Neurobiology of Tobacco Dependence and Neurobiology of Tobacco Dependence and Current Best TreatmentsCurrent Best Treatments

Richard D. Hurt, M.D.Richard D. Hurt, M.D.

Professor of MedicineProfessor of Medicine

Director, Nicotine Dependence CenterDirector, Nicotine Dependence Center

Mayo ClinicMayo Clinic

http://ndc.mayo.eduhttp://ndc.mayo.edu

Richard D Hurt MDRichard D Hurt MDFinancial Disclosure 1/08Financial Disclosure 1/08

• Current consulting (Scientific Advisory Current consulting (Scientific Advisory Boards) : PfizerBoards) : Pfizer

• Current Industry Grants: Eli LilyCurrent Industry Grants: Eli Lily

• Past Consulting: Glaxo Wellcome, Elan, Past Consulting: Glaxo Wellcome, Elan, Dynagen, Mcneil, Lederle, Bristol Myers Dynagen, Mcneil, Lederle, Bristol Myers Squibb, Pharmacia, Inhale, NovartisSquibb, Pharmacia, Inhale, Novartis

• Past Industry Grants: Glaxo Wellcome, Past Industry Grants: Glaxo Wellcome, Mcneil, Dupont Merck, Elan, Lederle, Lilly, Mcneil, Dupont Merck, Elan, Lederle, Lilly, Pfizer, SANO, GlaxoSmithKline, Knoll, Pfizer, SANO, GlaxoSmithKline, Knoll, Sanofi- Synthelabo, SomaxonSanofi- Synthelabo, Somaxon

Cigarette DesignCigarette Design

• Tobacco smoke – complex mixture of Tobacco smoke – complex mixture of 4,000 chemicals with over 60 known 4,000 chemicals with over 60 known carcinogenscarcinogens

• Most efficient delivery device for nicotine Most efficient delivery device for nicotine that exists- better than intravenousthat exists- better than intravenous

• Cigarette manufacturers have modified Cigarette manufacturers have modified cigarettes over the past decades to cigarettes over the past decades to maximize nicotine delivery to the brainmaximize nicotine delivery to the brain

• High doses of arterial nicotine cause High doses of arterial nicotine cause upregulation of the nicotinic acetylcholine upregulation of the nicotinic acetylcholine receptorsreceptors

Hurt RD, Robertson CR JAMA 280:1173, 1998Hurt RD, Robertson CR JAMA 280:1173, 1998

NicotineNicotine

• Not a carcinogenNot a carcinogen

• Liquid in its native stateLiquid in its native state

• Distilled from burning tobacco and Distilled from burning tobacco and carried on tar dropletscarried on tar droplets

• Only free (unprotonated) nicotine Only free (unprotonated) nicotine crosses biological membranescrosses biological membranes

• Inhalation Inhalation peak arterial concentrations peak arterial concentrations 2-4 X venous concentrations2-4 X venous concentrations

• Half-life 120 minutesHalf-life 120 minutes

Smoking Saturates Nicotinic ReceptorsSmoking Saturates Nicotinic Receptors

Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006

0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette

kBq/mL

9

0

Nondisplaceable

MRI

Forms of Nicotine vs. pHForms of Nicotine vs. pH

All evidence indicates that the relatively high smoke pH (high alkalinity) shown by Marlboro (and other Philip Morris brands) and Kool is deliberate and controlled.

All evidence indicates that the relatively high smoke pH (high alkalinity) shown by Marlboro (and other Philip Morris brands) and Kool is deliberate and controlled.

Methods which may be used to increase smoke pH and/or nicotine “kick” include:…(3) use of alkaline additives, usually ammonia compounds, to the blend.

Methods which may be used to increase smoke pH and/or nicotine “kick” include:…(3) use of alkaline additives, usually ammonia compounds, to the blend.

““Low Tar Low Nicotine” CigarettesLow Tar Low Nicotine” CigarettesVentilationVentilation

• Ventilation holes one of key technologies to Ventilation holes one of key technologies to manipulate tar and nicotine yieldsmanipulate tar and nicotine yields

• Electrostatic or laser perforations of the filter Electrostatic or laser perforations of the filter or paperor paper

• Ventilation holes in most brands are not visibleVentilation holes in most brands are not visible

• 2/3’s of U.S. smokers are unaware of 2/3’s of U.S. smokers are unaware of ventilation holes or that blocking then ventilation holes or that blocking then increases tar/nicotine yieldincreases tar/nicotine yield

• Many smokers block (consciously or not) the Many smokers block (consciously or not) the ventilation holes with their lips on fingersventilation holes with their lips on fingers

USPHS Clinical Practice GuidelineUSPHS Clinical Practice GuidelinePharmacotherapyPharmacotherapy

• First lineFirst line• nicotine gumnicotine gum• nicotine patchesnicotine patches• nicotine nasal spraynicotine nasal spray• nicotine inhalernicotine inhaler• nicotine lozengenicotine lozenge• bupropionbupropion• vareniclinevarenicline

• Second lineSecond line• clonidineclonidine• nortriptylinenortriptyline

CotinineCotinine

• Major metabolite of nicotineMajor metabolite of nicotine

• Pharmacologically inactivePharmacologically inactive

• 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

Nicotine Patch TherapyNicotine Patch TherapyBackgroundBackground

• Placebo-controlled trials show Placebo-controlled trials show doubling of stop ratesdoubling of stop rates

• Growing literature showing a dose Growing literature showing a dose responseresponse

• ~50% median replacement with ~50% median replacement with standard dosestandard dose

• Reduced smoking while using Reduced smoking while using nicotine patchnicotine patch

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

High Dose Patch TherapyHigh Dose Patch TherapyDosing Based on Smoking RateDosing Based on Smoking Rate

<10 cpd<10 cpd 7-14 mg/d7-14 mg/d

10-20 cpd10-20 cpd 14-21 mg/d14-21 mg/d

21-40 cpd21-40 cpd 21-42 mg/d21-42 mg/d

>40 cpd>40 cpd 42+ mg/d42+ mg/d

Dale LC, et al. Mayo Clin Proc 75:1311, 1316, 2000Dale LC, et al. Mayo Clin Proc 75:1311, 1316, 2000

High Dose Patch TherapyHigh Dose Patch TherapyDose Based on Plasma CotinineDose Based on Plasma Cotinine

<200 ng/ml<200 ng/ml 14-21 mg/d14-21 mg/d

200-300 ng/ml200-300 ng/ml 21-42 mg/d21-42 mg/d

>300 ng/ml>300 ng/ml 42+ mg/d42+ mg/d

Dale LC, et al. JAMA 274:1353, 1995Dale LC, et al. JAMA 274:1353, 1995

Nicotine Patch TherapyNicotine Patch TherapyClinical UseClinical Use

• Individualize the dose and durationIndividualize the dose and duration

• Base initial dose on smoking rate or Base initial dose on smoking rate or blood cotinineblood cotinine

• Usual length of therapy: 6-8 weeksUsual length of therapy: 6-8 weeks

• Return visit or phone call at 1 or 2 Return visit or phone call at 1 or 2 week intervalsweek intervals

• Adjust dose and determine length of Adjust dose and determine length of Rx based on responseRx based on response

BupropionBupropionBackgroundBackground

• Monocyclic antidepressantMonocyclic antidepressant

• 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

BupropionBupropionSide EffectsSide Effects

• Relatively free of anticholinergic, Relatively free of anticholinergic, sedative, cardiovascular or sexual sedative, cardiovascular or sexual dysfunction side effectsdysfunction side effects

• Most common side effects: dry mouth Most common side effects: dry mouth and insomniaand insomnia

• Seizure incidence 0.1%Seizure incidence 0.1%

• HypertensionHypertension

Bupropion for Relapse Prevention Bupropion for Relapse Prevention

Weeks 1-7Weeks 1-7

Open label Open label bupropionbupropion300 mg/d300 mg/d

Bupropion 300 mg/dBupropion 300 mg/d

PlaceboPlacebo

Follow-upFollow-up

Week Week 5252

Week Week 104104

Hays JT, et al. Ann Intern Med 135:423, 2001Hays JT, et al. Ann Intern Med 135:423, 2001

Bupropion for Relapse PreventionBupropion for Relapse PreventionResultsResults

• 58.8% smoking abstinence at week 758.8% smoking abstinence at week 7

• Relapse rate lower in active group through Relapse rate lower in active group through weeks 12 and 24 but not thereafterweeks 12 and 24 but not thereafter

• Median time to relapse 156 d (active) vs. 65 d Median time to relapse 156 d (active) vs. 65 d (placebo)(placebo)

• Smoking abstinence 47.7% (active) vs. 37.7% Smoking abstinence 47.7% (active) vs. 37.7% (placebo) through week 78(placebo) through week 78

• Weight gain 3.8 and 4.1 kg (active) vs. 5.6 Weight gain 3.8 and 4.1 kg (active) vs. 5.6 and 5.4 kg (placebo) at weeks 52 and 104and 5.4 kg (placebo) at weeks 52 and 104

Hays JT. Ann Intern Med 135:423, 2001Hays JT. Ann Intern Med 135:423, 2001

BupropionBupropionDosingDosing

• Bupropion SR – 150 mg/d x 3 d, then BIDBupropion SR – 150 mg/d x 3 d, then BID

• Duration of treatment – 6-12 weeksDuration of treatment – 6-12 weeks

• Safe to use for longer durationSafe to use for longer duration

• No need to taper at end of treatmentNo need to taper at end of treatment

Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003

BupropionBupropionSummarySummary

• Dose response efficacy in treating Dose response efficacy in treating smokerssmokers

• Attenuates weight gainAttenuates weight gain

• May be more effective than nicotine patch May be more effective than nicotine patch therapytherapy

• 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

NortriptylineNortriptyline

• Continuous abstinence – nortriptyline Continuous abstinence – nortriptyline 24% vs placebo 12%24% vs placebo 12%

• Smoking abstinence rates independent Smoking abstinence rates independent of PHMDDof PHMDD

• Nortriptyline alleviated negative mood Nortriptyline alleviated negative mood associated with smoking abstinenceassociated with smoking abstinence

• CB therapy more effective in subjects CB therapy more effective in subjects with PHMDDwith PHMDD

Hall SM. Arch Gen Psych 55:683, 1998Hall SM. Arch Gen Psych 55:683, 1998

VareniclineVareniclineMode of ActionMode of Action

• PPartial agonist with specificity for the artial agonist with specificity for the αα4B2 4B2 nicotinic acetylcholine receptornicotinic 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 Varenicline Mechanism of ActionMechanism of Action

Varenicline vs. Bupropion vs. PlaceboVarenicline vs. Bupropion vs. Placebo

Jorenby, D.E., et. al. JAMA; 296:56-63, 2006

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%

SubjectsSubjects• Male or female outpatient cigarette smokers Male or female outpatient cigarette smokers • 18-75 yr old, motivated to quit smoking18-75 yr old, motivated to quit smoking• Average of ≥10 cigarettes/day during past yearAverage of ≥10 cigarettes/day during past year

Secondary Endpoint:Secondary Endpoint:CO-confirmed continuous CO-confirmed continuous abstinence rate wk abstinence rate wk 13–5213–52

Wk12Wk12 2424 5252

NONTREATMENTNONTREATMENTFOLLOW-UPFOLLOW-UP

DOUBLE-BLIND DOUBLE-BLIND OPEN-LABELOPEN-LABEL

Primary Endpoint:Primary Endpoint:CO-confirmed continuous abstinence rate wk CO-confirmed continuous abstinence rate wk 13–2413–24

Varenicline 1mg bidVarenicline 1mg bid Varenicline 1mg bidVarenicline 1mg bid

PlaceboPlacebo

Quitters randomizedQuitters randomized

12 weeks

Maintenance of AbstinenceMaintenance of AbstinenceStudy DesignStudy Design

Varenicline Maintenance StudyVarenicline Maintenance Study

Tonstad, S., et. al. JAMA; 296:64-71, 2006

Long-Term Safety TrialLong-Term Safety TrialVareniclineVarenicline

Williams KE et al, Curr Med Res and Opin 23:793, 2007Williams KE et al, Curr Med Res and Opin 23:793, 2007

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

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

• Shorter acting NRT products as supplementsShorter acting NRT products as supplements

• Combination pharmacotherapy frequently usedCombination pharmacotherapy frequently used

Hurt RD, VA in the Vanguard, 2005Hurt RD, VA in the Vanguard, 2005