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New anti-smoking treatments: anything to get fired-up about?
Janet Webb, BSc(Pharm), MSc
Last December a systematic review summarizing recent evidence of effectiveness of
smoking cessation strategies, compiled for the National Institutes of Health, was
published in the Annals of Internal Medicine.[1] The authors concluded that
pharmacotherapy, either with or without counselling, can significantly increase the
likelihood of smoking cessation. Their findings confirmed that the use of nicotine
replacement therapy (NRT) significantly increases the chances of quitting, and that
evidence remains sufficient for bupropion to retain first-line status for smoking cessation.
Despite apparently encouraging results, where NRT may double quit rates, it is estimated
that at least 70% of people using this treatment will relapse within a year.[2] With such
statistics, alternative approaches are still needed. This article will briefly describe a few
new and novel agents targetting successful smoking cessation.
Varenicline
Varenicline was recently approved for smoking cessation in the United States (brand
name Chantix®) and in the UK (marketed as Champix®). Varenicline is a partial agonist
at central alpha4-beta2 nicotinic receptors, which modulate dopamine release in response
to nicotine.[3] The partial activation at nicotinic receptors helps lessen withdrawal
symptoms. At the same time, by occupying this receptor, varenicline attenuates
dopamine release which is responsible for the pleasurable effects of smoking.
Two clinical trials of 12 weeks duration compared varenicline 1 mg twice daily with
bupropion SR 150 mg twice daily, or placebo in combination with clinical counselling in
1027 [4] and 1025 [5] patients. The percentage of patients who maintained a continuous
quit rate during the last 4 weeks of the 12-week treatment period were 44% for
varenicline, compared with 30% for bupropion (p<0.001), and 18% with placebo
(p<0.001) in both trials.[4,5] Adverse effects, which were significantly increased with
varenicline, included nausea in nearly 30% of subjects, and abnormal dreams, plus an
increased incidence of insomnia and headache.[4,5] In another trial, 1210 subjects who
had successfully quit smoking during 12 weeks of varenicline were randomized to further
treatment or placebo for an additional 12 weeks.[6] Subjects were followed for an
additional 28 weeks post-treatment (i.e., 52 weeks since beginning treatment). Between
weeks 13-24, 71% of varenicline subjects remained abstinent compared with 50%
receiving placebo (p<0.001), and at week 52, 44% of the varenicline group, and 37% of
the placebo group were still not smoking (p<0.02). An accompanying editorial
mentioned several limitations including the high adverse event incidence, dropout rates,
possible introduction of bias in an intention-to-treat analysis which would favour the
study drug, inclusion criteria which may not reflect the population at large, and study
settings in which patients are likely to receive optimal instruction and monitoring.[7]
Despite these shortcomings, the editorialists conclude that varenicline is likely to aid with
successful smoking cessation.[7] There are no published trials comparing varenicline to
nicotine replacement.
Dianicline, which is similar to varenicline, is currently undergoing phase III testing for
smoking cessation.[8]
Rimonabant
The endocannabinoid system is thought to be involved in controlling food intake, and
also to play a role in dependence and habituation, with receptors in both the brain and
adipose tissue.[9] Rimonabant (Acomplia) is the first selective cannabinoid CB1 receptor
antagonist.[10] It has received much attention for obesity, especially in patients with
diabetes or dyslipidemia, and is approved as adjunctive therapy for this indication in the
UK. There was initial hope that it would prove useful in smoking cessation, with the
added benefit of preventing weight gain. Three trials have been undertaken, known as
the STRATUS (Studies with Rimonabant and Tobacco Use) trials, and although
preliminary results were presented in 2004 and the trials were to be terminated at the end
of 2004, the results have not been formally published.[10,11] Study design involved
administration of rimonabant 5 mg/day, 20 mg/day or placebo along with weekly
counselling for a 10-week treatment period with 42 weeks of follow-up.[10] Preliminary
results (from the STRATUS-US trial involving 787 patients) presented at the 2004
American College of Cardiology annual meeting demonstrated quit rates of 20%, 36%,
and 20%, in the 5 mg, 20 mg, and placebo groups, respectively.[10] This was
accompanied by a loss of 0.3 kg in the 20 mg group, and a gain of 1.1 kg in those
receiving placebo (not reported for 5 mg). The results from STRATUS-Europe,
however, were considered neutral.[11] In early 2006 the United States Food and Drug
Administration considered rimonabant “approvable” for weight loss, but not for smoking
cessation.[11] The European Medicines Agency granted an approval for weight loss,
similarly did not approve rimonabant as an aid to smoking cessation.[12] Whether or not
a smoking cessation indication will be further pursued by the developers is unknown.[11]
Nicotine vaccine
Because nicotine readily crosses the blood-brain barrier, strategies are being developed to
prevent nicotine delivery into the central nervous system so it cannot act on receptor
sites. The goal of vaccine treatment is to induce antibody formation, by administration
of a nicotine-protein complex. The nicotine-specific antibodies would then bind to
nicotine, and the resultant complex would be too large to cross the blood-brain
barrier.[13]
Several companies based in Europe and North America are pursuing this approach, and
vaccines are at various stages of development.[14] Trial results assessing safety and
immunogenicity of a nicotine-conjugate vaccine, NicVAX, and its effect on smoking
behaviour have been published.[15] The study involved 63 adult smokers who were
given one of three doses of the vaccine or placebo, in a series of four injections over 26
weeks, with 38 weeks of monitoring. The vaccine appeared safe and well-tolerated.
Immunogenic response was dose-related, and those receiving the highest dose (200
micrograms) had antibody levels deemed consistent with vaccine efficacy. This group
also had the highest rate of 30-day biochemically-confirmed abstinence from smoking
(6/16 subjects vs 2/23 receiving placebo), although the study was not designed to
measure efficacy. There were no reports of compensatory increases in smoking, or withdrawal reactions. The National Institute on Drug Abuse in the United States is currently recruiting patients for an efficacy study.[16] Other agents which are being investigated, but with insufficient evidence to draw conclusions, include: • Cytisine which is found in Cytisus laburnum, and is the molecule from which • Lazabemide, a reversible inhibitor of monoamine oxidase type B originally • Mecamylamine, a nicotine antagonist.[19] Summary
Current approaches to aid in smoking cessation have been disappointing. Increasing the
ability to successfully quit smoking without relapse is an active area of research has lead
to the development of innovative pharmacotherapeutic approaches. As further
investigation is undertaken and research results are published, hope for meaningful
advances remains.
References:
1. Ranney L, Melvin C, Lux L, McClain E, Lohr KN. Systematic review: smoking cessation intervention strategies for adults and adults in special populations. Ann Intern Med. 2006;145:845-56. 2. McRobbie H, Lee M, Juniper Z. Non-nicotine pharmacotherapies for smoking 3. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective α4β2 nicotinic receptor partial agonist. Arch Intern Med. 2006;166:1561-8. 4. Gonzales D, Rennard SI, Mides M et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;296:47-55. 5. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296:56-63. 6. Tonstad S, Tønnesen P, Hajek P et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006;296:64-71. 7. Klesges RC, Johnson KC, Somes G. Varenicline for smoking cessation: definite promise, but no panacea. JAMA. 2006;296:94-95. 8. Clinical trial: Efficacy and safety of dianicline treatment as an aid to smoking cessation in cigarette smokers (Ameridian). [U.S. National Institutes of Health Clinical Trials Web site]. Available at: http://www.clinicaltrials.gov. Accessed January 16, 2007. 9. Hey K, Ussher MH, Lancaster T. Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation [protocol]. Cochrane Database of Systematic Reviews. 2006; Volume 4. 10. Boyd ST, Fremming BA. Rimonabant – a selective CB1 antagonist. Ann 11. Wood S. FDA gives nod to antiobesity effects of rimonabant but balks at smoking-cessation indication. [theheart Web site]. February 20, 2006. Available at: http://www.theheart.org. Accessed February 23, 2006. 12. Adcock H. Clinical developments in 2006. Pharm J. 2007;278;21-4. 13. Hall W. The prospects for immunotherapy in smoking cessation. Lancet. 14. Le Houezec J. Why a nicotine vaccine? Clin Pharmacol Ther. 2005;78:453-5. 15. Hatsukami DK, Rennard S, Jorenby D et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther. 2005;78:456-67. 16. Clinical trial: Efficacy of NicVAX in smokers who want to quit smoking. [U.S. National Institutes of Health Clinical Trials Web site]. Available at: http://www.clinicaltrials.gov. Accessed January 16, 2007. 17. Etter J-F. Cytisine for smoking cessation: a literature review and meta-analysis. 18. Berlin I, Aubin H-J, Pedarriosse A-M, et al. Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation. Addiction. 2002;97:1347-54 19. Lancaster T, Stead LF. Mecamylamine (a nicotine antagonist) for smoking cessation [reviews]. Cochrane Database of Systematic Reviews. 2006; Volume 4.  2007 BC Drug and Poison Information Centre

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