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Tobacco Dependence: Hot Topics. Richard D. Hurt, M.D. Professor of Medicine Director, Mayo Clinic Nicotine Dependence Center rhurt@mayo.edu http://ndc.mayo.edu. Richard D Hurt MD Financial Disclosure 3/11. Current consulting (Scientific Advisory Boards) : GSK

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Tobacco Dependence: Hot Topics


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    1. Tobacco Dependence: Hot Topics Richard D. Hurt, M.D.Professor of MedicineDirector, Mayo Clinic Nicotine Dependence Center rhurt@mayo.edu http://ndc.mayo.edu

    2. Richard D Hurt MDFinancial Disclosure 3/11 • Current consulting (Scientific Advisory Boards) : GSK • Current Industry Grants: Pfizer Medical Education Grant • HAVE NOT AND WILL NEVER ACCEPT ANY MONEY FROM THE TOBACCO INDUSTRY

    3. Objectives • Neurobiology • Advanced Pharmacotherapy • Smokeless tobacco • New tobacco/nicotine delivery products

    4. Treating Tobacco Dependence in a Medical SettingBest Practices • USPHS Guideline (www.ahrq.gov) • Behavioral, addictions, pharmacologic treatment, and relapse prevention • Neurobiology of tobacco dependence • “Teachable moment” • Telephone quitlines and internet sites • Public policy-Taxes and smoke-free workplaces Hurt RD, et al CA Cancer J Clin 59:314, 2009

    5. Cigarettes and Tobacco Dependence • Cigarette smoke – complex mixture of 4,000 chemicals with over 60 known carcinogens • Most efficient delivery device for nicotine that exists- better than intravenous • Cigarette manufacturers have modified cigarettes over the past decades to maximize nicotine delivery to the brain • High doses of arterial nicotine cause upregulation of the nicotinic acetylcholine receptors • Genetic factors influence tobacco dependence • Left untreated 60% of smokers die from a tobacco-caused disease Hurt RD, Robertson CR JAMA 280:1173, 1998

    6. Perry, DC, et al. J Pharmacol Exp Ther, 289:1545, 1999

    7. Smoking Saturates Nicotinic Receptors MRI kBq/mL 9 0 Nondisplaceable 0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006

    8. USPHS Clinical Practice Guideline- 2008Pharmacotherapy • First line • nicotine gum • nicotine patch • nicotine lozenge • nicotine nasal spray • nicotine inhaler • bupropion • varenicline • combinations • Second line • clonidine • nortriptyline

    9. Treating Tobacco Dependence in a Medical SettingPharmacotherapy • Clinical decision-making using clinician skills and knowledge of pharmacology to decide on medication selection and doses • Patient involvement: past experience and/or preference • Nicotine patch, varenicline and/or bupropion viewed as “floor” medications • Short acting NRT products for withdrawal symptom control • Combination pharmacotherapy frequently used Hurt RD, et al CA Cancer J Clin 59:314, 2009

    10. Cotinine • Major metabolite of nicotine • Pharmacologically inactive • Quantitative marker of nicotine intake • Pre-abstinence levels correlate with withdrawal and treatment outcome • Half-life 18-20 hours

    11. Hurt RD, et al. Clin Pharmacol Ther 54:98-106, 1993

    12. Lawson GM, et al. J Clin Pharmacol 38:502-509, 1998

    13. High Dose Patch TherapyConclusions • High dose patch therapy safe for heavy smokers • Smoking rate or blood cotinine to estimate initial patch dose • Assess adequacy of nicotine replacement by patient response or percent replacement • More complete nicotine replacement improves withdrawal symptom relief • Higher percent replacement may increase efficacy of nicotine patch therapy Dale LC, et al. JAMA 274:1353, 1995

    14. Nicotine Patch Rx in Smokers with Perfusion Defect • 36 smokers all with reversible perfusion defect on exercise thallium • Mean smoking rate 31 cpd for 40 yrs • Rx 14 or 21mg nicotine patch → 74% ↓ in cpd • Initial perfusion defect 17.5 • ↓ size of perfusion defect to 12.6 and 11.8 % & ↓ CO ( Both P<0.001) Mahmarian, JJ et al, J Am Coll Cardiol 30:125, 1997

    15. Extended Nicotine Patch Therapy • 24 weeks (n= 287) vs 8 weeks (288) 21 mg/d dose • Similar smoking abstinence at week 8 • At week 24 point prevalence smoking abstinence 32% vs 20% (OR 1.81) • At week 52 prolonged smoking abstinence > with extended patch therapy (P=0.0270 • Delayed relapse to smoking with extended patch therapy Schnoll RA, et al Ann Int Med 152:144, 2010

    16. Schnoll RA, et al. Annals of Intern Med 2010; (152)3:149

    17. <10 cpd 7-14 mg/d 10-20 cpd 14-21 mg/d 21-40 cpd 21-42 mg/d >40 cpd 42+ mg/d High Dose Patch TherapyDosing Based on Smoking Rate Dale LC, et al. Mayo Clin Proc 75:1311, 1316, 2000

    18. High Dose Patch TherapyDose Based on Plasma Cotinine <200 ng/ml 14-21 mg/d 200-300 ng/ml 21-42 mg/d >300 ng/ml 42+ mg/d Dale LC, et al. JAMA 274:1353, 1995

    19. BupropionBackground • Monocyclic antidepressant • Inhibits reuptake of norepinephrine and dopamine • May inhibit nicotinic ACH receptor function • Mechanism in helping smokers stop is not clear • May attenuate weight gain in abstinent smokers

    20. BupropionSummary • Dose response efficacy in treating smokers • Attenuates weight gain • More effective than nicotine patch therapy • Delays relapse to smoking • Can be prescribed to diverse populations of smokers with expected comparable results Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003

    21. VareniclineMode of Action • Partial agonist with specificity for the α4B2 nicotine acetylcholine receptor • Agonist action: stimulates the nACHr to ↓ nicotine withdrawal • Antagonist action: blocks the nACHr to ↓ the reinforcing effect of smoking

    22. Varenicline vs. Bupropion vs. Placebo Jorenby, D.E., et. al. JAMA; 296:56-63, 2006

    23. VareniclineLong-Term Safety Trial • Smokers randomized to varenicline 1 mg BID (N=251) or placebo (N=126) for 52 wks. • 95 varenicline treated and 43 placebo treated subjects completed 52 wks. • Nausea most frequent AE in varenicline treated group • Smoking abstinence 3-4 x greater in varenicline compared to placebo Williams KE et al, Curr Med Res and Opin 23:793, 2007

    24. Long-Term Safety TrialVarenicline Williams KE et al, Curr Med Res and Opin 23:793, 2007

    25. Varenicline vs. Bupropion vs. PlaceboSide Effects

    26. Varenicline for Smokers with Cardiovascular Disease • For smokers with coronary heart disease stopping smoking decreases all cause mortality by 36% • Randomized double-blind placebo controlled trial in 714 smokers with stable cardiovascular disease • Mean age 56, 78% male, 22 CPD, 40 years of smoking, FTND 5.7 • EOT continuous smoking abstinence- 47% vs 14% (OR 6.11, CI 4.18-8.93) Rigotti, NA et al Circ 121:221, 2010

    27. Seven-day point prevalence tobacco abstinence rates Rigotti NA et al. Circulation 121:221, 2010

    28. Varenicline for Smokers with COPD • LHS showed 50% ↓ in rate of age related decline of FEV1 for those who stopped smoking • Randomized placebo controlled trial in 504 smokers with mild-moderate COPD • Mean age 57, 625 male, 24-25 cpd, 40 years of smoking, FTND 6 • EOT continuous smoking abstinence- 42% vs 9% (OR 8.4, CI 4.99- 14.14 Tashkin, DP et al Chest 139:591, 2011

    29. Tashkin DP, et al. Chest 139:151, 2011

    30. Varenicline vs. Nicotine Patch Therapy • Open-label trial of varenicline (N=376) vs. 21 mg nicotine patch (N=370) • Varenicline ↓ withdrawal, ↓ craving, and ↓ smoking satisfaction better than nicotine patch • Nausea most frequent AE: varenicline 37% vs. nicotine patch 9.7% Aubin HJ, et al. Thorax 63:717, 2008.

    31. Aubin HJ, et al. Thorax 63:717, 2008.

    32. Varenicline vs. NRT in Smokers With Mental Illness • Group program of National Health Service Tobacco Dependence Clinic in London • Total of 412 participants receiving routine care. NRT (N=204) varenicline (N=208) • Short-term (4 weeks post quit day) smoking abstinence higher (72% vs. 61%) in varenicline vs. NRT (OR 1.70 CI 1.09-2.67) • Cravings were less severe in varenicline subjects • No exacerbation of mental illness symptoms Stapleton JA, et al. Addiction 103:146, 2007

    33. Flexible Dosing Study • Randomized clinical trial varenicline(n=157) vs placebo(n=155) • Week 1 dose titrated up from 0.5mg/d to 1 mg/d • Weeks 2 through 12 self-regulated dosing of 0.5 to 2mg/d • Mean dose/d 1.35mg for varenicline and 1.63 for placebo • Insomnia(22%),HA(16%), Nausea(13%) most common AE’s for varenicline Niaura R et al. Curr Med Res Opin 24:1931,2008

    34. Flexible Dosing Study Niaura R et al. Curr Med Res Opin 24:1931,2008

    35. Varenicline plus Bupropion • Open label pilot study in 38 smokers • Mean age 49 years, smoking 20 CPD for 30 years • 12 weeks of varenicline and bupropion SR • Smoking abstinence at EOT 71% and at 6 months 58% • Sleep distrubance 26% and nausea 24% Ebbert, JO et al, Nic & Tob Res, 3:234, 2009

    36. Varenicline & NRT • Residential Treatment Program patients treated before (n=135) & after (n=104) August 2006 • In “after” patients71% used nicotine patch therapy at mean dose of 32 mg/d and 73% used 2 types of NRT • Adverse events in 59% in “before” vs 39% in “after” patients • No difference in smoking abstinence at 6 months- 59% vs 54% Ebbert JO et al, Nic & Tob Res 5:572, 2009

    37. Varenicline: FDA Warning “All patients being treated with Chantix should be observed for neuropsychiatric symptoms including changes in behavior, agitation, depressed mood, suicidal ideation, and suicidal behavior. These symptoms, as well as worsening of pre-existing psychiatric illness, have been reported in patients attempting to quit smoking while taking Chantix…”

    38. Varenicline and Neuropsychiatric Symptoms • Advise patients and family members that this has been observed • Ask patients and/or family to report any symptoms like this to you • Patients with serious psychiatric comorbidity were not included in clinical trials • No cause and effect relationship has been established

    39. VareniclineSummary • First selective α4B2 partial agonist • Effective in initiating smoking abstinence and longer term use improves long term smoking abstinence • Nausea is a frequent but mild side effect • To date appears to be safe and effective • First line pharmacotherapy • Possible combination use- bupropion

    40. Triple Pharmacotherapy In Medically Ill Smokers • RCT nicotine patch (10 wks) vs nicotine patch + bupropion + nicotine inhaler (flexible duration) • Mean medication use: 35 d vs 89 d • Time to relapse: 23 d vs 65 d • AE generated discontinuance same in both groups • Smoking Abstinence at 6 months: 35% vs 19% Steinberg MB et al, Ann Intern Med, 150: 447, 2009

    41. Treating Tobacco Dependence in a Medical SettingPharmacotherapy • Clinical decision-making using clinician skills and knowledge of pharmacology to decide on medication selection and doses • Patient involvement: past experience and/or preference • Nicotine patch, varenicline and/or bupropion viewed as “floor” medications • Short acting NRT products for withdrawal symptom control • Combination pharmacotherapy frequently used Hurt RD, et al CA Cancer J Clin 59:314, 2009

    42. Nicotine Patch for ST Users Study • 42 ST users • Randomized to: • Placebo • 21 mg/d • 42 mg/d • 63 mg/d Ebbert et al., NTR, 2007

    43. Median Serum Nicotine Concentration According to Patch Dose 63 mg 42 mg 21 mg Placebo ng/mL AM PM AM PM AM PM Day 1 Day 2 Day 3 Ad lib ST use Patch Ebbert et al., NTR, 2007 CP1189473-2

    44. High Dose Nicotine Patch: Abstinence Rates Point Prevalence Abstinence 6 months, biochemically-confirmed

    45. Varenicline for ST Users • Randomized placebo-controlled trial of varenicline in 76 chewers • Mean age 41, all men, mean ST use 3-4 cans/pouches/week, FTND – ST 5 • EOT 7-day point prevalence tobacco abstinence 55.3% vs 42.1% (P=0.126) and 6 months 47.4% vs 31.6% (P=0.08) • ↓ craving in varenicline group Ebbert JO, et al NTR

    46. Varenicline for ST Users • 431 Snus users (Norway and Sweden) • Double blind placebo-controlled trial of varenicline • 12 weeks of Rx with f/u to 26 weeks • 90% men, average age 44yrs, average use 15x/day • ↑ EOT tobacco abstinence with varenicline 59% vs 39% p= 0.001 Fagerstrom KO, et al BMJ 341: c6549, 2010

    47. Recommended ST Treatment Approach 1) Behavioral treatment Telephone support (Quitline/support calls) +/- oral (self) examination +/- oral replacement products 2) Bupropion SR • Weight gain prevention • Craving reduction 3) Tailored nicotine patch therapy +/- lozenge/gum for self-titration 4) Varenicline