Tobacco Dependence: Hot Topics Richard D. Hurt, M.D. Professor of Medicine Director, Mayo Clinic Nicotine Dependence Center

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

Objectives Neurobiology Neurobiology Advanced Pharmacotherapy Advanced Pharmacotherapy Smokeless tobacco Smokeless tobacco New tobacco/nicotine delivery products New tobacco/nicotine delivery products

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

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

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

Smoking Saturates Nicotinic Receptors Brody, A.L. Arch Gen Psychiatry. 63; , Cigarette0.1 Cigarette0.3 Cigarette1.0 Cigarette3.0 Cigarette kBq/mL 9 0 Nondisplaceable MRI

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

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

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

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

Lawson GM, et al. J Clin Pharmacol 38: , 1998

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

Nicotine Patch Rx in Smokers with Perfusion Defect 36 smokers all with reversible perfusion defect on exercise thallium 36 smokers all with reversible perfusion defect on exercise thallium Mean smoking rate 31 cpd for 40 yrs Mean smoking rate 31 cpd for 40 yrs Rx 14 or 21mg nicotine patch → 74% ↓ in cpd Rx 14 or 21mg nicotine patch → 74% ↓ in cpd Initial perfusion defect 17.5 Initial perfusion defect 17.5 ↓ size of perfusion defect to 12.6 and 11.8 % & ↓ CO ( Both P<0.001) ↓ 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

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

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

High Dose Patch Therapy Dosing Based on Smoking Rate <10 cpd7-14 mg/d cpd14-21 mg/d cpd21-42 mg/d >40 cpd42+ mg/d Dale LC, et al. Mayo Clin Proc 75:1311, 1316, 2000

High Dose Patch Therapy Dose Based on Plasma Cotinine <200 ng/ml14-21 mg/d ng/ml21-42 mg/d >300 ng/ml42+ mg/d Dale LC, et al. JAMA 274:1353, 1995

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

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

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

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

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

Long-Term Safety Trial Varenicline Williams KE et al, Curr Med Res and Opin 23:793, 2007

Varenicline vs. Bupropion vs. Placebo Side Effects Varenicline vs. Bupropion vs. Placebo Side Effects VareniclineN=692BupropionN=669PlaceboN=684 Nausea28%10%9% Headache14%11%12% Insomnia14%22%13% Abnormal Dreams 12%6%5% Dry Mouth 6%8%4% Discontinuation because of AE’s 10%14%8%

Varenicline for Smokers with Cardiovascular Disease For smokers with coronary heart disease stopping smoking decreases all cause mortality by 36% 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 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 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 ) EOT continuous smoking abstinence- 47% vs 14% (OR 6.11, CI ) Rigotti, NA et al Circ 121:221, 2010

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

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

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

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

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

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

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

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

Varenicline & NRT Residential Treatment Program patients treated before (n=135) & after (n=104) August 2006 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 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 Adverse events in 59% in “before” vs 39% in “after” patients No difference in smoking abstinence at 6 months- 59% vs 54% No difference in smoking abstinence at 6 months- 59% vs 54% Ebbert JO et al, Nic & Tob Res 5:572, 2009

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…”

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

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

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

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

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

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

High Dose Nicotine Patch: Abstinence Rates Placebo 21 mg 42 mg 63 mg 2/11 (18%) 2/10 (20%) 3/11 (27%) 4/10 (40%) Point Prevalence Abstinence 6 months, biochemically-confirmed

Varenicline for ST Users Randomized placebo-controlled trial of varenicline in 76 chewers 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 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) 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 ↓ craving in varenicline group Ebbert JO, et al NTR Ebbert JO, et al NTR

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

© 2011 Mayo Foundation for Medical Education and Research. All Rights Reserved. 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 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

Anatomy of a Waterpipe

Types of Waterpipe Tobacco Maasel/Mu’essel: Combination of tobacco and molasses, honey or fruit Tumbak/Ajami: Dark tobacco paste Jurak: Combination of tobacco and fruits, oils, honey or molasses. Moist tobacco  requires charcoal to keep burning Maasel/Mu’essel: Combination of tobacco and molasses, honey or fruit Tumbak/Ajami: Dark tobacco paste Jurak: Combination of tobacco and fruits, oils, honey or molasses. Moist tobacco  requires charcoal to keep burning Source: Knishkowy & Amitai. (2005). Pediatrics, 116, e113-e119.

Waterpipe - Health Effects 1-hour session involves inhaling times volume of smoke from a single cigarette Smoke contains CO, heavy metals, and carcinogens Charcoal added to keep tobacco burning increases health risks Sharing = tuberculosis & hepatitis 1-hour session involves inhaling times volume of smoke from a single cigarette Smoke contains CO, heavy metals, and carcinogens Charcoal added to keep tobacco burning increases health risks Sharing = tuberculosis & hepatitis WHO. TobReg Advisory Note. Waterpipe Tobacco Smoking Google: “ who tobreg water pipe”

Toxicant Exposure to Waterpipe vs Cigarette Smoking 54 subjects completed 2 sessions each 45 minutes long 54 subjects completed 2 sessions each 45 minutes long Mean smoking time- waterpipe episode 43 minutes vs cigarette 6.1 minutes Mean smoking time- waterpipe episode 43 minutes vs cigarette 6.1 minutes Plasma nicotine – waterpipe 9.8 ng/mL vs cigarette 9.4 ng/mL Plasma nicotine – waterpipe 9.8 ng/mL vs cigarette 9.4 ng/mL COHb – waterpipe 4.5% vs cigarette 1.2% COHb – waterpipe 4.5% vs cigarette 1.2% ↑ C0 – waterpipe 32.9 ppm vs cigarette 7.4 ppm ↑ C0 – waterpipe 32.9 ppm vs cigarette 7.4 ppm Cobb CO, et al NTR 13:78, 2011

© 2010 Mayo Foundation for Medical Education and Research. All Rights Reserved. Electronic Nicotine Delivery Systems aka “E-cigarettes”

© 2010 Mayo Foundation for Medical Education and Research. All Rights Reserved. “Vaping”

© 2010 Mayo Foundation for Medical Education and Research. All Rights Reserved. E Cigarette Basic Structure

© 2010 Mayo Foundation for Medical Education and Research. All Rights Reserved. “E-Juice” or “Smoke Juice” Total nicotine = 720 mg Lethal nicotine dose = 40–60 mg ( mg/kg) Total nicotine = 720 mg Lethal nicotine dose = 40–60 mg ( mg/kg)

© 2010 Mayo Foundation for Medical Education and Research. All Rights Reserved. Vansickel, AR et al Cancer Epidemiol Biomarkers Prev 19:1945, 2010 Crown 7 Hydro Njoy NPRO

Center for Tobacco-Free Living

Started smoking as a teenager Started smoking as a teenager 1987 Non-healing toe ulcerations 1987 Non-healing toe ulcerations 30 CPD 30 CPD Dx Buerger’s Disease 1988 Thoracic Sympathectomy 1988 Thoracic Sympathectomy 1989 Amputation, right 5 th toe 1989 Amputation, right 5 th toe Auto amputation, right thumb Auto amputation, right thumb Stopped smoking (5 years) 2000 Hazelden Alcohol/drug Dependence Treatment 2000 Hazelden Alcohol/drug Dependence Treatment 50 y/o man with Buerger’s Disease

2002 Residential Treatment at NDC 2002 Residential Treatment at NDC (20 CPD) Ulcerations right heel & right lateral malleolus “Like someone pounding nails in my leg and foot” Bupropion started before admission Nicotine patch therapy at 35 mg/d 50 y/o man with Buerger’s Disease cont.

Reluctant to use two patches Baseline serum cotinine 300 ng/mL Steady state cotinine 188 ng/mL or 21 mg/d patch Eventually ↑ patch dose to 35 mg and then to 42 mg/d → much improved – less withdrawal Eventually ↑ patch dose to 35 mg and then to 42 mg/d → much improved – less withdrawal 50 y/o man with Buerger’s Disease cont.

Post Residential Treatment Post Residential Treatment Continued 42 mg/d nicotine patch dose for 6 weeks then slowly tapered Continued bupropion for 2 years Panelist at our Conference May 2010 Panelist at our Conference May 2010 Still abstinent from smoking 50 y/o man with Buerger’s Disease cont.