1 Smoking Cessation: What works and why… A Medical Model Stephen I Rennard University of Nebraska Florianopolis, Brazil October 2009

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5 Student Smoking Behavior in the United States ( ) Johnston et al. U. Michigan Students ever using cigarettes (%) Year 12th Grade 10th Grade 8th Grade

6 NICOTINE WITHDRAWAL SYMPTOMS Craving to smokeCraving to smoke IrritabilityIrritability Awakening from sleepAwakening from sleep BradycardiaBradycardia AnxietyAnxiety Impaired concentrationImpaired concentration Inpaired reaction timeInpaired reaction time Restlessness Drowsiness Impotence Confusion Hunger Weight gain Depression

7 Nicotine: Addiction and Conditioning Nicotine Increased Receptors Increased Occupancy Withdrawal

8 Nicotine: Addiction and Conditioning Cues

9 Nicotine: Addiction and Conditioning Cues Conditioned Response

10 Nicotine: Addiction and Conditioning Nicotine Cues Conditioned Response

11 Nicotine: Addiction and Conditioning Nicotine Increased Receptors Increased Occupancy Withdrawal Cues Conditioned Response

12 Nicotine: Addiction and Conditioning Nicotine Increased Receptors Increased Occupancy Withdrawal Cues Conditioned Response Persistent Smoking

Nicotine Levels in a Smoker High Withdrawal Time Nicotine Level

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17 Nicotine formulations: Efficacy Placebo Odds Ratio Patch GumInhaler Nasal Spray Lozenge (2mg)

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Nicotine Levels in a Smoker High Withdrawal Time Nicotine Level

Dose, exposure Effect 0% 100% Maximum effect 50% Rationale – Partial Agonist Full agonist Craving; Withdrawal relief Blocks reward Partial agonist

21 Effect of Varenicline on Craving and Reward Gonzales et al. JAMA 296: 47, 2006 Score SatisfactionRewardEnjoymentCraving VareniclineBupropion Placebo

22 Studies I & II: 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) Study IStudy II Response Rate (%) VareniclineBupropionPlacebo N=349N=329N=344 N=343N=340 OR = odds ratio * p<0.0001

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24 Varenicline Warning Psychiatric symptomsPsychiatric symptoms AgitationAgitation Depressed moodDepressed mood Suicidal ideationSuicidal ideation Suicidal behaviorSuicidal behavior Warning: patients should be monitored and they and their families and caregivers should be alerted to monitor for these symptomsWarning: patients should be monitored and they and their families and caregivers should be alerted to monitor for these symptoms Advise patients and caregivers that the patient should stop taking CHANTIX and contact a health care provider immediately if agitation, depressed mood, or changes in behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior (May, 2008)Advise patients and caregivers that the patient should stop taking CHANTIX and contact a health care provider immediately if agitation, depressed mood, or changes in behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior (May, 2008) July 1:July 1: FDA has required the manufacturers of the smoking cessation aid varenicline (Chantix)…to add new Boxed Warnings and develop patient Medication Guides highlighting the risk of serious neuropsychiatric symptoms in patients using these products.

Nicotine Levels in a Smoker High Withdrawal Time Nicotine Level

Carrier Protein Carrier Protein Linker Drug IMMUNOGEN

+ Blood Brain

28 Antibody Concentration Over Time Schedule 1 & Schedule 2 TQD Schedule 1 Schedule 2

29 12-Month Abstinence NicVAX High Antibody* 16%(n=10/61)p=0.03 NicVAX Low Antibody 8%(n=11/140)p=0.49 Placebo 6% (n=6/100) Continuous Abstinence at 12 Months by Anti-Nicotine Antibody Levels *Top 30% by AUC per protocol

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Bupropion Seizures Neuropsychiatric symptoms Insomnia Allergic reactions July 1, 2009: FDA has required the manufacturers of the smoking cessation aid…bupropion (Zyban and generics) to add new Boxed Warnings and develop patient Medication Guides highlighting the risk of serious neuropsychiatric symptoms in patients using these products. These symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.

Anti-depressants Evaluated for Smoking Cessation TricyclicsTricyclics –Doxepin –Imipramine –Nortriptyline MAO inhibitorsMAO inhibitors –Moclobemide –(*Selegiline) Hughes, Stead and Lancaster Cochrane Database Syst Rev 2005 SSRIsSSRIs –Fluoxetine –Paroxetine –Sertraline AtypicalAtypical –Bupropion –Tryptophan –Venlafaxine

Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) for Smoking Cessation Fluoxetine Niaura Spring Fluoxetine Blondal Paroxetine Killen Paroxetine Killen Sertraline Covey Total Favors Treatment Favors Control Hughes, Stead and Lancaster Cochrane Database Syst Rev 2005

Novel Treatments for Smoking Cessation Off label use –Nortriptyline –Clonidine New treatments –Bromocriptine –Reboxetine –Selegeline –Topiramate –Naltrexone –EVT302 –Dianicline –Gabapentin –GW –Memantine –Sibutramine –Nalmefene –Eszopiclone –Mecamylamine –Phospholipid –Rimonabant –Surinabant –Taranabant –Lis-dexamphetamine –Guanfacine –Vaccine