In the United States, cigarette smoking remains the most. New and Emerging Treatments in Smoking Cessation. clinical review

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1 clinical review New and Emerging Treatments in Smoking Cessation Cindy Mui, MD, and Scott E. Sherman, MD, MPH Abstract Objective: To review recently approved and emerging medications for smoking cessation. Methods: Studies on newer smoking cessation aids were identified using MEDLINE ( ), the Society for Research on Nicotine and Tobacco abstracts database, and the U.S. Patents and Trademark Office database. All randomized controlled trials evaluating 1 or more medications used in smoking cessation (including vaccines) were included. Phase 1 and animal studies were excluded. Results: Varenicline has been effective in smoking cessation despite the unquantified risk of serious psychiatric effects. Rimonabant appears to be effective for smoking cessation and possibly relapse prevention and is generally well tolerated. Nicotine vaccines, mecamylamine, topiramate, and selegiline all appear effective for use in smoking cessation in preliminary trials, but additional studies are needed to confirm these findings both in the short and long term. Conclusion: Currently available first-line treatments for smoking cessation include nicotine replacement (eg, nicotine patch, nicotine gum), bupropion, and varenicline and have proven efficacy in published studies. Several treatments currently under study appear promising. In the United States, cigarette smoking remains the most preventable cause of mortality, causing 1 out of every 5 deaths annually [1]. Despite 40 years of government warnings and published data highlighting the negative health effects of cigarette smoking, 21% of Americans (45 million people) continue to smoke [2]. Current pharmacotherapies to aid in smoking cessation include nicotine replacement therapies (NRTs), such as the nicotine patch and nicotine gum, and bupropion. These therapies have consistently proven their effectiveness for smoking cessation compared with placebo, but abstinence rates remain low at 6 to 12 months. The most recent addition to the armamentarium for smoking cessation is varenicline, which was approved by the U.S. Food and Drug Administration (FDA) in Increased knowledge of the neurophysiology of nicotine dependence has led to trials evaluating the use of nicotine vaccines as well as a renewed interest in drugs used for other medical conditions to assist in smoking cessation (eg, mecamylamine, topiramate, selegiline). The purpose of this article is to review new and emerging medications to aid in smoking cessation. Methods Relevant studies were identified through a review of article titles and abstracts using a MEDLINE search for the period 1996 to Search terms included smoking cessation/all subheadings and each of the medications that are either newly approved, pending approval, or being investigated for smoking cessation (ie, varenicline, rimonabant, NicVax, NicQb, TA-NIC, mecamylamine, topiramate, and selegiline), resulting in 121 articles. Ten abstracts of ongoing smoking cessation trials were identified using the Society for Research on Nicotine and Tobacco (SRNT) Web site. A search of the patent literature through the U.S. Patents and Trademark Office (USPTO) database yielded 41 results. The last search on MEDLINE and the SRNT Web site occurred in April 2007, and the USPTO Web site was last searched in September We included randomized controlled trials testing 1 or more medications for smoking cessation in adults, but phase 1 trials and animal studies were excluded. A total of 15 studies met inclusion criteria. Results Varenicline Varenicline tartrate is a nonnicotine α 4 β 2 nicotinic acetylcholine receptor partial agonist approved by the FDA in Nicotine activates acetylcholine receptors, which increases the release of dopamine in the nucleus accumbens and prefrontal cortex, a key pathway in the reinforcing effects of nicotine. Varenicline partially activates acetylcholine receptors, which stimulates the release of an adequate amount of dopamine to reduce cravings for and withdrawal from nicotine. Varenicline also acts as a partial antagonist by blocking From the Department of Medicine, New York University School of Medicine (Drs. Mui and Sherman) and VA New York Harbor Healthcare System (Dr. Sherman), New York, NY. Vol. 15, No. 11 November 2008 JCOM 545

2 smoking cessation treatment Table 1. Results of Initial Major Clinical Trials of Varenicline for Smoking Cessation Abstinent at Week 12 Abstinent at Week 24 Abstinent at Week 52 Study N Varenicline Placebo OR (95% CI) Varenicline Placebo OR (95% CI) Varenicline Placebo OR (95% CI) Gonzales et al [4] % 18% 3.9 ( ) 30% 11% 3.7 ( ) 22% 08% 3.1 ( ) Jorenby et al [5] % 18% 3.9 ( ) 30% 13% 2.8 ( ) 23% 10% 2.7 ( ) Tonstad et al [6] 1210 * * 71% 50% 2.5 ( ) 44% 37% 1.3 ( ) CI = confidence interval; OR = odds ratio. *Participants who successfully stopped smoking were re-randomized to receive an additional 12 weeks of varenicline or placebo. the binding of nicotine, thereby attenuating the rewarding effects of nicotine [3]. Three randomized, double-blind, controlled trials have compared varenicline with placebo and bupropion, and all have shown that varenicline is efficacious for smoking cessation (Table 1) [4 6]. All of the studies included predominantly young, generally healthy smokers (mean age, early to mid 40s, smoking a mean 10 cigarettes/day). In a study by Gonzales et al [4] evaluating 1025 participants, significantly more participants in the varenicline group remained abstinent than placebo-treated participants at 12, 24, and 52 weeks. Varenicline was also superior to bupropion through 12 and 24 weeks but not at 1 year [4]. The study by Jorenby et al [5] involving 1027 adult smokers was identical to the Gonzales et al [4] study in its study design and showed similar results. Participants in the varenicline group were much more likely to remain abstinent at the end of treatment as compared with those in the placebo and bupropion groups. At 24 and 52 weeks of follow-up, significantly more participants continued to abstain from smoking in the varenicline group than either the placebo or bupropion groups [5]. Tonstad et al [6] showed that smokers who successfully quit after 12 weeks of varenicline remained continuously abstinent with an additional 12 weeks of treatment compared with placebo through 24 and 52 weeks of follow-up. The most common side effect with varenicline was nausea, seen in nearly one third of participants, but it was generally reported as mild to moderate and rarely resulted in discontinuation of the study medication. Other side effects include insomnia (14% 20%), abnormal dreams (10% 13%), and headache (13% 16%). Varenicline is well tolerated in smokers aged 65 years and older, and no dose adjustment is necessary in these patients [7]. However, varenicline is renally cleared, and caution should be exercised in patients with decreased renal function, especially the elderly. Varenicline is relatively contraindicated in patients using NRT due to an increased incidence of nausea. Recent postmarketing reports of suicidal ideation, new-onset depressed mood, and exacerbation of underlying psychiatric illness within days or weeks of initiating varenicline have led the FDA to recommend monitoring for behavioral changes while this issue continues to be investigated [8]. Some psychiatric side effects have occurred in individuals with no prior history of psychiatric illness. Rimonabant Rimonabant is a selective cannabinoid receptor 1 (CB1) antagonist in the endocannabinoid system, which is involved in the regulation of addiction as well as body weight and adipose tissue function. Blockade of CB1 receptors, which are highly concentrated on presynaptic nerve terminals in the reward pathways of the central nervous system, could attenuate the rewarding effects of nicotine. CB1 receptors are also found in peripheral organs such as the gastrointestinal tract. Rimonabant has been approved in Europe for the management of obesity. In the phase 3 STRATUS-US (STudies with Rimonabant And Tobacco Use US) trial, a significantly higher rate of smoking cessation was demonstrated in participants in the rimonabant group as compared with those in the placebo group. This double-blind, placebo-controlled trial randomized 787 participants to rimonabant 20 mg or 5 mg or placebo for 10 weeks. Rimonabant 20 mg was superior to placebo for achieving continuous smoking cessation during the last 4 weeks of treatment (28% vs. 16%; odds ratio [OR], 2.0 [95% confidence interval {CI}, ]), but there was no significant difference in the rate of abstinence between rimonabant 5 mg and placebo (16% vs. 16%; OR, 0.9 [95% CI, ]) [9]. Higher abstinence rates persisted at week 50 of follow-up for the higher dose of rimonabant (15% vs. 7% for placebo; OR, 2.1 [95% CI, ]) but not with the lower dose of rimonabant (8% vs. 7% for placebo; OR, 1.1 [95% CI, ]) [10]. The STRATUS-EU trial, a randomized, double-blind, placebo-controlled trial undertaken in 7 countries in Europe involving 783 participants, had an identical study design to the STRATUS-US trial. However, no significant difference was seen between either dose of rimonabant and placebo at the end of treatment or at 50-week follow-up. This discrepancy between the 2 trials may be explained by the statistically significantly higher dropout rate in the 20-mg group 546 JCOM November 2008 Vol. 15, No. 11

3 clinical review compared with the placebo group in the STRATUS-EU trial due to adverse events (15% vs. 7%; P = 0.004) [11]. However, a recent Cochrane review using data from both trials showed that participants receiving the higher dose of rimonabant (20 mg) were more likely to remain smoke-free after the end of treatment (OR, 1.6 [95% CI, ]) and at 1 year (OR, 1.6 [95% CI, ]) [10]. Preliminary results from STRATUS-WW trial were presented at the 2005 Society for Research on Nicotine and Tobacco annual meeting. The STRATUS-WW trial is a multicountry, multicenter, randomized, double-blind, placebocontrolled trial involving 5055 smokers undertaken to evaluate the efficacy of rimonabant 5 or 20 mg in relapse prevention in successful quitters. At week 10, 1672 successful quitters were re-randomized to rimonabant 5 or 20 mg or placebo (depending on the initial dose) for 42 weeks and followed for an additional 52 weeks. The rates of smoking cessation maintenance were similar at the end of 10 weeks for both doses of rimonabant (32% for 5 mg vs. 34% for 20 mg). However, in patients who initially quit smoking on rimonabant 5 mg, there was no significant difference in smoking cessation rates at 52 weeks among those re-randomized to treatment or placebo. Participants who quit smoking on rimonabant 20 mg were more likely to remain abstinent at 1 year if they were randomized to either dose of rimonabant as compared with placebo (OR, 1.5 for 20-mg maintenance group [95% CI, ]; OR, 1.5 for 5-mg maintenance group [95% CI, ]) [12]. Participants taking the higher dose of rimonabant gained less weight as compared with those taking the lower dose of rimonabant or placebo. Overweight or obese participants tended to lose weight on 20 mg, while normal weight participants did not [10]. Rimonabant is generally well tolerated, but dose-dependent side effects include nausea, dizziness, fatigue, nasopharyngitis, and upper respiratory tract infections. The FDA advisory board recently voted unanimously not to approve rimonabant for use in the United States pending further long-term safety data, citing concerns over reports of suicidal ideation, anxiety, depression, and seizures in patients taking rimonabant for weight loss [13]. Nicotine Vaccine Thus far, treatments to aid in smoking cessation have focused on replacing nicotine or blocking the effect of nicotine on the reward pathways in the brain. New immunologic approaches to smoking cessation have centered on the development of a nicotine vaccine, which would sequester nicotine in the blood and prevent it from reaching the brain, resulting in a decreased rewarding effect. Once nicotine binds to acetylcholine receptors, its half-life increases, thereby prolonging the effects of nicotine and preventing relapse if the user smokes while attempting to quit. Results of clinical trials have shown that nicotine vaccines NicVax and NicQb produce antinicotine antibody levels after multiple doses. In a phase 2 trial examining the immunogenicity of NicVax, the antibody concentration was low after the first vaccine dose but increased with second and third doses, and antibody levels responded to a booster dose at 6 months. Although efficacy was not a primary endpoint in this study, a significantly greater abstinence rate at 30 days was seen in the group receiving the highest vaccine dose compared with placebo [14]. A phase 2 clinical trial for NicQb involving 341 smokers showed that all smokers who received all 5 doses of the nicotine vaccine mounted an antinicotine antibody response [15]. Significantly more participants who achieved high levels of antibody remained continuously abstinent from smoking at 6 months of follow-up compared with placebo (57% vs. 31%; P = 0.004). The mean number of cigarettes smoked was also less in participants who responded to the vaccine but who continued to smoke as compared with placebo-treated patients, but this number did not reach statistical significance [15]. At 12 months, significantly more responders remained nonsmokers than participants receiving placebo (42% vs. 21%; P = 0.012) [16]. A phase 2b clinical trial evaluating TA-NIC, another nicotine vaccine, has completed enrollment with preliminary results expected in With the highest vaccine dose, side effects include local reactions such as tenderness (88%) or redness (25%) at the injection site. Mild systemic reactions were also reported, including headache (88%), myalgia (81%), malaise (75%), and fever (19%) [14]. Symptoms occurred in both the placebo and treatment groups, suggesting that these events were not due to the active vaccine. Side effects resolved without treatment within 1 to 4 days. There were no reports of withdrawal symptoms, possibly because the development of antibody concentrations occurs at a sufficiently slow rate to prevent their development. Despite promising effects, any nicotine vaccine would require repeated booster doses to maintain maximal antibody levels for more than a few months. There is also considerable interindividual variability in antibody response. Results from phase 3 trials for these vaccines will not be available for a few years. Mecamylamine Originally used as an antihypertensive agent, mecamylamine is an acetylcholinergic nicotinic receptor antagonist that blocks the rewarding effect of nicotine, thereby reducing the urge to smoke. In early studies, doses required to block the effect of nicotine produced significant side effects, including drowsiness, postural hypotension, and constipation [17]. More recent studies of lower doses of mecamylamine suggest that its use in combination with NRT may enhance the effectiveness of NRT. Vol. 15, No. 11 November 2008 JCOM 547

4 smoking cessation treatment Table 2. Summary of Medications for Smoking Cessation Treatment Mechanism of Action Typical Dosage Side Effects First-line treatment Bupropion SR (Wellbutrin, Zyban) Nicotine patch (Nicoderm CQ, Nicotrol, generic brands available) Blocks neural reuptake of dopamine and/or norepinephrine Start 1 2 wks prior to quit date 150 mg every morning 3 days, then 150 mg every 12 hr for 7 12 wks following quit date, up to 6 mo for maintenance therapy Nicotine replacement Nicoderm CQ: 21 mg/24 hr 4 wks, then 14 mg/24 hr 2 wks, then 7 mg 2 wks Nicotrol: 15 mg/16 hrs 8 wks Insomnia, xerostomia, headache Contraindicated in patients with seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, use of MAO inhibitors within the previous 14 days Local skin reaction at patch site, which improves with rotation of site; insomnia, which is minimized by removing patch at bedtime or using 16-hr patch; bizarre dreams Nicotine gum (Nicorette) Nicotine inhaler (Nicotrol inhaler) Nicotine nasal spray (Nicotrol NS) Nicotine lozenge (Commit) Varenicline (Chantix) Nicotine replacement 2 4 mg/piece up to 24 pieces/day for no more than 12 wks; gum should be chewed until peppery taste emerges and then placed between the cheek and gum. Once taste dissipates, gum should be rechewed 2-mg gum for < 25 cigarettes/day, 4-mg gum for 25 cigarettes/day Nicotine replacement 4-mg cartridges; 6 16 cartridges/day up to 6 mo; taper dose during final 6 12 wks Nicotine replacement 0.5 mg/spray; usual dose is 1 spray/nostril; 8 40 doses/day for 3 6 mo Nicotine replacement 2 or 4 mg/lozenge; recommend 9 lozenges/ day in the first 6 wks, use up to 12 wks Use 2 mg if first cigarette smoked is > 30 min after waking, 4 mg if first cigarette is < 30 min after waking Agonist and antagonist effects at α 4 β 2 nicotinic acetylcholine receptors Start 1 wk prior to quit date and treat for 12 wks; titrate to 1 mg twice daily as follows: 0.5 mg daily on days 1 3, 0.5 mg twice daily on days 4 7, and 1 mg twice daily on day 8 until end of treatment Side effects usually occur from improper chewing technique; mouth soreness, hiccups, dyspepsia, jaw ache, nausea Mouth/throat irritation, cough, rhinitis Minor burning and stinging of nasal mucosa, throat irritation, cough, sneeze, increased lacrimation, rhinorrhea, nausea Local mouth irritation, headache, nausea, diarrhea, flatulence, hiccup, heartburn, cough Nausea, insomnia, headache, abnormal dreams; possible suicidal ideation, exacerbation of psychiatric conditions Estimated OR (95% CI) at 6 Months* Estimated Abstinence Rate (95% CI) at 6 Months, %* 2.0 ( ) 24.2 ( ) High-dose patch (> 25 mg): 2.3 ( ) Used > 14 wks: 1.9 ( ) Used 6 14 wks: 1.9 ( ) Used > 14 wks: 2.2 ( ) Used 6 14 wks: 1.5 ( ) High-dose patch (> 25 mg): 26.5 ( ) Used > 14 wks: 23.7 ( ) Used for 6 14 wks: 23.4 ( ) Used > 14 wks: 26.1 ( ) Used 6 14 wks: 19 ( ) 2.1 ( ) 24.8 ( ) 2.3 ( ) 26.7 ( ) With 1 mg/day: 2.1 ( ) With 2 mg/day: 3.1 ( ) With 1 mg/day: 25.4 ( ) With 2 mg/day: 33.2 ( ) 548 JCOM November 2008 Vol. 15, No. 11

5 clinical review Table 2. Summary of Medications for Smoking Cessation (continued) Treatment Mechanism of Action Typical Dosage Side Effects Estimated OR (95% CI) at 6 Months* Estimated Abstinence Rate (95% CI) at 6 Months, %* Second-line treatment Clonidine (Catapres) α 2 -Adrenergic agonist Doses varied in trials: mg/day by mouth to mg/day transdermal Initial dose is 0.1 mg twice daily by mouth or 0.1 mg/day transdermal, increasing by 0.1 mg/day per wk for 3 10 wks Nortriptyline Noradrenergic-serotonergic reuptake inhibitor Start days prior to quit date Initial dose of 25 mg/day increasing gradually to mg/day for 12 wks Postural hypotension, bradycardia, dry mouth, drowsiness, dizziness, sedation, constipation, nausea, vomiting (may be dose-related), nervousness, agitation, headache, tremor, rebound hypertension with abrupt cessation Sedation, dry mouth, blurred vision, urinary retention, lightheadedness, tremor 2.1 ( ) 25 ( ) 1.8 ( ) 22.5 ( ) Medications in phase 3 trials Rimonabant Blocks cannabinoid receptor 1, which is involved in pathways regulating addiction, body weight, and adipose tissue function Nicotine vaccines (TA- NIC, NicVax, NicQb) Induces production of antibodies against nicotine; prevents nicotine from crossing blood-brain barrier 20 mg daily shown to be effective in trials Nausea, dizziness, upper respiratory tract infections Vaccination schedules vary from 2 6 injections at intervals of 2 4 wks Tenderness at injection site, malaise, myalgia, headache Medications under consideration Mecamylamine Nicotine antagonist mg twice daily Constipation, blurred vision, dizziness, dry mouth, weakness, abdominal pain, difficulty urinating (may be dose-dependent) Topiramate Anticonvulsant; inhibits dopamine release by facilitating the action of GABA receptors and inhibiting glutamate receptors 150 mg twice daily; start at 25 mg daily with dose escalation over 12 wks Selegiline Selective MAO-B inhibitor 5 mg twice daily; trials started at doses of 2.5 mg twice daily or 5 mg daily for the first wk Dizziness, paresthesia, psychomotor slowing, memory/concentration impairment, weight loss Headache, constipation, diarrhea, nausea, vomiting, dry mouth NOTE: Clonidine and nortriptyline are not approved by the U.S. Food and Drug Administration for smoking cessation. CI = confidence interval; GABA = γ-aminobutyric acid; MAO = monoamine oxidase; NA = not available; OR = odds ratio. *Compared with placebo. Vol. 15, No. 11 November 2008 JCOM 549

6 smoking cessation treatment Table 3. Effectiveness and Abstinence Rates for Medication Combinations Used for Smoking Cessation Combination Therapies Estimated OR (95% CI) Estimated Abstinence Rate (95% CI), % Patch (use >14 wks) ( ) 36.5 ( ) as needed NRT (gum, spray) Patch + bupropion SR 2.5 (1 3.4) 28.9 ( ) Patch + inhaler 2.2 ( ) 25.8 ( ) Patch + nortriptyline 2.3 ( ) 27.3 ( ) NOTE: Varenicline is not recommended for use in combination with nicotine replacement therapy (NRT). CI = confidence interval; OR = odds ratio. (Adapted from Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. Rockville [MD]: U.S. Dept. of Health and Human Services, Public Health Service; Available at path/tobacco.htm.) Rose et al [18] studied 48 healthy participants in a randomized, double-blind, placebo-controlled trial that compared the efficacy of a nicotine patch plus mecamylamine with a nicotine patch plus placebo. At 7 weeks (1 week after the end of treatment), 3 times as many mecamylaminetreated participants were continuously abstinent from smoking compared with placebo-treated patients (50% vs. 17%; P = 0.015). The percentage of participants who remained abstinent with mecamylamine continued to be significantly greater than placebo at 6- and 12-month follow-up (38% vs. 13% at 6 months [P = 0.046]; 38% vs. 4% at 12 months [P = 0.004]) [18]. Another randomized, double-blind, controlled trial by Rose et al [19] evaluated 80 participants who received either the nicotine patch plus mecamylamine, nicotine patch alone, mecamylamine alone, or no drug for 4 weeks prior to their quit date. After the quit date, all participants received nicotine patch plus mecamylamine. This study found that precessation treatment with mecamylamine significantly prolonged the duration of continuous smoking abstinence through 10 weeks. However, by 6 months, this percentage was no longer significant (40% in nicotine/mecamylamine group, 20% nicotine alone, 15% mecamylamine alone, 15% no drug) [19]. The primary side effect of mecamylamine was constipation, which improved with a dose reduction. Other side effects included blurred vision, dizziness, dry mouth, weakness, abdominal pain, or difficulty urinating. Topiramate Topiramate, an anticonvulsant, may be effective for smoking cessation given its effects on the dopaminergic pathways. Topiramate facilitates the actions of the inhibitory neurotransmitter γ-aminobutyric acid and inhibits excitatory glutamate receptors, thereby preventing dopamine release. By inhibiting dopamine release, topiramate may block the rewarding effects of nicotine. Topiramate showed promise in smoking cessation in a subgroup analysis of a larger randomized, double-blind, controlled 12-week study that compared topiramate versus placebo for alcohol dependence [20]. Ninety-four participants were randomized to either topiramate or placebo, and significantly more participants in the topiramate group had stopped smoking by week 12 (17% vs. 7%; OR, 4.46 [95% CI, ]). Topiramate recipients did not compensate for drinking less by smoking more, suggesting that topiramate has a direct antismoking effect. This study was limited by a small sample size, lack of long-term follow-up, and study design [20]. Khazaal et al [21] recruited 13 smokers in an open, flexible-dose pilot study of topiramate. After 2 months of treatment with topiramate, 6 of 13 participants were abstinent from smoking and 2 participants had reduced their cigarette consumption by more than 50%. This study found that doses as low as 50 mg/day were sufficient to change smoking behavior; however, the small sample size, open design, and lack of control group were limitations [21]. The results from both studies are intriguing, and more clinical trials could better evaluate topiramate as a potential medication for both alcohol and nicotine dependence. Side effects were generally mild or moderate and resolved without medical intervention. The most frequent side effects included dizziness, paresthesia, psychomotor slowing, memory/concentration impairment, and weight loss. These effects can be minimized with a low initial dose, slow titration, and use of the lowest effective dose. Selegiline Nicotine induces dopamine production in the mesolimbic area of the brain and decreases dopamine metabolism through its inhibition of monoamine oxidase-b (MAO-B). In smokers, MAO-B levels are reduced, and when smokers quit, levels of MAO-B rebound to normal levels and degrade more dopamine, resulting in a sense of craving and nicotine withdrawal [22]. Selegiline is a selective irreversible MAO-B inhibitor indicated for the treatment of Parkinson s disease, but it may have a role in smoking cessation by alleviating withdrawal symptoms through its effect on dopamine levels. In a randomized placebo-controlled trial of 40 participants, selegiline-treated participants were more likely to have stopped smoking at 8 weeks as compared with placebo-treated participants (45% vs. 15%; OR, 4.6 [95% CI, ]). More participants in the selegiline group remained continuously smoke-free during the last 4 weeks of treatment compared with those in the placebo group, but the results did not reach statistical significance (30% vs. 5%; OR, 8.1 [95% CI, ]). At 6-month follow-up, participants in 550 JCOM November 2008 Vol. 15, No. 11

7 clinical review the selegiline group were still more likely to remain abstinent of smoking, but the results were no longer significant (20% vs. 5%; OR, 4.8 [95% CI, ]) [23]. The wide CIs are due to the small sample size. In a randomized placebocontrolled trial of 109 smokers comparing the effect of selegiline or placebo with a nicotine patch, selegiline doubled the cessation rate but the result was not statistically significant. Participants used the nicotine patch until week 8 of the trial and selegiline or placebo until week 26. At week 52, continuous abstinence rates were higher in the selegiline group but rates did not reach statistical significance (25% vs. 11%; P = 0.08). Like the trial by George et al [23], the lack of statistical significance may be explained by the small sample size [24]. However, these 2 trials suggest the potential of selegiline as another medication for smoking cessation. The main side effects of selegiline were headache, constipation, diarrhea, nausea, vomiting, and dry mouth. At the recommended doses of 10 mg daily or 5 mg twice daily, selegiline is not associated with the hypertensive effect of MAO-A inhibitors. However, at higher doses ( 15 mg/day), selegiline also inhibits MAO-A and the metabolism of tyramine. Selegiline should not be started until 5 weeks after the discontinuation of selective serotonin reuptake inhibitors or until 2 weeks after the discontinuation of bupropion. Conclusion Research into the neurobiology of nicotine dependence has led to a better understanding of the mechanisms of addiction and has introduced potential medications for smoking cessation, either by preventing nicotine from crossing the blood-brain barrier with vaccines or by affecting the receptors involved in dependence. In addition to currently available options for smoking cessation (eg, NRTs, bupropion, varenicline), trials are under way examining the role of new and emerging medications in smoking cessation, either alone or as an adjunct to NRTs (Table 2 and Table 3). Rimonabant, nicotine vaccines, mecamylamine, topiramate, and selegiline have generally proven efficacious in the short term, but several studies were limited by small sample sizes, emphasizing the need for further clinical trials. Corresponding author: Scott E. Sherman, MD, MPH, VA New York Harbor Healthcare System, 423 East 23rd St., New York, NY 10010, scott. sherman@va.gov. Financial disclosures: Dr. Sherman has consulted for Pfizer. References 1. Centers for Disease Control and Prevention (CDC). Annual smoking-attributable mortality, years of potential life lost, and productivity losses United States, MMWR Morb Mortal Wkly Rep 2005;54: Centers for Disease Control and Prevention (CDC). Tobacco use among adults United States MMWR Morb Mortal Wkly Rep 2006;55: Coe JW, Brooks PR, Veteline MG, et al. Varenicline: an alpha- 4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005;48: Gonzales D, Rennard SI, Nides M, et al; Varenicline Phase 3 Study Group. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006;296: Jorenby DE, Hays JT, Rigotti NA, et al; Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial [published erratum appears in JAMA 2006;296:1355]. JAMA 2006;296: Tonstad S, Tonnesen P, Hajek P, et al; Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006; 296: Burstein A, Fullerton T, Clark DK, Faessel HM. Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers. J Clin Pharmacol 2006; 46: US Food and Drug Administration; Center for Drug Evaluation and Research. Early communication about an ongoing safety review: varenicline (marketed as Chantix). Available at Accessed 14 Oct Dale L, Anthenelli RM, Despres JP, et al. Effects of rimonabant in the reduction of major cardiovascular risk factors. Results from the STRATUS-US Trial (Smoking Cessation in Smokers Motivated to Quit) and the RIO-LIPIDS Trial (Weight Reducing and Metabolic Effects in Overweight/Obese Patients with Dyslipidemia). Presented at the American College of Cardiology Scientific Sessions; 2004 Mar 7 10; New Orleans, LA. 10. Cahill K, Ussher M. Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation. Cochrane Database Syst Rev 2007;(4):CD Cinciripini PM, Aubin HJ, Dale LC, et al. Pooled analysis of three short-term, randomised, double-blind, placebocontrolled trials with rimonabant 20 mg/d in smoking cessation [PI-TS-01]. Presented at the Society for Research on Nicotine and Tobacco 8th European Conference; 2006 Sept 23 26; Kusadasi, Turkey. 12. Niaura R. Long-term treatment with rimonabant for smoking cessation and the maintenance of abstinence: results from the STRATUS-Worldwide Trial. Presented at the Society for Research on Nicotine and Tobacco Annual Meeting; 2005 Mar 20 23; Prague, Czech Republic. 13. Rosen CJ. Summary minutes of the Endocrinologic and Metabolic Drugs Advisory Committee meeting on June 13, US Food and Drug Administration; Center for Drug Evaluation and Research. Available at 07/minutes/ m1 final.pdf. Accessed 14 Oct Hatsukami D, Rennard S, Jorenby D, et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Vol. 15, No. 11 November 2008 JCOM 551

8 smoking cessation treatment Clin Pharmacol Ther 2005;78: Cornuz J, Klingler K, Mueller F, et al. A therapeutic vaccine for nicotine dependence: results of a phase I and a randomized phase II study [abstract]. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology; 2005 May 13 17; Orlando, FL. 16. Cytos Biotechnology AG. Vaccine to treat nicotine addiction promotes 12 months continuous abstinence in subjects who achieve high antibody levels. Available at Cytos_Press_E_ pdf. Accessed 15 Oct Shytle RD, Penny E, Silver AA, et al. Mecamylamine (Inversine): an old antihypertensive with new research directions. J Hum Hypertens 2002;16: Rose JE, Behm FM, Westman EC, et al. Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone. Clin Pharmacol Ther 1994; 56: Rose JE, Behm FM, Westman EC. Nicotine-mecamylamine treatment for smoking cessation: the role of pre-cessation therapy. Exp Clin Pyschopharmacol 1998;6: Johnson BA, Ait-Daoud N, Akhtar FZ, Javors MA. Use of oral topiramate to promote smoking abstinence among alcoholdependent smokers: a randomized controlled trial. Arch Intern Med 2005;165: Khazaal Y, Cornuz J, Bilancioni R, Zullino DF. Topiramate for smoking cessation. Psychiatry Clin Neurosci 2006;60: Houtsmuller EJ, Thornton JA, Stitzer ML. Effects of selegiline (L-deprenyl) during smoking and short-term abstinence. Psycopharmacology (BERL) 2002;163: George TP, Vessicchio JC, Termine A, et al. A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation. Biol Psychiatry 2003;53: Biberman R, Neumann R, Katzir I, Gerber Y. A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation. Addiction 2003;98: Copyright 2008 by Turner White Communications Inc., Wayne, PA. All rights reserved. 552 JCOM November 2008 Vol. 15, No. 11