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Varenicline: A Tale of Three Molecules Douglas E. Jorenby, Ph.D. Associate Professor of Medicine Univ. of WI School of Medicine and Public Health The Center for Tobacco Research and Intervention The University of Wisconsin School of Medicine and Public Health Disclosures Research support from NIDA (P50DA019706-09) , Pfizer, Nabi Biopharmaceuticals The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Tobacco results in a true drug dependence • Tobacco dependence exhibits classic characteristics of drug dependence • Nicotine: – Is Psychoactive – Produces Tolerance – Causes physical dependence characterized by withdrawal symptoms upon cessation The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Is It All About Withdrawal? • Kenford et al. (2002) analysis of 505 smokers from three nicotine patch studies: “Indeed, it appears that the extent that withdrawal symptomatology predicts relapse is largely due to the ability of withdrawal measures to tap affect…” The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Stewart, de Wit & Eikelboom. Psych Review, 1984. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health This is your brain on dopamine Tapper et al. Science, 2004. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Varenicline • Small, water soluble molecule • 92% excreted unchanged in urine • 24 hr. half-life • No competition for P450 pathway Obach et al. Drug Metab Dispos., 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Comparative Evidence Base • Bupropion SR 2 RCTs with 1,508 participants • Varenicline 5 RCTs with 5,265 participants The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Dose Level & Titration • Placebo-controlled, doubleblind RCT • N=647 • 0.5 mg BID vs. 1.0 mg BID • Titrated vs. Non-titrated • Weekly individual counseling Oncken et al. Arch Intern Med, 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Point Prevalence Outcome Oncken et al. Arch Intern Med, 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Oncken et al. Arch Intern Med, 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Comparative Efficacy • Placebo-controlled, doubleblind RCT • N=1027 (+1025) • 1.0 mg BID vs. 150 mg BID bupropion SR • Weekly individual counseling Jorenby et al., JAMA. 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Point Prevalence Outcome Jorenby et al., JAMA. 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Modified Cigarette Evaluation Questionnaire Subscales Varenicline p-value vs. Placebo Smoking Satisfaction <.001 Psychological Reward <.001 Respiratory Tract Sensations .01 Craving Reduction .04 Aversion n.s. Bupropion SR Smoking Satisfaction Psychological Reward <.001 <.001 The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Extended Treatment • Open-label treatment for 12 weeks • Then randomized, double-blind assignment to 12 additional weeks of varenicline or placebo • N=1210 • Weekly individual counseling Tonstad et al. JAMA, 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Point Prevalence Outcome Tonstad et al. JAMA, 2006. The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health Looking to the future • Withdrawal relief may be just a first step • More than one way to alter rewarding properties of smoking? • Extending both treatment and the population? • Matching treatments to patients The Center for Tobacco Research and Intervention University of Wisconsin School of Medicine and Public Health