, under the name Zyban, as the first non-nicotine medication to aid in smoking cessation for adults. Bupropion inhibits the reuptake of dopamine and norepinephrine in the central nervous system Randomized clinical trials (RCT)-Four RCTs have assessed the efficacy of bupropion for smoking cessation with adolescents. In the only study to examine bupropion SR in combination with NP therapy, Killen and colleagues randomized adolescent smokers (n = 211) to receive eight weeks of NP therapy and nine weeks of either 150 mg/day bupropion SR or placebo pills. Finally, Gray and colleagues examined the efficacy of 300 mg/day bupropion SR and contingency management (CM). Summary of efficacy See None of the studies with 300 mg/day bupropion SR were longer than six weeks in duration. The full dose was well tolerated by adolescent smokers and resulted in higher end of treatment abstinence than 150 mg/day bupropion SR in the only adolescent multi-dose study. However, similar to the few multi-dose studies in adults, the higher dose did not produce a better outcome at follow-up. Paediatr Drugs. Author manuscript; available in PMC 2012 April 4. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Given that none of the studies that have examined the use of bupropion SR for adolescent nicotine dependence followed the dosage recommendations for adult smokers, a future study that adheres to these guidelines is warranted. Safety/tolerability The most common adverse events reported by adolescent smokers were similar to those reported by their adult counterparts Although bupropion SR was generally well tolerated by adolescent smokers, hospitalizations occurred on three occasions. One was due to the intentional ingestion of Jimson weed in combination with bupropion SR, resulting in an anticholinergic crisis. Compliance rates Three of the five studies provided compliance data, but the methods used to assess compliance varied across the three studies. Special considerations for use in adolescent smokers Zyban contains the same active ingredient as the antidepressant medications Wellbutrin, Wellbutrin SR, and Wellbutrin XL. In 2004, the FDA directed manufacturers to add a "black box" to the health professional label of all antidepressants warning that antidepressants increased the risk compared to placebo of suicidal thinking and suicidal behavior in NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. In the RCTs with bupropion SR for smoking cessation in adolescent smokers, two adverse events were deemed to be intentional suicide attempts. Varenicline In 2006, the United States FDA approved varenicline as a prescription-only pharmacological aid for adult smoking cessation. It is also an approved smoking cessation aid in some countries outside of the U.S. Varenicline is a selective nicotinic acetylcholine receptor partial antagonist that binds to the α 4 β 2 receptor subtype, thereby reducing the reinforcing effects of nicotine. Due to its mixed agonist-antagonist properties, varenicline is effective at relieving craving and withdrawal during abstinence and blocking the reinforcing effects of smoking. Literature on varenicline in adolescent smokers One RCT examined the pharmacokinetics, safety and tolerability of varenicline in adolescent smokers
