Tobacco Dependence: Hot Topics Tobacco Dependence: Hot Topics Richard D. Hurt, M.D. Richard D. Hurt, M.D. Professor of Medicine Professor of Medicine Director, Mayo Clinic Director, Mayo Clinic Nicotine Dependence Center Nicotine Dependence Center [email protected][email protected]http://ndc.mayo.edu http://ndc.mayo.edu
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Tobacco Dependence: Hot Topics Richard D. Hurt, M.D. Professor of Medicine Director, Mayo Clinic Nicotine Dependence Center [email protected].
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Tobacco Dependence: Hot TopicsTobacco Dependence: Hot Topics
Richard D. Hurt, M.D.Richard D. Hurt, M.D.Professor of MedicineProfessor of Medicine
Director, Mayo Clinic Nicotine Director, Mayo Clinic Nicotine Dependence Center Dependence Center
• Behavioral, addictions, pharmacologic Behavioral, addictions, pharmacologic treatment, and relapse preventiontreatment, and relapse prevention
• Neurobiology of tobacco dependenceNeurobiology of tobacco dependence
• ““Teachable moment”Teachable moment”
• Telephone quitlines and internet sitesTelephone quitlines and internet sites
• Public policy-Taxes and smoke-free Public policy-Taxes and smoke-free workplacesworkplacesHurt RD, et al CA Cancer J Clin 59:314, 2009Hurt RD, et al CA Cancer J Clin 59:314, 2009
Cigarettes and Tobacco DependenceCigarettes and Tobacco Dependence
• Cigarette smoke – complex mixture of 4,000 Cigarette smoke – complex mixture of 4,000 chemicals with over 60 known carcinogenschemicals with over 60 known carcinogens
• Most efficient delivery device for nicotine that Most efficient delivery device for nicotine that exists- better than intravenousexists- better than intravenous
• Cigarette manufacturers have modified cigarettes Cigarette manufacturers have modified cigarettes over the past decades to maximize nicotine over the past decades to maximize nicotine delivery to the braindelivery to the brain
• High doses of arterial nicotine cause upregulation High doses of arterial nicotine cause upregulation of the nicotinic acetylcholine receptorsof the nicotinic acetylcholine receptors
• Second lineSecond line• clonidineclonidine• nortriptylinenortriptyline
Treating Tobacco Dependence in a Treating Tobacco Dependence in a Medical SettingMedical SettingPharmacotherapyPharmacotherapy
• Clinical decision-making using clinician skills Clinical decision-making using clinician skills and knowledge of pharmacology to decide on and knowledge of pharmacology to decide on medication selection and dosesmedication selection and doses
• Patient involvement: past experience and/or Patient involvement: past experience and/or preferencepreference
• Nicotine patch, varenicline and/or bupropion Nicotine patch, varenicline and/or bupropion viewed as “floor” medicationsviewed as “floor” medications
• Short acting NRT products for withdrawal Short acting NRT products for withdrawal symptom controlsymptom control
• Combination pharmacotherapy frequently usedCombination pharmacotherapy frequently usedHurt RD, et al CA Cancer J Clin 59:314, 2009Hurt RD, et al CA Cancer J Clin 59:314, 2009
CotinineCotinine
• Major metabolite of nicotineMajor metabolite of nicotine
• Quantitative marker of nicotine intakeQuantitative marker of nicotine intake
• Pre-abstinence levels correlate with Pre-abstinence levels correlate with withdrawal and treatment outcomewithdrawal and treatment outcome
• Half-life 18-20 hoursHalf-life 18-20 hours
Hurt RD, et al. Clin Pharmacol Ther 54:98-106, 1993Hurt RD, et al. Clin Pharmacol Ther 54:98-106, 1993
Lawson GM, et al. J Clin Pharmacol 38:502-509, 1998Lawson GM, et al. J Clin Pharmacol 38:502-509, 1998
High Dose Patch TherapyHigh Dose Patch TherapyConclusionsConclusions
• High dose patch therapy safe for heavy smokersHigh dose patch therapy safe for heavy smokers
• Smoking rate or blood cotinine to estimate Smoking rate or blood cotinine to estimate initial patch doseinitial patch dose
• Assess adequacy of nicotine replacement by Assess adequacy of nicotine replacement by patient response or percent replacementpatient response or percent replacement
• More complete nicotine replacement improves More complete nicotine replacement improves withdrawal symptom reliefwithdrawal symptom relief
• Higher percent replacement may increase Higher percent replacement may increase efficacy of nicotine patch therapyefficacy of nicotine patch therapy
Dale LC, et al. JAMA 274:1353, 1995Dale LC, et al. JAMA 274:1353, 1995
Nicotine Patch Rx in Smokers with Nicotine Patch Rx in Smokers with Perfusion DefectPerfusion Defect
• 36 smokers all with reversible 36 smokers all with reversible perfusion defect on exercise thallium perfusion defect on exercise thallium
• Mean smoking rate 31 cpd for 40 yrsMean smoking rate 31 cpd for 40 yrs
• Rx 14 or 21mg nicotine patch Rx 14 or 21mg nicotine patch → 74% → 74% ↓ ↓ in cpdin cpd
• Inhibits reuptake of norepinephrine and Inhibits reuptake of norepinephrine and dopaminedopamine
• May inhibit nicotinic ACH receptor May inhibit nicotinic ACH receptor functionfunction
• Mechanism in helping smokers stop is Mechanism in helping smokers stop is not clearnot clear
• May attenuate weight gain in abstinent May attenuate weight gain in abstinent smokerssmokers
BupropionBupropionSummarySummary
• Dose response efficacy in treating Dose response efficacy in treating smokerssmokers
• Attenuates weight gainAttenuates weight gain
• More effective than nicotine patch therapyMore effective than nicotine patch therapy
• Delays relapse to smokingDelays relapse to smoking
• Can be prescribed to diverse populations Can be prescribed to diverse populations of smokers with expected comparable of smokers with expected comparable resultsresults
Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003
VareniclineVareniclineMode of ActionMode of Action
• PPartial agonist with specificity for the artial agonist with specificity for the αα4B2 4B2 nicotine acetylcholine receptornicotine acetylcholine receptor
• Agonist action: stimulates the nACHr Agonist action: stimulates the nACHr to to ↓ nicotine withdrawal↓ nicotine withdrawal
• Antagonist action: blocks the nACHr Antagonist action: blocks the nACHr to to ↓ the reinforcing effect of smoking↓ the reinforcing effect of smoking
Varenicline vs. Bupropion vs. PlaceboVarenicline vs. Bupropion vs. Placebo
• Smokers randomized to varenicline 1 mg BID Smokers randomized to varenicline 1 mg BID (N=251) or placebo (N=126) for 52 wks. (N=251) or placebo (N=126) for 52 wks.
Williams KE et al, Curr Med Res and Opin 23:793, 2007Williams KE et al, Curr Med Res and Opin 23:793, 2007
Varenicline vs. Bupropion vs. PlaceboVarenicline vs. Bupropion vs. PlaceboSide EffectsSide Effects
VareniclineVarenicline
N=692N=692
BupropionBupropion
N=669N=669
PlaceboPlacebo
N=684N=684
NauseaNausea 28%28% 10%10% 9%9%
HeadacheHeadache 14%14% 11%11% 12%12%
InsomniaInsomnia 14%14% 22%22% 13%13%
Abnormal Abnormal DreamsDreams 12%12% 6%6% 5%5%
Dry MouthDry Mouth 6%6% 8%8% 4%4%
Discontinuation Discontinuation because of AE’sbecause of AE’s 10%10% 14%14% 8%8%
Varenicline for Smokers with Varenicline for Smokers with Cardiovascular DiseaseCardiovascular Disease
• For smokers with coronary heart disease For smokers with coronary heart disease stopping smoking stopping smoking decreases all cause decreases all cause mortality by 36%mortality by 36%
• Randomized double-blind placebo Randomized double-blind placebo controlled trial in 714 smokers with stable controlled trial in 714 smokers with stable cardiovascular diseasecardiovascular disease
• Mean age 56, 78% male, 22 CPD, 40 years Mean age 56, 78% male, 22 CPD, 40 years of smoking, FTND 5.7of smoking, FTND 5.7
• EOT continuous smoking abstinence- 47% EOT continuous smoking abstinence- 47% vs 14% (OR 6.11, CI 4.18-8.93)vs 14% (OR 6.11, CI 4.18-8.93)
Rigotti, NA et al Circ 121:221, 2010Rigotti, 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 COPDVarenicline for Smokers with COPD
• LHS showed 50% LHS showed 50% ↓ in rate of age ↓ in rate of age related decline of FEV1 for those who related decline of FEV1 for those who stopped smokingstopped smoking
• Randomized placebo controlled trial Randomized placebo controlled trial in 504 smokers with mild-moderate in 504 smokers with mild-moderate COPDCOPD
• Mean age 57, 625 male, 24-25 cpd, 40 Mean age 57, 625 male, 24-25 cpd, 40 years of smoking, FTND 6years of smoking, FTND 6
• EOT continuous smoking abstinence- EOT continuous smoking abstinence- 42% vs 9% (OR 8.4, CI 4.99- 14.1442% vs 9% (OR 8.4, CI 4.99- 14.14
Tashkin, DP et al Chest 139:591, Tashkin, DP et al Chest 139:591, 20112011
Tashkin DP, et al. Chest 139:151, 2011
Varenicline vs. Nicotine Patch TherapyVarenicline vs. Nicotine Patch Therapy
• Open-label trial of varenicline (N=376) vs. 21 mg Open-label trial of varenicline (N=376) vs. 21 mg nicotine patch (N=370)nicotine patch (N=370)
• Varenicline Varenicline ↓↓ withdrawal, withdrawal, ↓ ↓ craving, and craving, and ↓↓ smoking satisfaction better than nicotine patch smoking satisfaction better than nicotine patch
• Nausea most frequent AE: varenicline 37% vs. Nausea most frequent AE: varenicline 37% vs. nicotine patch 9.7%nicotine patch 9.7%
Aubin HJ, et al. Thorax 63:717, 2008. Aubin HJ, et al. Thorax 63:717, 2008.
Aubin HJ, et al. Thorax 63:717, 2008. Aubin HJ, et al. Thorax 63:717, 2008.
Varenicline vs. NRT in Smokers With Varenicline vs. NRT in Smokers With Mental IllnessMental Illness
• Group program of National Health Service Tobacco Group program of National Health Service Tobacco Dependence Clinic in LondonDependence Clinic in London
• Total of 412 participants receiving routine care. Total of 412 participants receiving routine care. NRT (N=204) varenicline (N=208)NRT (N=204) varenicline (N=208)
• Short-term (4 weeks post quit day) smoking Short-term (4 weeks post quit day) smoking abstinence higher (72% vs. 61%) in varenicline vs. abstinence higher (72% vs. 61%) in varenicline vs. NRT (OR 1.70 CI 1.09-2.67)NRT (OR 1.70 CI 1.09-2.67)
• Cravings were less severe in varenicline subjectsCravings were less severe in varenicline subjects
• No exacerbation of mental illness symptomsNo exacerbation of mental illness symptoms
Stapleton JA, et al. Addiction 103:146, 2007 Stapleton JA, et al. Addiction 103:146, 2007
Flexible Dosing StudyFlexible Dosing Study
• Randomized clinical trial Randomized clinical trial varenicline(n=157) vs placebo(n=155)varenicline(n=157) vs placebo(n=155)
• Week 1 dose titrated up from 0.5mg/d to Week 1 dose titrated up from 0.5mg/d to 1 mg/d1 mg/d
• Weeks 2 through 12 self-regulated Weeks 2 through 12 self-regulated dosing of 0.5 to 2mg/ddosing of 0.5 to 2mg/d
• Mean dose/d 1.35mg for varenicline and Mean dose/d 1.35mg for varenicline and 1.63 for placebo1.63 for placebo
• Insomnia(22%),HA(16%), Nausea(13%) Insomnia(22%),HA(16%), Nausea(13%) most common AE’s for vareniclinemost common AE’s for varenicline
Niaura R et al. Curr Med Res Opin 24:1931,2008
Flexible Dosing StudyFlexible Dosing Study
Niaura R et al. Curr Med Res Opin 24:1931,2008
Varenicline plus BupropionVarenicline plus Bupropion• Open label pilot study in 38 smokersOpen label pilot study in 38 smokers
• Mean age 49 years, smoking 20 CPD Mean age 49 years, smoking 20 CPD for 30 yearsfor 30 years
• 12 weeks of varenicline and 12 weeks of varenicline and bupropion SRbupropion SR
• Smoking abstinence at EOT 71% and Smoking abstinence at EOT 71% and at 6 months 58%at 6 months 58%
• Sleep distrubance 26% and nausea Sleep distrubance 26% and nausea 24%24%
Ebbert, JO et al, Nic & Tob Res, 3:234, 2009Ebbert, JO et al, Nic & Tob Res, 3:234, 2009
Varenicline & NRTVarenicline & NRT• Residential Treatment Program Residential Treatment Program
patients treated before (n=135) & patients treated before (n=135) & after (n=104) August 2006after (n=104) August 2006
• In “after” patients71% used nicotine In “after” patients71% used nicotine patch therapy at mean dose of 32 patch therapy at mean dose of 32 mg/d and 73% used 2 types of NRTmg/d and 73% used 2 types of NRT
• Adverse events in 59% in “before” vs Adverse events in 59% in “before” vs 39% in “after” patients39% in “after” patients
• No difference in smoking abstinence No difference in smoking abstinence at 6 months- 59% vs 54%at 6 months- 59% vs 54%
Ebbert JO et al, Nic & Tob Res 5:572, 2009Ebbert JO et al, Nic & Tob Res 5:572, 2009
Varenicline: FDA WarningVarenicline: FDA Warning
““All patients being treated with Chantix All patients being treated with Chantix should be observed for should be observed for neuropsychiatric symptoms including neuropsychiatric symptoms including changes in behavior, agitation, changes in behavior, agitation, depressed mood, suicidal ideation, depressed mood, suicidal ideation, and suicidal behavior. These and suicidal behavior. These symptoms, as well as worsening of symptoms, as well as worsening of pre-existing psychiatric illness, have pre-existing psychiatric illness, have been reported in patients attempting been reported in patients attempting to quit smoking while taking to quit smoking while taking Chantix…Chantix…””
Varenicline and Neuropsychiatric SymptomsVarenicline and Neuropsychiatric Symptoms
• Advise patients and family members that Advise patients and family members that this has been observedthis has been observed
• Ask patients and/or family to report any Ask patients and/or family to report any symptoms like this to yousymptoms like this to you
• Patients with serious psychiatric Patients with serious psychiatric comorbidity were not included in clinical comorbidity were not included in clinical trialstrials
• No cause and effect relationship has been No cause and effect relationship has been establishedestablished
VareniclineVareniclineSummarySummary
• First selective First selective αα4B2 partial agonist4B2 partial agonist
• Effective in initiating smoking abstinence and Effective in initiating smoking abstinence and longer term use improves long term smoking longer term use improves long term smoking abstinenceabstinence
• Nausea is a frequent but mild side effectNausea is a frequent but mild side effect
• To date appears to be safe and effectiveTo date appears to be safe and effective
• First line pharmacotherapyFirst line pharmacotherapy
• Possible combination use- bupropion Possible combination use- bupropion
Triple Pharmacotherapy In Medically Ill Triple Pharmacotherapy In Medically Ill Smokers Smokers
• Mean medication use: 35 d vs 89 dMean medication use: 35 d vs 89 d
• Time to relapse: 23 d vs 65 dTime to relapse: 23 d vs 65 d
• AE generated discontinuance same AE generated discontinuance same in both groupsin both groups
• Smoking Abstinence at 6 months: Smoking Abstinence at 6 months: 35% vs 19% 35% vs 19%
Steinberg MB et al, Ann Intern Med, 150: 447, 2009Steinberg MB et al, Ann Intern Med, 150: 447, 2009
Treating Tobacco Dependence in a Treating Tobacco Dependence in a Medical SettingMedical SettingPharmacotherapyPharmacotherapy
• Clinical decision-making using clinician skills Clinical decision-making using clinician skills and knowledge of pharmacology to decide on and knowledge of pharmacology to decide on medication selection and dosesmedication selection and doses
• Patient involvement: past experience and/or Patient involvement: past experience and/or preferencepreference
• Nicotine patch, varenicline and/or bupropion Nicotine patch, varenicline and/or bupropion viewed as “floor” medicationsviewed as “floor” medications
• Short acting NRT products for withdrawal Short acting NRT products for withdrawal symptom controlsymptom control
• Combination pharmacotherapy frequently usedCombination pharmacotherapy frequently usedHurt RD, et al CA Cancer J Clin 59:314, 2009Hurt RD, et al CA Cancer J Clin 59:314, 2009
Nicotine Patch for ST Users StudyNicotine Patch for ST Users Study
• Randomized placebo-controlled trial Randomized placebo-controlled trial of varenicline in 76 chewersof varenicline in 76 chewers
• Mean age 41, all men, mean ST use 3-Mean age 41, all men, mean ST use 3-4 cans/pouches/week, FTND – ST 54 cans/pouches/week, FTND – ST 5
• EOT 7-day point prevalence tobacco EOT 7-day point prevalence tobacco abstinence 55.3% vs 42.1% (P=0.126) abstinence 55.3% vs 42.1% (P=0.126) and 6 months 47.4% vs 31.6% and 6 months 47.4% vs 31.6% (P=0.08)(P=0.08)
• ↓↓ craving in varenicline groupcraving in varenicline group
Ebbert JO, et al NTR Ebbert JO, et al NTR
Varenicline for ST Users Varenicline for ST Users
• 431 Snus users (Norway and 431 Snus users (Norway and Sweden) Sweden)
Steady state cotinine 188 ng/mL or 21 Steady state cotinine 188 ng/mL or 21 mg/d patchmg/d patch
Eventually Eventually ↑↑ patch dose to 35 mg and patch dose to 35 mg and then to 42 mg/d then to 42 mg/d →→ much improved much improved – less withdrawal – less withdrawal
50 y/o man with Buerger’s Disease cont.50 y/o man with Buerger’s Disease cont.
• Post Residential TreatmentPost Residential Treatment
Continued 42 mg/d nicotine patch dose Continued 42 mg/d nicotine patch dose for 6 weeks then slowly tapered for 6 weeks then slowly tapered
Continued bupropion for 2 yearsContinued bupropion for 2 years
Panelist at our Conference May 2010Panelist at our Conference May 2010
Still abstinent from smokingStill abstinent from smoking
50 y/o man with Buerger’s Disease cont.50 y/o man with Buerger’s Disease cont.