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. WHY DO SMOKERS KEEP SMOKING? Pharmacologic nicotine dependence DOPAMINE

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

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

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

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 nEffective treatments n More is better but brief intervention works n Treating tobacco is highly cost-effective Counseling Pharmacotherapy Combination - better than either one alone

16. COUNSELING – Content nSmokers who want to quit nCognitive-behavioral counseling nSocial support nEncourage medication use and adherence nSmokers who are unwilling to quit nMotivational interviewing n Effective in meta-analysis, quit rates low

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

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 1 st Line - 2008 US Public Health Service Guidelines Nicotine replacement OR 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 Short-acting Intermediate onset → oral (gum, lozenge, inhaler) More rapid onset → nasal (spray) Constant nicotine level to avoid withdrawal Simplest to use, best compliance User has no control of dose 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  Reduces post-cessation weight gain  Quit rates higher if add counseling  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. OR 2.86 (95% CI,1.72, 4.11) p < 0.001 25 20 15 10 0 Continuous Abstinence (%) n = 355n = 359 19.2 7.2 OR: 3.14 (95% CI: 1.93 – 5.11) p < 0.0001 18.6 5.6 OR 4.04 (95% CI, 2.13, 7.67) p < 0.001 22.4 9.3 Stable CVD 1 n = 344n = 341 Healthy smokers 3 n = 248n = 251 COPD 2 Varenicline Placebo 5 Varenicline efficacy across studies Continuous Abstinence Rates (Weeks 9–52) 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 Drug Estimated OR (95% CI) Nicotine patch 1.0 (reference) Other nicotine products or bupropion Not significantly different from nicotine patch Varenicline 1.6 (1.3-2.0) Combinations Long-term patch + gum or nasal spray 1.9 (1.3-2.7) Patch + bupropion SR 1.3 (1.0-1.8)

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

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

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 ASKall patients about smoking ADVISEall 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. SMOKING CESSATION METHODS 2008 US Public Health Service Guidelines nEffective treatments n More is better but brief intervention works n Treating tobacco is highly cost-effective Counseling Pharmacotherapy Combination - better than either one alone

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