1. Primary Care Conference Case Presentation: A New Smoking Cessation Treatment Option 25 October 2006 Douglas E. Jorenby, Ph.D.

2. Disclosures Research support from Pfizer, Nabi Biopharmaceuticals, NIDA Research support from Pfizer, Nabi Biopharmaceuticals, NIDA Consulting and educational honoraria from Nabi Biopharmaceuticals, Veterans’ Administration Consulting and educational honoraria from Nabi Biopharmaceuticals, Veterans’ Administration

3. Learning Objectives Understand the mechanism of action of varenicline for smoking cessation Understand the mechanism of action of varenicline for smoking cessation Be informed regarding the pros and cons of this treatment Be informed regarding the pros and cons of this treatment Apply evidence-based smoking cessation treatments in a patient with multiple complicating factors Apply evidence-based smoking cessation treatments in a patient with multiple complicating factors

4. Case History Caucasian male in his late 40s Caucasian male in his late 40s Currently smoking 15 cpd Currently smoking 15 cpd Daily smoker for over 30 years Daily smoker for over 30 years Longest period of cessation = 6 mos. Longest period of cessation = 6 mos. Failed “cold turkey” Failed “cold turkey” Not using other forms of tobacco Not using other forms of tobacco

5. SCPC Assessments BP 140/82 BP 140/82 CO = 18 ppm CO = 18 ppm FVC = 3.91 l (79%) FVC = 3.91 l (79%) FEV1 = 3.26 l (82%) FEV1 = 3.26 l (82%) FEF25-75 = 3.75 l/s (96%) FEF25-75 = 3.75 l/s (96%)

6. Complicating Factors Seizure disorder Seizure disorder Sleep apnea Sleep apnea Visual impairment Visual impairment Caffeine use Caffeine use Alcohol use Alcohol use

7. Things Go Better With Dopamine Nicotine Nicotine Bupropion Bupropion Cytisine Cytisine Varenicline Varenicline

8. The α4β2 Receptor Subtype Key to the rewarding effects of nicotine Key to the rewarding effects of nicotine Modulates dopamine release Modulates dopamine release Varenicline has 35-60% of the agonist effect Varenicline has 35-60% of the agonist effect Affinity is higher than for nicotine Affinity is higher than for nicotine

9. Randomized Controlled Trial Phase 3 placebo-controlled comparison Phase 3 placebo-controlled comparison 1.0 mg twice daily (n=344) 1.0 mg twice daily (n=344) 150 mg bupropion SR twice daily (n=342) 150 mg bupropion SR twice daily (n=342) Placebo (n=341) Placebo (n=341)

10. Participant Characteristics Varenicline Bupropion SR Placebo % Male 55.260.258.1 Age 44.642.942.3 % White 85.582.785 Years 27.125.424.4 CPD 22.521.821.5 FTND 5.39 5.16

11. Point Prevalence Outcome Jorenby DE, et al. JAMA. 2006;296:56-63.

12. Rates of Discontinuation Jorenby DE, et al. JAMA. 2006;296:56-63.

13. Nausea As AE Jorenby DE, et al. JAMA. 2006;296:56-63.

14. Oncken C, et al. Arch Intern Med. 2006;166:1571-1577.

16. Point Prevalence Outcome Replication Gonzales D, et al. JAMA. 2006;296:47-55.

17. Dosing Regimen 0.5 mg in the morning for 3 days, then 0.5 mg in the morning for 3 days, then 0.5 mg twice a day for 4 days, then 0.5 mg twice a day for 4 days, then 1 mg twice a day (target quit date) 1 mg twice a day (target quit date) Continue for 3-6 months Continue for 3-6 months

18. Dose & Titration Effects On Nausea Oncken C, et al. Arch Intern Med. 2006;166:1571-1577.

19. A Matter Of Scale Bupropion SR Bupropion SR Hurt et al. (1997) Hurt et al. (1997) Jorenby et al. (1999) Jorenby et al. (1999) N = 1,508 N = 1,508 Varenicline Varenicline Gonzales et al. (2006) Gonzales et al. (2006) Jorenby et al. (2006) Jorenby et al. (2006) Tonstad et al. (2006) Tonstad et al. (2006) Nides et al. (2006) Nides et al. (2006) Oncken et al. (2006) Oncken et al. (2006) N = 5,265 N = 5,265

20. Case Outcome Medication well-tolerated Medication well-tolerated Attended SCPC support group for 4 weeks Attended SCPC support group for 4 weeks Reported no withdrawal symptoms (?!) Reported no withdrawal symptoms (?!) Smoke-free Smoke-free Follow-up at 6 months Follow-up at 6 months Repeat PFT at 12 months Repeat PFT at 12 months