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

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Disclosures Research support from NIDA ( P50DA ), Pfizer, Nabi Biopharmaceuticals

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 The Center for Tobacco Research and Intervention 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

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention 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…”

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Stewart, de Wit & Eikelboom. Psych Review, 1984.

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 The Center for Tobacco Research and Intervention This is your brain on dopamine Tapper et al. Science, 2004.

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 The Center for Tobacco Research and Intervention 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.

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Comparative Evidence Base Bupropion SR 2 RCTs with 1,508 participants Varenicline 5 RCTs with 5,265 participants

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Dose Level & Titration Placebo-controlled, double- blind RCT N= mg BID vs. 1.0 mg BID Titrated vs. Non-titrated Weekly individual counseling Oncken et al. Arch Intern Med, 2006.

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Point Prevalence Outcome Oncken et al. Arch Intern Med, 2006.

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Oncken et al. Arch Intern Med, 2006.

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Comparative Efficacy Placebo-controlled, double- blind RCT N=1027 (+1025) 1.0 mg BID vs. 150 mg BID bupropion SR Weekly individual counseling Jorenby et al., JAMA

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Point Prevalence Outcome Jorenby et al., JAMA

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention 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 <.001 Psychological Reward <.001

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention 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.

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention Point Prevalence Outcome Tonstad et al. JAMA, 2006.

University of Wisconsin School of Medicine and Public Health The Center for Tobacco Research and Intervention 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