Nancy Rigotti, MD

1. Nancy Rigotti, MD Treatment Review: Overview of the Evidence Base for Tobacco Dependence Treatment 10/09/2011

2. OVERVIEW • Why is tobacco treatment necessary for global tobacco control? • Why do smokers keep smoking? • What smoking cessation treatments are effective? • Behavioral • Pharmacological • Role of health care providers

3. WHY TREATMENT MATTERS • Tobacco use is the #1 preventable cause of death • Stopping tobacco use reduces health risks • Tobacco prevention works slowly

4. CESSATON vs. PREVENTION

5. WHY TREATMENT MATTERS • Tobacco use is the #1 preventable cause of death • Stopping tobacco use reduces health risks • Tobacco prevention works slowly • Tobacco use is an addictive disorder • Tobacco treatment aids tobacco control policies overall (and vice versa)

6. MPOWER Report World Health Organization – 2008 • M onitor tobacco use and tobacco control policy • P rotect people from tobacco smoke • O ffer help to quit tobacco use • W arn about the dangers of tobacco • E nforce bans on tobacco advertising, promotion • R aise taxes on tobacco

7. OVERVIEW • Why is tobacco treatment necessary for global tobacco control? • Why do smokers keep smoking? • What smoking cessation treatments are effective? • Behavioral • Pharmacological • Role of health care providers

8. DOPAMINE WHY DO SMOKERS KEEP SMOKING? • Pharmacologic nicotine dependence

9. Irritability, anger, impatience Restlessness Difficulty concentrating Insomnia Anxiety Depressed mood Increased appetite WHY DO SMOKERS KEEP SMOKING? • Pharmacologic nicotine dependence→ Craving (nicotine “hunger”) →Nicotine withdrawal symptoms

10. WHY DO SMOKERS KEEP SMOKING? • Psychological factors • Cues(meals, alcohol, other smokers) • Coping with stress, emotions(anger) Pharmacologic nicotine dependence

11. WHY DO SMOKERS KEEP SMOKING? • Psychological factors • Psychiatric co-morbidity • Depression • Schizophrenia • Substance abuse Pharmacologic nicotine dependence

12. THE CHALLENGE FOR TREATMENT • We have effective treatments, but… • We need better treatments • We need to deliver the treatments we have to more of the smokers who need them

13. OVERVIEW • Why is tobacco treatment necessary for global tobacco control? • Why do smokers keep smoking? • What smoking cessation treatments are effective? • Behavioral • Pharmacological • Role of health care providers

14. LIMITATION OF OUR EVIDENCE • The evidence about treatment comes mostly from studies done in high-income countries • Few trials have been done in middle- or low-income countries • Less awareness of health risks • Fewer have tried to quit and failed • Biology is relatively constant • Cultural context varies by country

15. SMOKING CESSATION METHODS 2008 US Public Health Service Guidelines • Counseling • Pharmacotherapy Effective treatments • Combination - better than either one alone • More is better but brief intervention works • Treating tobacco is highly cost-effective

16. Smokers who want to quit Cognitive-behavioral counseling Social support Encourage medication use and adherence Smokers who are unwilling to quit Motivational interviewing Effective in meta-analysis, quit rates low COUNSELING – Content

17. In-person * - one-on-one or group By telephone * - proactive quitlines Self-help materials – little efficacy Newer technologies Web- based – evidence is growing but not definitive Text-messaging – 1 randomized trial (Lancet 2011) Social media – little evidence * Endorsed as effective by 2008 USPHS Guideline Update COUNSELING – Method of Delivery

18. TELEPHONE QUITLINES • Definition Proactive multi-session counseling by phone • Advantages Convenience Privacy • Effective (pooled OR 1.4, 95% CI 1.3-1.6)* • Quitlines can also provide medication Facilitate access to medications Strategy for promoting calls to a quitline *Stead LF et al. Tobacco Control 2007;16(suppl 1):i3

19. PHARMACOTHERAPY 1st Line - 2008 US Public Health Service Guidelines • Nicotine replacementOR • Skin patch 1.9 • Gum 1.5 • Oral inhaler 2.1 • Nasal spray 2.3 • Lozenge 2.0 • Bupropion SR(Zyban,Wellbutrin SR)2.0 • Varenicline (Chantix/Champix)3.1

20. PLASMA NICOTINE LEVELS Cigarettes vs. Nicotine Replacement Products

21. NICOTINE REPLACEMENT Long-acting, slow onset →skin patch • Constant nicotine level to avoid withdrawal • Simplest to use, best compliance • User has no control of dose Short-acting Intermediate onset → oral(gum, lozenge, inhaler) More rapid onset →nasal(spray) • User controls dose • Nicotine blood levels fluctuate more • Requires more training to use properly

22. New Ways to Use NICOTINE REPLACEMENT (Supported by evidence and USPHS*) • * Combine short- and long-acting forms “Patch plus” regimen • * Extend treatment to prevent relapse • Start NRT 2 weeks before quit date • Reduce to quit strategy

23. BUPROPION SR (Zyban, Wellbutrin SR) • Doubles cessation rate independent of its antidepressant effect • Quit rates higher if add counseling • Reduces post-cessation weight gain • Reduces seizure threshold (risk: 1/1000)

24. VARENICLINE • Binds selectively to the α4β2 nicotinic receptor, which mediates nicotine dependence • Dual mechanism of action • Partial agonist Stimulates receptor to treat craving, withdrawal • Antagonist Prevents nicotine from binding to the receptor → Blocks reward, reinforcement of smoking

25. Varenicline efficacy across studiesContinuous Abstinence Rates (Weeks 9–52) OR 2.86 (95% CI,1.72, 4.11) p < 0.001 OR 4.04 (95% CI, 2.13, 7.67) p < 0.001 OR: 3.14 (95% CI: 1.93 – 5.11) p < 0.0001 25 22.4 Varenicline Placebo 20 19.2 18.6 15 Continuous Abstinence (%) 9.3 10 7.2 5.6 5 0 n = 355 n = 359 n = 248 n = 251 n = 344 n = 341 Stable CVD 1 COPD 2 Healthy smokers 3 1 Rigotti et al, Circulation 2010; 2 Tashkin D et al. Chest 2010. 3 Gonzales et al., JAMA 2006; Jorenby et al., JAMA 2006.

26. FDA Public Health Advisory July 2009 • “Chantix (varenicline) or Zyban (bupropion) has been associated with reports of changes in behavior such as hostility, agitation, depressed mood, and suicidal thoughts or actions.”  • “FDA is requiring the manufacturers of both products to add a new Boxed Warning: People who are taking Chantix or Zyban and experience any serious and unusual changes in mood or behavior or who feel like hurting themselves or someone else should stop taking the medicine and call their healthcare professional right away. Friends or family members …”

27. VARENICLINE SAFETY The dilemma • Smokers have an increased risk of suicide. • Stopping smoking produces nicotine withdrawal symptoms (depressed mood, anxiety, and irritability) • When these symptoms occur in a smoker who is stopping smoking on varenicline, did the drug or did quitting smoking cause the symptom? • Case reports cannot answer this question. • Clinical trials of varenicline detected no excess of depression or suicidal thoughts, but these studies did not include patients with mental illness.

28. VARENICLINE SAFETY Cohort study (Gunnell et al, BMJ 2009) • UK General Practice Research Database • Population based data: 3.6 million patients in 500 practices • Data from electronic medical records • Patients starting smoking medication (9/06 – 5/08) • NRT (n=63,265) • Bupropion (n=6422) • Varenicline (n=10,973) • Outcome: rates of suicide, suicide attempt, suicidal thoughts, and new antidepressant therapy • Results: No evidence of increased risk of suicidal outcomes for varenicline vs NRT, bupropion vs NRT

29. VARENICLINE SAFETY My Bottom Line • Varenicline may increase risk of psychiatric symptoms in some patients. The potential risk is not yet well defined. • Prescribing varenicline, like prescribing any drug, requires balancing risks and benefits. - Varenicline is one of the most effective drugs available to treat tobacco dependence - Continuing to smoke is clearly hazardous • In most cases, the benefits of varenicline outweigh the risks

30. Which drug is most effective?Meta-analysis for 2008 USPHS Guideline

31. Varenicline vs bupropion vs placeboCO-Confirmed 4-Wk Continuous Quit Rates -Wks 9–12 100 OR=3.91* (95% CI 2.74, 5.59) OR=3.85*(95% CI 2.69, 5.50) 60 OR=1.96*(95% CI 1.42, 2.72) OR=1.89*(95% CI 1.37, 2.61) 40 44.0 44.4 Response Rate (%) 30.0 29.5 20 17.7 17.7 0 N=343 N=340 N=340 N=349 N=329 N=344 Study I Study II Varenicline Zyban Placebo *p<0.0001 Jorenby et al, Gonzales et al, JAMA, July 5, 2006

32. VARENICLINE vs. NICOTINE PATCHOpen label randomized controlled trial(5 countries, n= 746) 56 43 26 20 End of treatment OR 1.70 (1.26-2.28) Continuous abstinence OR 1.40 (0.99-1.99) Aubin HJ. Thorax 2008

33. 2 head-to-head randomized trials Piper, Arch Gen Psychiat 2009; Smith, Arch Int Med 2010 • Tested 5 drug treatments (vs placebo) • Monotherapy: Patch, lozenge, bupropion • Combos: Patch + lozenge, bupropion + lozenge • Tested drugs in 2 settings • Clinical trial (on-site counseling) • Primary care clinics (using state quitline) • Results • Each drug was better than placebo • Combinations > monotherapy • No 1 combination was better than the other in both trials

34. CYTISINE (Tabex) • Used for many years in Eastern Europe, Russia • Pharmacology is similar to varenicline • Binds selectively to the α4β2 nicotinic receptor • Cheaper than varenicline ($6 in Russia, $15 in Poland)* • Missing data: Is it effective (and safe)? • New large placebo controlled trial * • 740 adult smokers in Poland • 25 days of treatment (6 pills/day → 2 pills/day) • Validated abstinence at 1 yr : 8.4% vs 2.4% (p<.001) • 7-day abstinence at 1 yr: 13.2% vs 7.3% (p<.01) * West et al, NEJM 2011;365:1193

35. PHYSICIAN INTERVENTION • Routine advice to quit is effective  Odds of quitting by 66% (vs no advice) * • Brief counseling is more effective •  Odds of quitting by 37% (vs brief advice) * • Brief intervention by other clinicians is effective * Cochrane reviews

36. 5A BRIEF COUNSELING MODEL 2000 U.S. Public Health Service Guidelines • ASK all patients about smoking • ADVISE all smokers to quit • ASSESS smoker’s readiness to quit • ASSIST smokers to quit • ARRANGE follow-up care

37. 5A BRIEF COUNSELING MODEL 2000 U.S. Public Health Service Guidelines • ASK • ADVISE Core physician role • ASSESS • ASSIST • ARRANGE

38. 5A BRIEF COUNSELING MODEL 2000 U.S. Public Health Service Guidelines • ASK Done by office staff (‘vital sign’) • ADVISE Core physician role • ASSESS • ASSIST • ARRANGE

39. 5A BRIEF COUNSELING MODEL 2000 U.S. Public Health Service Guidelines • ASK Done by office staff • ADVISE Core physician role • ASSESS • ASSIST Connect to office or community • ARRANGE supports (clinics, quit lines,…)

40. TOBACCO USE BY HEALTH PROFESSIONALS A problem in many countries Health professionals act as role models Clinicians who smoke are less likely to counsel patients who smoke Treatment strategies must include cessation programs for health care professionals and students

41. Effective treatments SMOKING CESSATION METHODS 2008 US Public Health Service Guidelines • Counseling • Pharmacotherapy • Combination - better than either one alone • More is better but brief intervention works • Treating tobacco is highly cost-effective

42. FCTC Article 14 - Implementation World Health Organization Countries should offer 3 types of treatment • Advice to quit in primary health care • Telephone quit lines – free and accessible • Pharmacotherapies – low-cost and accessible

43. Thank You