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Cacpr.caOctober 2007, Volume 16, No.1 Current Issues in Medical Management
Varenicline: The Newest Pharmacotherapy for Smoking Cessation
Andrew L. Pipe, CM, MD, Robert Reid, PhD, MBA, Bonnie Quinlan, RN, BScN, APN
Minto Prevention and Rehabilitation Centre, University of Ottawa Heart Institute, Ottawa, Ontario
Smoking cessation is deemed to be the most powerful of all the is essential, in all professional settings, that systematic approaches to preventive interventions in any clinical setting. It assumes special the identification and treatment of smokers become the norm.3 significance among a cardiac population; there is no other initiative The effectiveness of smoking-cessation interventions can be that will as dramatically reduce the risk of recurrence, complication, enhanced by a systematic approach to their application. All patients or re-admission.1,2 Smoking cessation must be seen as a priority in should have their smoking status clearly documented, receive the care of such patients; sadly, this has not often been the case. It personally relevant non-judgmental advice regarding the importance of cessation, be offered assistance with cessation, and be provided with appropriate treatment. The likelihood of successful cessation is significantly increased with brief counselling and the use of pharmacotherapy. Initially, pharmacotherapy was provided in the form of nicotine replacement therapy (NRT), (delivered through the Varenicline: The Newest Pharmacotherapy for venous system by skin-patch, gum and more recently by a vaporizer) which produced levels of nicotine markedly below those produced by Recommendations for the Diagnosis and smoking without any of the thousands of other chemical constituents Treatment of Dyslipidemia and Prevention of of cigarette smoke. By eliminating craving and easing the discomfort Cardiovascular Disease: Reflection on the of withdrawal, pharmacotherapy can allow a patient to more easily 2006 Canadian Guidelines . . . . . . . . . . . . . 4Drug-Eluting Stents – Up-to-"DAT" Evidence . . 8 develop a whole new repertoire of non-smoking behaviours.4 The use of NRT has been compromised by the degree to which many physicians and other health professionals are unaware of the need, in Evidence-Based Therapy after Hospitalization many cases, to titrate NRT to meet the customary nicotine needs of for Acute Myocardial Infarction in particular patients, and a failure to recognize that there is substantial evidence attesting to the safety of the administration of NRT to Research in Progress:
patients with cardiovascular disease.
The "Ottawa Model": A Hospital-Based Approach to Smoking Cessation in Canada . . . 12 "The effectiveness of smoking-cessation References & Reviews:
interventions can be enhanced by a systematic approach to their application." The antidepressant bupropion (Zyban™) was found, serendipitously, to dramatically assist cessation efforts and ultimately Book Review: Healing from the Heart: became the second pharmacotherapy to be used to aid smokers A Practical Guide to Creating Excellent Experiences for Patients and their Families . . . . . 17 during quit-attempts. Its use is contraindicated in those who have a history of, or predisposition to, seizure disorders and its use may National Ofﬁce News . . . . . . . . . . . . . . . 17
be problematic in those using other psychotropic medications. It is not unusual for patients to complain of a variety of discomforting CACR Member Benefit Survey Results . . . . . 19 side effects (many of which will respond to a reduction in dosage Continued on Page 3 Continued from Page 1 with minimal effect on smoking-cessation effectiveness). Varenicline is a compound that is completely absorbed Bupropion is presumed effective because of its effect on orally, does not interact with other commonly used stimulating a variety of neuroreceptors involved in the medications, does not influence the activities of the mediation of smoking's effects and the production, following Cytochrome P450 pathways, and is excreted in the urine abstinence, of the symptoms of craving and withdrawal.5 virtually unchanged.7 It has a half-life of several hours and Until recently, bupropion was seen as the most effective therapeutic levels are achieved after four days of twice-daily pharmaceutical aid for cessation.
administration. In initial clinical investigations, nausea For many years, the leaves of "golden chain", a plant occurred in many subjects, but resulted in discontinuation native to western Eurasia, have been chewed to "treat" of therapy in only 3-4% of subjects.6 As a consequence of nicotine addiction. The active ingredient of golden chain, these early investigations, varenicline is titrated over a seven- cytisine, became the basis of the development of a third day period in advance of the "quit-date", to a dose of 1.0 mg pharmacotherapy for smoking cessation. Modification of twice a day; the development of nausea has been noted to the cytisine molecule has resulted in the creation of a new be reduced with such a dosing strategy. Because this drug is compound varenicline, which has been shown to be highly excreted by the kidneys, those with significantly impaired efficacious in aiding cessation.
renal function should receive a reduced dose of varenicline. It is known that specific nicotine receptors, principally The drug is prescribed for an initial twelve-week period; it may be continued for a further 12 weeks in those who located in the ventral tegmental area of the brain stem, operate have initially responded but who continue to struggle with to mediate the effects of nicotine. Several classes of such relapse to smoking.8 "nicotinic acetylcholine receptors" have been identified; the Clinical trials of varenicline in comparison with bupropion alpha-4-beta-2 (α4β2) receptor is felt to play a specific role in have demonstrated the former's clinical superiority.9,10,11 It initiating and maintaining nicotine addiction. (Smokers are has recently become available in Canada (known here as known to have increased numbers of α4β2 receptors; their Champix™) and has been available in Europe and the USA numbers increasing with exposure to nicotine.) Stimulation for almost a year or more (known as Chantix™ in the USA). of this receptor causes it to open, like a pore, permitting an The results of initial clinical trials show that fifty-two weeks increased ionic flow through the pore into the brainstem after commencing therapy, varenicline produced cessation neurons which, in turn, stimulates neurotransmitters to rates of 21.9% in comparison to rates of 16.1% with the use release at the axon. Those neurotransmitters stimulate of bupropion and 8.4% with placebo.5 other neurons ultimately resulting in increased dopamine release in areas of the forebrain. The release of dopamine "…fifty-two weeks after commencing therapy, is commonly associated with sensations of pleasure or varenicline produced cessation rates of 21.9%." satisfaction, and smokers become accustomed to elevations The superiority of varenicline in clinical trials will need in the levels of dopamine. The combination of declining to be replicated in clinical practice, but the trial evidence levels of nicotine and dopamine are intimately involved in suggests that this product can provide specific and additional the production of craving and the symptoms of withdrawal assistance to those attempting smoking cessation when which typically accompany any (often very short) period of compared to other pharmacotherapies. Its demonstrated abstinence from smoking. efficacy, unique mode of activity, apparent freedom from Varenicline has a particular affinity for the α4β2 nicotinic drug interactions, and a low incidence of side effects offer receptors and, acting as a partial agonist, stimulates them to advantages that will be welcome in many clinical settings.12 a lesser degree than does nicotine – which results in a Varenicline represents a very specific approach to reduction of craving and forestalls the development of smoking cessation through its particular affinity for, withdrawal symptoms. But because of its affinity for the and interaction with, the α4β2 nicotinic acetylcholine receptors, varenicline prevents any attachment of nicotine to receptors. Nevertheless, it is important to appreciate that these same receptors should an individual smoke – thereby pharmacotherapies for smoking cessation, while enhancing serving as a partial antagonist. An individual smoking while the likelihood of cessation, are not "magic bullets"! It has taking varenicline will therefore not experience many of the already been noted that clinicians should provide specific sensations normally associated with smoking. Therein lies advice, supportive and sympathetic counselling, and ensure the basis of varenicline's success as a smoking cessation aid. appropriate follow-up in order to maximize the chances In the presence of therapeutic levels of varenicline, the α4β2 of smoking cessation success.13 In cardiac settings such receptors are occupied and partially stimulated.
approaches should be seen as a standard of care.14 Current Issues in Cardiac Rehabilitation and Prevention As the neurophysiology of nicotine addiction becomes pharmacotherapy for tobacco dependence: past, present and future. more completely understood, it is likely that our ability Drug Alcohol Rev 2006;25(1):59-71.
5. Hughes J, Stead L, Lancaster T. Antidepressants for smoking cessation. to help smokers shed their tenacious addiction with the Cochrane Database Syst Rev 2007;1:CD000031.
assistance of increasingly effective pharmacotherapies will 6. Coe JW, Brooks PR, Vetelino MG et al. Varenicline: an alpha4beta2 continue to be enhanced. nicotinic receptor partial agonist for smoking cessation. J Med Chem Drs. Pipe and Reid have received research support, speaking 7. Obach RS, Reed-Hagen AE, Krueger SS et al. Metabolism and fees and honoraria from Pfizer. Dr. Reid is supported by disposition of varenicline, a selective alpha4beta2 acetylcholine receptor a New Investigator Award from the Heart and Stroke partial agonist, in vivo and in vitro. Drug Metab Dispos 006;34(1):121- Foundation of Canada. The authors wish to acknowledge 30. Epub Oct 12 2005.
the ongoing support of Smoke-Free Ontario and the Ontario 8. Tonstad S, Tonnesen P, Hajek P et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. Ministry of Health Promotion, and funding from Health Canada's Prevention, Cessation and Education Activities 9. Gonzales D, Rennard SL, Nides M et al. Varenicline, an alpha4beta2 under the Federal Tobacco Control Strategy (6549-15- nicotinic acetylcholine receptor partial agonist, vs sustained-release 2006/3530095). bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006;296(1):47-55.
Zyban (bupropion hydrochloride) is a trademark used under license by 10. Jorenby DE, Hays JT, Rigotti NA et al. Efficacy of varenicline, an Biovail Pharmaceuticals Canada.
alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo Champix (varenicline) is a trademark of Pfizer Canada.
or sustained-release bupropion for smoking cessation: a randomized Chantix is a trademark of Pfizer Inc.
controlled trial. JAMA 2006;296(1):56-63.
11. Nides M, Oncken C, Gonzales D et al. Smoking cessation with 1. Rea TD, Heckbert SR, Kaplan RC et al. Smoking status and risk varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: for recurrent events after myocardial infarction. Ann Intern Med results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006;166(15):1561-68.
2. Critchley J, Capewell S. Smoking cessation for the secondary 12. Lam S, Patel PN. Varenicline: a selective alpha4beta2 nicotinic prevention of coronary heart disease. Cochrane Database Syst Rev acetylcholine receptor partial agonist approved for smoking cessation. Cardiol Rev 2007;15(3):154-61.
3. Reid RD, Quinlan B, Riley D, Pipe AL. Smoking cessation: 13. Nides M, Lesichow S, Sarna L, Evans SE. Maximizing smoking lessons learned from clinical trial evidence. Curr Opin Cardiol cessation in clinical practice: pharmacologic and behavioral interventions. Prev Cardiol 2007;10(2 Suppl 1):23-30.
4. Foulds J, Steinberg MB, Williams JM et al. Developments in 14. Pipe A. Smoking. Can J Cardiol 1999;15 Suppl G:77G-80G.
Current Issues in Cardiac Rehabilitation and Prevention
Antibiotic resistance is ancient Vanessa M. D'Costa1,2*, Christine E. King3,4*, Lindsay Kalan1,2, Mariya Morar1,2, Wilson W. L. Sung4, Carsten Schwarz3,Duane Froese5, Grant Zazula6, Fabrice Calmels5, Regis Debruyne7, G. Brian Golding4, Hendrik N. Poinar1,3,4 & Gerard D. Wright1,2 The discovery of antibiotics more than 70 years ago initiated a with high concentrations of Escherichia coli harbouring the gfp (green