1. Treatment of Tobacco Dependence in 2012 J. Taylor Hays, MD Professor of Medicine Associate Director Nicotine Dependence Center Mayo Clinic Rochester, MN

2. Disclosures Relevant Financial Relationship(s) –Grant/Research Support – Pfizer –Grant/Research Support- Nabi Biopharmaceuticals Off Label Usage –Nicotine replacement therapy; Manufacturer - various Learning Objectives Participants will be able to: Choose appropriate pharmacotherapy for a smoker motivated to quit Identify the optimal length of pharmacological treatment for smokers Describe brief behavioral treatment for tobacco dependence 2

3. Behavioral Risk Factor Surveillance System Centers for Disease Control and Prevention 17.3% 3

4. Case #1 55 yo man with CAD; asymptomatic after successful stent placement 6 months ago Smokes 25+ cigarettes per day and smokes his first one within 5 minutes of waking He quit smoking for 2 weeks by trying a 14 mg nicotine patch after his stent, but “was a bear to live with” until he relapsed He is here for a follow-up with you, and when asked tells you he is willing to try quitting again 4

5. Case # 1 Which of the following recommendations will result in the best tobacco abstinence outcome 6 months from now? 1.Nicotine patch 21 mg per day for 8 weeks 2.Nicotine gum 2 mg as needed for 12 weeks 3.Nicotine lozenge 4 mg as needed for 4 weeks 4.Nicotine patch 21 mg per day plus nicotine lozenge 2 mg as needed for 12 weeks 5.Bupropion SR 150 mg twice daily for 7 weeks 5

6. Case # 1 Which of the following recommendations will result in the best tobacco abstinence outcome 6 months from now? 1.Nicotine patch 21 mg per day for 8 weeks 2.Nicotine gum 2 mg as needed for 12 weeks 3.Nicotine lozenge 4 mg as needed for 4 weeks 4.Nicotine patch 21 mg per day plus nicotine lozenge 2 mg as needed for 12 weeks 5.Bupropion SR 150 mg twice daily for 7 weeks 6

7. USPHS Guideline Identify every tobacco user Provide advice to quit and practical counseling no matter how brief (behavioral therapy) Motivate health behavior change (MI) Combine brief behavioral treatment with effective pharmacotherapy for everyone making a quit attempt –Exceptions include contraindications and special populations where evidence is poor 7

8. USPHS Clinical Practice Guideline- 2008 The 5 A’s ASK about tobacco use ADVISE to stop ASSESS willingness to make an attempt ASSIST in the stop attempt ARRANGE for a follow-up visit S- Smoking status M- Motivational message A- and R- Refer for T- Treatment www.ahrq.gov 8

9. Effect of Contact Intensity Cessation by intensity of person-to-person contact Contact*O.R.Cessation% None1.010.9 Minimal1.313.4 Brief1.616.0 Counseling2.322.1 *minimal 3 to 10mins. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. 9

10. Motivational Interviewing Method of enhancing motivation for health behavior change Brief intervention for patients not ready to make a quit attempt Spirit of MI: –Express empathy –Develop discrepancy –Roll with resistance –Support self-efficacy 10

11. Motivational Interviewing Baron von Raschke It’s a dance… …not a wrestling match! 11

12. MedicationArmsEstimated abstinence rate (95% CI) Estimated OR vs Placebo (95% CI) Estimated OR vs Nicotine patch* (95% CI) Monotherapies Varenicline (2 mg/d)533.2 (28.9-37.8)3.1 (2.5-3.8)1.6 (1.3-2.0) Nicotine nasal spray426.7 (21.5-32.7)2.3 (1.7-3.0)1.2 (0.9-1.6) High-dose nicotine patch (>25 mg) (includes both standard or long-term duration) 426.5 (21.3-32.5)2.3 (1.7-3.0)1.2 (0.9-1.6) Long-term nicotine gum (>14 weeks)626.1 (19.7-33.6)2.2 (1.5-3.2)1.2 (0.8-1.7) Varenicline (1 mg/d)325.4 (19.6-32.2)2.1 (1.5-3.0)1.1 (0.8-1.6) Nicotine inhaler624.8 (19.1-31.6)2.1 (1.5-2.9)1.1 (0.8-1.5) Bupropion SR2624.2 (22.2-26.4)2.0 (1.8-2.2)1.0 (0.9-1.2) Nicotine patch (6-14 weeks)3223.4 (21.3-25.8)1.9 (1.7-2.2)1.0 Long-term nicotine patch (>14 weeks)1023.7 (21.0-26.6)1.9 (1.7-2.3)1.0 (0.9-1.2) Nortriptyline522.5 (16.8-29.4)1.8 (1.3-2.6)0.9 (0.6-1.4) Nicotine gum (6-14 weeks)1519.0 (16.5-21.9)1.5 (1.2-1.7)0.8 (0.6-1.0) Effectiveness and Abstinence Rates for Medications Compared With Placebo or Standard-Dose Nicotine Patch at 6-Months *Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. 12

13. Combination Therapies Patch (long-term; >14 weeks) + ad lib NRT (gum or spray) 336.5 (28.6-45.3)3.6 (2.5-5.2)1.9 (1.3-2.7) Patch + bupropion SR328.9 (23.5-35.1)2.5 (1.9-3.4)1.3 (1.0-1.8) Patch + nortriptyline227.3 (17.2-40.4)2.3 (1.3-4.2)0.9 (0.6-1.4) Patch + inhaler225.8 (17.4-36.5)2.2 (1.3-3.6)1.1 (0.7-1.9) MedicationArmsEstimated abstinence rate (95% CI) Estimated OR vs Placebo (95% CI) Estimated OR vs Nicotine patch* (95% CI) Effectiveness and Abstinence Rates for Medication Combinations Compared With Placebo or Standard-Dose Nicotine Patch at 6-Months * Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. 13

14. Combination Pharmacotherapy Sustained release NRT (patch) + Immediate release NRT –Provides steady nicotine level –Allows patient to respond to urges Medications with different targets –NRT + Bupropion SR –Varenicline + Bupropion SR? Monotherapy with immediate release NRT should be used rarely 14

15. COMBINATION THERAPY RCT of 1504 smokers in a research clinic Received 1 of 6 treatments for 8 weeks 6 brief counseling sessions 7-day point prevalence abstinence at 8 wks and 6 months Piper M, et al. Arch Gen Psychiat 2009;66:1253-62. 15

16. COMBINATION THERAPY RCT of 1346 smokers recruited from 12 primary care clinics in Wisconsin Received 1 of 5 active treatments for 8 weeks Referred for counseling via telephone “quitline” 7-day point prevalence at 8 wks and 6 months Smith SS, et al. Arch Intern Med 2009;169:2148-55 16

17. RCT of 127 smokers with known CVD, COPD, cancer, diabetes Compared triple combination (nicotine patch + bupropion + nicotine inhaler) to patch alone Triple therapy mean treatment duration 89 days Patch alone mean treatment duration 35 days At 6 months 7 day point prevalence abstinence: Triple therapy 35% Patch 19% (OR 2.57, 95% CI 1.05 to 6.32, p-value 0.04) TRIPLE COMBINATION THERAPY Steinberg MB, et al. Annals Intern Med 2009; 150:447-454. 17

18. USPHS Clinical Practice Guideline- 2008 Long-term Medication Use Smokers who report persistent withdrawal symptoms. Smokers who have had relapse after stopping medication. Smokers at higher risk for relapse –More dependent (>20 CPD; smokes w/in 30 minutes of waking) –Other smokers in household –Psychiatric comorbidity (includes substance abuse hx) Smokers who desire long-term therapy. Use does not present a known health risk. 18

19. How Long to Treat with NRT? Most patients want to stop NRT too soon We cannot predict who will have better outcomes with longer treatment Nicotine patch therapy for 6 months outperforms a standard 8 week treatment course Cost per additional quitter was $2482 (95% CI, $1519 to $6781) 19

20. Adherence to NRT Treatment Balmford J, et al. Nicotine & Tobacco Research 2011;13:94-102 Only 28.6% of NRT users completed the recommended 8 weeks of treatment Most quit prematurely because they believed the medication was not working, had unwanted side effects or believed that they no longer needed treatment. 20

21. Schnoll R A et al. Ann Intern Med 2010;152:144-151 ©2010 by American College of Physicians Nicotine patch 8 vs 24 weeks: RCT of 568 smokers 21

22. Bupropion SR Prolonged Treatment Hays JT, et al. Annals Intern Med 2001;135:423-433. N= 461 smokers Abstinent after 8 weeks of open label bupropion SR treatment Randomized to placebo or bupropion for additional 44 weeks (total 52 weeks of treatment) Bupropion compared with placebo at 12, 24 and 52 weeks p-value < 0.05 22

23. Varenicline Maintenance of Abstinence Study N=602 Varenicline N=604 Placebo N=602 Varenicline N=604 Placebo Wks 13–24 OR=2.47 p<0.0001 1.35 p=0.0126 Wks 13–52 OR= 70.6 44.0 Tonstad et al. JAMA 2006;296:64-71 23

24. Higher Dose Nicotine Patch There is a dose-response effect Long-term abstinence improved; RR of 1.15 (95% CI: 1.01 to 1.30)* Treatment-related AE’s are uncommon Withdrawal symptoms less with higher dose NRT *Cochrane Database of Systematic Reviews 2008 24

25. CotinineCigs per dayPatch dose <200 ng/ml< 1514-21 mg/d 200-300 ng/ml16-4021-35 mg/d >300 ng/ml> 4035-42+ mg/d Nicotine Patch Dose Based on Cotinine and CPD 25

26. Patch Dosing Schedule Use initial dose for 4-6 weeks Taper 7-14mg steps every 2-6 wks Length of therapy varies based on patient response Withdrawal symptoms while tapering are mild to nonexistent Advise using overnight 26

27. Take Home #1 Brief behavioral treatment is effective for treating tobacco dependence Pharmacotherapy is effective for treating tobacco dependence (NRT, bupropion, varenicline) Behavioral treatment and pharmacotherapy together are best Combination pharmacotherapy results in superior abstinence compared with single agent therapy for many smokers Use combinations in smokers who have tried and relapsed with monotherapy AND in smokers with important comorbidity 27

28. Take Home #2 Use pharmacotherapy for at least 12 weeks in everyone Consider higher doses of NRT for heavier smokers Treat those at risk for relapse for 6+ months –persistent strong urges to smoke –higher dependence –comorbid medical/psychiatric illness –past substance abuse –unable to quit on target date 28