CSAM: Addiction Medicine Review Course, October 29, 2010 An Overview of Nicotine Dependence: Clinical Features, Treatment, and Brain Imaging Findings Arthur L. Brody, M.D. Professor-in-Residence, UCLA Department of Psychiatry Director, Los Angeles Veterans Affairs (VA) Smoking Cessation Programs Richard Metzner Endowed Chair in Clinical Neuropharmacology
Disclosure of Financial Relationships Arthur L. Brody, M.D. Disclosure: I am a collaborator on a research grant from Pfizer.
Objectives: Tobacco Dependence Talk 1. Become familiar with the general epidemiology and clinical features of cigarette smoking 2. Understand some basic pharmacology of nicotine (receptors, half-life, life, clinical effects) 3. Understand the medical risks of cigarette smoking 4. Learn about pharmacological treatment and outcomes (NRT formulations, Buproprion, Varenicline) 5. Learn about psychosocial treatment and outcomes 6. Be able to describe brain imaging findings in smokers
Cigarette Smoking: FAST FACTS (Prevalence) 21% of American adults (~46 million) smoke cigarettes (down from 42% in 1965 and > 50% in 1940s)* Lowest rates in UT (~10%), CA (13%), NE, NJ, NY, MA, HI Highest rates (>30%) in KY, WV, and southern states F almost = M *CDC. Cigarette smoking among adults and trends in smoking cessation - United States 2008. MMWR Morb Mortal Wkly Rep. 2009;58:1227-1232.
Cigarette Smoking: FAST FACTS 20 cigs/pack (General) - Regular cigarette: 1.1 to 1.4 mg nicotine - Light cigarette: 0.7 to 1.0 mg nicotine ~ $5.00 per pack in CA Most smokers are nicotine dependent (50 to 90%) Cigarette smoke contains several thousand constituents* * Green CR, Rodgman A. The Tobacco Chemists Research Conference. Recent Advances in Tobacco Science 1996;22:131 304
Cigarette Smoking: FAST FACTS *http://stopcigarettes.net/anatomy-of-a-cigarette/
Cigarette Smoking: FAST FACTS (Nicotine) Cigarette smoking leads to rapid nicotine absorption into the pulmonary circulation and uptake into the brain Nicotine exerts its action through binding to nicotinic acetylcholinergic receptors (nachrs) (> 20 types; ligand-gated ion channels found on neurons that normally bind the neurotransmitter acetylcholine) Binding of nicotine opens the ligand-gated d channel, thereby allowing entry of sodium or calcium into the cell One effect of the entry of calcium into the neuron is neurotransmitter release *Benowitz NL. Nicotine Addiction. N Engl J Med 2010; 362:2295-2303
Cigarette Smoking: FAST FACTS (Nicotine in Brain cont.) Nicotine binding to α4β2* nachrs (most common nicotine receptor subtype in mammalian brain) in the ventral tegmental area of the midbrain leads to dopamine release in the ventral striatum/nucleus accumbens (presumably leading to the pleasurable effects of smoking) Nicotine administration also leads to release of glutamate and GABA, which modulate dopamine release In addition, nicotine inhibits the activity of monoamine oxidases A and B, leading to decreased breakdown of dopamine (Chronic smoking leads to up-regulation and desensitization of nachrs) *Benowitz NL. Nicotine Addiction. N Engl J Med 2010; 362:2295-2303
Cigarette Smoking: FAST FACTS (Nicotine Metabolism) Nicotine is metabolized primarily by the liver enzyme CYP2A6, and variation in the rate of nicotine metabolism contributes to differences in vulnerability to tobacco dependence and response to treatment (slow metabolizers smoke less and are more likely to quit) 70 to 80% of nicotine is metabolized to cotinine (5 other major metabolites) Plasma t 1/2 of nicotine is ~2 to 2.5 h; t 1/2 of cotinine is ~16 h Both nicotine and cotinine clearance are higher in women than in men Total nicotine clearance is decreased by 23% in the elderly *Benowitz NL, Hukkanen J, Jacob P 3 rd : Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 2009;(192):29-60
Cigarette Smoking: FAST FACTS (Course of Nicotine Dependence) Onset of smoking - 15 to 20 years old (17.2% of high school students t report current use of cigarettes) Progresses over 1 to 12 months to daily smoking Most teenagers who smoke believe they will quit within 5 years Nicotine Dependence - 1 to 16 years later (in part from Breslau et al, Arch Gen Psychiatry, 2001)
Cigarette Smoking: FAST FACTS (Menthol Cigarettes) 33% of smokers primarily use menthol cigarettes Among African-American smokers 70 to 80% (Caucasian 23 to 30%; Hispanic - 32 to 52%) Marketing aimed at younger smokers, presumably because menthol makes smoking more palatable Menthol flavoring may inhibit nicotine metabolism, leading to increased nicotine/cotinine/exhaled carbon monoxide (CO) levels More difficulty quitting in standard treatment programs FDA considering making menthol in cigs illegal *SAMHSA. Substance Abuse and Mental Health Services Administration. Office of Applied Studies. The NSDUH Report: Use of Menthol Cigarettes. 2009.
Cigarette Smoking: FAST FACTS (Comorbidity) 44% of cigarettes in the U.S. are smoked by people with substance abuse/mental illness* Elevated rates of smoking among people with mental Illness/substance abuse Drug/Alcohol Abuse (63 to 80%) (people with alcohol dependence more often die from tobacco-related causes than from alcohol-related causes) Bipolar Disorder (60 to 69%) Schizophrenia (64 to 88%) Major Depressive Disorder (44 to 60%) Anxiety Disorders (32 to 55%) *Lasser K, Boyd JW, Woolhandler S, et al. Smoking and mental illness - A population-based prevalence study. JAMA. 2000;284:2606-2610
Cigarette Smoking: FAST FACTS (Health Risks - Morbidity) Debilitating cardiovascular and pulmonary diseases Impotence Infertility Impaired taste/smell Smoking in pregnancy associated with infant birth weight Household smoking g( (secondhand smoke) associated with childhood asthma, increased # of ENT infections, and SIDS
Cigarette Smoking: FAST FACTS (Health Risks - Mortality) Smokers have 2x the mortality risk of non-smokers Smokers have 50% chance of dying of smokingrelated causes Cancers (lung, oral cavity, esophagus, pancreas, bladder, cervix) Cardiovascular diseases (CAD, ischemic stroke and subarachnoid hemorrhage, PVD) Lung diseases (COPD, acceleration of age-related decline in lung function) Shortens life by an average of 7 years (if 35 to 69 yo, 23 years) also morbidity (~3 years) ~440,000 deaths annually in U.S. related to smoking
Why do people keep smoking? Nicotine Withdrawal (DSM-IV) Dysphoric or depressed mood Insomnia Irritability, frustration, or anger Anxiety Difficulty concentrating CRAVING Restlessness Decreased heart rate Increased appetite or weight gain
Enhancing Motivation to Quit 90% of smokers will endorse wanting to quit, but only 20% are willing to try within the next month Key Principals Maintain Empathy Advise to Quit Internal Motivation better than External Motivation Review Health Consequences (Mortality, Impaired Taste and Smell, Impotence, Infertility, COPD) Review Social Consequences ($$$, Less Socially Acceptable, Environmental Tobacco Smoke) Discuss Treatment Options
Treatment for Tobacco Dependence: General Principles Length of treatment based on patient progress (1-4 months) Longer treatment (up to 6 months or more) may be needed in smokers with predictors of poor outcome (such as heavy tobacco usage or certain co-morbidities) Chronic condition - often requires repeated intervention Strong Dose-Response Relationship
Treatment for Tobacco Dependence: Nicotine Fading General Principles (Cont.) Assess Motivation to Quit If a patient is willing to try quitting, treatment options should be discussed and offered If patient is unwilling, brief intervention should be made to enhance motivation to quit Extremely cost-effective
First Line Treatments (2010) Nicotine Replacement Therapy Patch, Gum, and Lozenge (available over-the-counter [OTC]) Inhaler and Nasal Spray (available by prescription) Bupropion HCl Sustained Release (SR) (Zyban) Varenicline HCl (Chantix) Group and/or Individual id Psychotherapy Combination treatment (Rapid Smoking) *(NOT Serotonin Reuptake Inhibitors)
2 to 3% 5% 3 to 6% Treatment Efficacy (3 to 4 months) Natural quit rate/no treatment Physician advice Placebo 5 to 15% Nicotine replacement therapy alone (OTC)??? Bupropion HCl or varenicline HCl alone 20 to 30% Group psychotherapy alone 30 to 40% Combination treatment programs With effective treatment, t t 20 to 25% sustained abstinence at 12 months
Nicotine Replacement Therapy (NRT)- (General) Type of NRT based on patient preference (roughly equally effective, though gum and lozenge may be more addictive) Taper dose every 2 to 4 weeks Contraindicated, if unstable angina, pregnant, or nursing No smoking while using NRT Side effects/toxicity (flushing, dizziness, headache, skin irritation [patch], insomnia/vivid dreams [patch], myocardial infarction, stroke) Recent study (Piper et al, Arch Gen Psychiatry, y 2009) indicates that the combination of nicotine patch plus lozenge may be more effective than these treatments alone
Nicotine Replacement Therapy- OTC Nicotine Patch (21-, 14-, 7-mg, 24 or 16 hour) Easy to use; Match current level of smoking with patch strength Peak blood levels start at 1 to 2 hours Decrease dose roughly every 2 to 4 weeks; typical course for 1 ppd smoker 4 weeks 21 mg, 2 weeks 14 mg, 2 weeks 7 mg Developed (in part) by Murray Jarvik and Jed Rose Nicotine Gum and Lozenge (2- or 4- mg) Control over dosing Park in cheek or under the tongue for 20 to 30 mins Absorbed better at higher ph, so avoid using with acidic beverages (e.g.- coffee, tea, citrus juice)
Nicotine Replacement Therapy- Nicotine Inhaler Prescription May help as substitute for oral and inhalation pleasures of smoking Puff repeatedly over 20 minutes Acidic beverages interfere with absorption Nicotine Nasal Spray Quickest peak levels (within 10-min) Need to clear nasal passages and tilt head back to maximize absorption Side effects include nasal and throat irritation, rhinitis, sneezing, coughing, and watery eyes
Bupropion HCl SR (Zyban) Effective for non-depressed as well as depressed smokers; may be preferable in smokers with CAD 150 mg PO QD for 3 days, then increase to 150 mg PO BID 300 mg total per day > 150 mg/d > placebo Treat for at least 2 to 4 weeks for full effect ( urges, withdrawal,?change taste of cigarettes) Side effects: anxiety, insomnia, i headache, h dry mouth, and nausea At 300 mg/d, seizures are rare (0.06%) 06%)
Varenicline HCl (Chantix) FDA approved (May 2006) - Partial agonist at the α 4 β 2 nicotinic acetylcholine receptor (the most common nicotine receptor subtype in the mammalian brain) Efficacy demonstrated in 6 clinical trials (5 placebo- controlled) of ~ 3600 chronic smokers (??? most effective medication???) Dosage: 0.5 mg PO QD for 3 days; 0.5 mg PO BID for 4 days; then 1.0 mg PO BID for 12 to 24 weeks Side effects: gastrointestinal (nausea, vomiting), headache, insomnia, and abnormal dreams May be combined with bupropion HCl (but not with nicotine replacement therapy same receptors)
Group/Individual Psychotherapy Education about Addiction, Health Consequences, Withdrawal, and Relapse Monitor Smoking Behavior Recognizing Relapse Situations/Triggers Nicotine Fading Exhaled carbon monoxide (CO) monitoring (non-smokers have levels of 0 to 3 ppm) Fagerström Test for Nicotine Dependence monitoring low 0 to 3; moderate 4 to 6; high > 7 Target Quit Date (2 to 3 weeks after initiation of treatment) *Marlatt & Gordon, 1985
Group/Individual Psychotherapy Developing Coping Skills Avoiding trigger situations Reducing overall stress Relaxation techniques (muscle relaxation and breathing retraining) Distracting attention from smoking urges with other activities Abstinence Violation Effect (Slip vs. Relapse) learning experience Social Support (Extra- and Intra- Treatment) Graduation
Alternatives to In-Person Group Therapy using Practical Counseling Telephone and Internet Counseling Convenient and anonymous Widespread access Often accessible in many languages (California Quitline available in 6 languages) Alone or in conjunction with medication Telephone programs now in almost all 50 states (1-800-QUIT-NOW or 1-800-NO-BUTTS) or American Lung Association (1-800-LUNG-USA) or American Cancer Society
Nortriptyline t Second Line Treatments Two randomized, double-blind, placebo-controlled studies demonstrating efficacy 25 mg starting dose, increased to target of 75 to 100 mg Side effects- sedation, dry mouth, blurry vision, urinary retention, constipation, light-headedness EKG (PR/QT prolongation) in patients over 40 years old Clonidine Alpha-2 agonist that dampens sympathetic activity and attenuates withdrawal symptoms 0.1 to 0.75 mg gp per day y( (in oral divided doses or transdermal) Side effects: sedation, dry mouth, constipation, postural hypotension
Joe Camel Case Examples 28 yo with Chronic Paranoid Schizophrenia. 20 cigs/d. States t that t smoking takes the edge off his auditory hallucinations Marlboro Man 43 yo with Alcohol/Cocaine Dependence and Major Depressive Disorder. 30 cigs/d. Abstinent for 21 days from alcohol and cocaine (attending AA) Winston Man 60 yo with Coronary Artery Disease and COPD. Has a family history of both Parkinson s s and Alzheimer s Diseases. 5 cigs/d. Enjoys smoking
Case Examples TELL THEM ALL TO QUIT SMOKING - maintain empathy
Case Examples Joe Camel (1987-1997) Schizophrenia/Smoking Tobacco/nicotine does not treat schizophrenia (or any other psychiatric illness) Clozapine (and newer antipsychotics) may be particularly useful in patients t with schizophrenia h i and tobacco dependence May need to do motivational interviewing and more intensive psychotherapy to improve likelihood of cessation Smoking cessation may increase levels of antipsychotic medications, so need to monitor for increased side effects Most medications for tobacco dependence (including bupropion) are effective (?varenicline)
Case Examples Marlboro Man (1954-1999) Alcohol/Drug Dependence, Major Depressive Disorder, and Smoking Should attempt smoking cessation after at least a few weeks of abstinence from other substances Smoking cessation outcomes may actually be improved by active treatment for substance abuse Unclear whether or not Major Depressive Disorder worsens the prognosis for smoking cessation May want to consider antidepressant treatments for Tobacco Dependence (e.g., bupropion, nortriptyline)
Case Examples Winston Man (late 1960s to early 1970s) Coronary Artery Disease, COPD, Family h/o Parkinson s and Alzheimer s s, and Smoking Some evidence that medical complications of smoking improve smoking cessation outcomes Risks of myocardial infarction and cancer start to diminish within a month or two of smoking cessation, and stabilize over the 10 to 15 years Risk of smoking greatly outweighs any potential protective effect for Parkinson s or Alzheimer s OPINION - smokers who enjoy smoking have the hardest time quitting
Brain Dopamine Pathways
Effects of Cigarette Smoke on: Nicotinic Acetylcholine Receptor (nachr) Occupancy Nicotinic acetylcholine receptors (nachrs) are widespread throughout the brain nachr density: thalamus > basal ganglia > cerebral cortex > brainstem > cerebellum > corpus callosum For examining nachrs in the human brain, 2-FA is a radiotracer for PET scanning that binds with relative specificity and high affinity to α 4 β 2 * nachrs (one of the most common receptor subtypes in the mammalian brain)
2-FA PET Session Timeline Smoking Abstinence Uptake Period PET Scan Cigarette Smoke Exposure PET Scan -36 h 0 min 3 h 4 h 4:10 h/5 h 9 h Last Cig Injection 3.8 mci 2-FA Continuous infusion 3.8 mci 2-FA
2-FA Binding Changes with 5 levels of Cigarette Smoking MRI kbq 9 0 00cig 0.0 01cig 0.1 03cig 0.3 10cig 1.0cig 30cig 3.0cig Non - Displaceable Brody et al, Arch Gen Psychiatry, 2006;63:907-15
2-FA Displacement (18 to 19%) with SHS Exposure
Results: 2-FA PET Studies In humans, smoking only 13% of a cigarette (1 to 2 puffs) or having a plasma nicotine concentration of 0.87 ng/ml were found to occupy 50% of available α4β2* nachrs Smoking a whole cigarette or smoking to satiety t nearly saturates nachrs Typical cigarette smokers have peak plasma nicotine levels of 10 to 50 ng/ml during the day Daily cigarette smokers maintain saturation of α4β2* nachrs throughout the day De-nicotinized cigarettes (0.05 mg nic) and moderate SHS exposure result in ~20% nachr occupancy
Effects of Cigarette Smoking on: Dopamine Concentration Pre-clinical work demonstrates that nicotine binding to nachrs (especially in the ventral tegmental area of the midbrain) leads to dopamine (DA) release in the ventral striatum/nucleus accumbens (VST/NAc) Over the past 5 to 10 years, several brain imaging studies of smoking- or nicotine- induced DA release have been performed in humans
11 C-Raclopride PET Session Timeline Rating Scales (HAM-D anda) CO monitor Pre-Break Scan Smoke or No Smoke Post-Break Scan O min 130 min 180 min 190 min 220 min Last Cig Urge to Smoke and State Anxiety scales Injection 5 mci Continuous infusion 11 C-Raclopride 11 C-raclopride at 3 mci/hr Brody et al, Am J Psychiatry, 2004; Arch Gen Psychiatry, 2006
11 C-Raclopride PET Method DA Neuron/ Midbrain/VTA DA DA DA DA DA DA DA DA DA DA Rac Rac DA Rac DA Rac VST/NAc Neuron SMOKING/Nicotine i stimulation of nachrs DA = Dopamine Rac = 11 C-raclopride = D 2 (and D 3 ) receptors nachrs = nicotinic acetylcholine receptors VTA = vent. tegmental area
Decreases in 11 C-Raclopride Binding from Pre- to Post- Cigarette Smoking Prebreak Postbreak Prebreak Postbreak VCD/NAc VCD/NAc VCD/NAc VCD/NAc Prebreak Postbreak Also, a positive correlation was found between change in craving and change in 11 C-raclopride binding potential (r =.65, p =.004) VCD/NAc VCD/NAc
Smoking-Induced Dopamine Release: Results Displacement of 11 C-Raclopride in VST/NAc: Regular cigarette (1.1 mg nic): -8.4 (± 1.5)% De-nicotinized cigarette (0.05 mg nic): -1.2 (± 2.5)% (p =.04) Thus, nicotine appears to be necessary for smoking-induced dopamine release Correlation between change in 11 C-raclopride binding potential ti and change in mood state (p =.01) Brody et al, Neuropsychopharmacology, 2009
Summary: Imaging of the Brain Dopamine Reward Pathway in Smokers Low levels of nicotine exposure (either from smoking a puff of a regular cigarette or secondhand smoke exposure) lead to substantial α4β2* nachr occupancy (including brainstem) Smoking to satiety leads to saturation of α4β2* nachrs Human cigarette smoking results in DA release in the VST/NAc (measured indirectly) Nicotine inhalation during cigarette smoking appears to be solely responsible for nachr occupancy and DA release DA release is associated with craving and mood
Imaging of the Brain Dopamine Pathway: Implications for Treatment Current Medications Nicotine replacement therapy (patch, gum, lozenge, inhaler, nasal spray) Bupropion HCl (Zyban) Varenicline HCl (Chantix) Novel/Theoretical Treatments Nicotine receptor antagonists (mecamylamine, dihydro-β-ethriodine) DA system modulation (agonists/bromocriptine or antagonists/haloperidol) Others: glutamate antagonists, opioid antagonists, GABAergic medications, substance P (NK-1) antagonists Nicotine Vaccine (phase II trials)
Collaborators Mark A. Mandelkern Edythe D. London David Sultzer Richard E. Olmstead James McCracken Matthew Costello Chris Culbertson Shahrdad Lotfipour Jed Rose Alexey Mukhin Funding Sources National Institute on Drug Abuse (R01 DA15059 and DA20872 [A.L.B.] and DA 14093 [E.D.L.]) Tobacco-Related Disease Research Program (TRDRP) (A.L.B. [7KT-0098 and 11RT-0024] and E.D.L. [10RT- 0091]) Veterans Administration Merit Review Award Program (A.L.B.) Richard Metzner Chair in Clinical i l Neuropharmacology (A.L.B.) Pfizer, Inc. (S.L.)