Treating Tobacco Dependence
Stacy Seikel, MDBoard Certified Addiction MedicineBoard Certified Anesthesiology
Cigarettes Tobacco smoke – complex mixture of 4,000
chemicals with over 60 known carcinogens Cigarette smoking – responsible for 1 in 5
deaths in USA (>400,000 deaths/year) 1965 to 1999 – Decline in smoking rate, 41%
to 22.8% Recent decrease in youth smoking
What Is Tobacco Dependence? Nicotine Dependence ≠
Tobacco Dependence
Medical Consequences ofNicotine Dependence Negligible Chronic nicotine medication use after
stopping tobacco use likelihood of cardiac events
Medical Consequences ofTobacco Dependence Massively Overwhelming!!
Cigarette smoking is thechief avoidable cause of
death in our society
Cigarettes Cause Lung Cancer COPD Heart Disease Other Cancers
The Cost of Smoking 442,000 deaths per years caused by smoking
– 18%
Cigarette Smoking is NOT a Habit
What Is Tobacco Dependence?
It Is aCHRONIC MEDICALDISEASE.
FDA Drug Abuse Advisory Committee – June 9, 1997 “Tobacco dependence is a…[serious,]
chronic, relapsing, life-threatening illness, that requires…long-term medical management.”
Curtis Wright, MD, PhD
Deputy Director, Div. of anesthetics, Critical Care, &
Addiction Drug Products
Food & Drug Administration
FACTORS UNDERPINNINGTOBACCO DEPENDENCE
Psychological Dependency Nicotine Addiction
Factors that perpetuate smoking Cheap “high”
Nicotine is a stimulant—releases HGH, epinephrine, serotonin, norepinephrine
Intravenous nicotine is indistinguishable from amphetamine for the first 10 minutes
Very rapid neuroadaptation (tolerance) to nicotine; smokers generally discount the stimulant effects
Factors that perpetuate smoking Withdrawal symptoms
Irritability, agitation, anxiety, hunger, difficulty concentrating
Relieved within a few seconds by smoking a cigarette
Symptoms are constant, uncomfortable, socially disruptive
Repeated episodes of withdrawal and relief of withdrawal induce avoidance of withdrawal
Factors that perpetuate smoking Relief of dysphoric feelings
Nicotine affects the ventral tegmental area and mesolimbic system as do most other drugs of addiction
Nicotine often substitutes for other (less socially acceptable) drugs
Very rapid CNS effects due to inhalation Relief of withdrawal symptoms (anxiety) can be
confused with relief of dysphoria (anxiety)
Factors that perpetuate smoking Conditioned responses (“triggers”): Smoking
is associated with a wide range of activities Drinking alcohol, eating a meal, drinking coffee Sexual activity Completion of a project, escape from danger, end of
the workday Celebrations Driving a car Waiting Seeing others smoke; smelling tobacco or smoke
ADDICTED SMOKERS Some are minimally dependent Others are severely dependent Genetic heritage affects dependence
ADDICTIONCIGARETTES
10% not dependent 90% are dependent
ALCOHOL 90% not dependent 10% are dependent
Treating Tobacco Dependence Severe but treatable 70% of smokers visit a physician and 50%
visit a dentist each year Most smokers want to stop and 46% try to
stop each year Multicomponent therapy
Chronic Disease Nature of Tobacco Dependence Just like asthma, hypertension, or diabetes
treatment, clinical deterioration is the rule and to be expected, when tobacco-dependence pharmacotherpy is stopped.
Interventionists Counselor Nurse CD Counselor Respiratory Therapist Psychologist Physician
Dentist Dental Hygienist Nurse Practitioner Physician Assistant Occupational Therapist
Clinical in Practice Guideline Major Conclusions/Recommendation Tobacco dependence is a chronic condition Effective treatments exist and all tobacco users should be
offered treatment Healthcare systems must systematize identification,
documentation, and treatment of every tobacco user Brief interventions are effective, but there is a strong dose
response Counseling effective Pharmacotherapy is effective, and at least one should be
prescribed Treatments are cost-effective
Treating Tobacco DependencePrinciples of Treatment Behavioral Addictive disorders Pharmacologic Relapse prevention
Treating Tobacco DependenceHealthcare Professional’s Role Identify the smoker Personalize the risks of smoking and benefits
of stopping Encourage patient to set stop date Provide and monitor pharmacologic therapy Follow-up and ongoing support Referral
FDA-Approved Tobacco-Dependence Medications CONTROLLER MEDICATIONS
Bupropion SR ((Zyban, Wellbutrin SR) Nicotine Patch – OTC Varenicline (Chantix)
RELIEVER MEDICATIONS Nicotine Inhaler Nicotine Nasal Spray Nicotine Polacrilex Gum (Nicorette) – OTC Nicotine Polacrilex Lozenge (Commit) – OTC Nicotine-8-Cyclodextrin – OTC
Sublingual tablet
NICOTINE MEDICATION SAFETY Nicotine does not cause lung cancer
Tobacco smoke does Nicotine does not cause COPD
Tobacco smoke does Nicotine does not cause acute MI
Tobacco smoke does Nicotine does not cause acute vascular injury
Tobacco smoke does
Benefit of Prescribing At Least One Medication – Evidence-Based All FDA-approved medications suppress
nicotine withdrawal signs and symptoms Any one medication probability of
stopping smoking 2-3 x
During medication treatment period 1 year after medication treatment-end
Benefit of Prescribing Two Medications – Evidence-Based Any pair of FDA-approved medications
further probability of stopping smoking 50-100% over any one, effective
medication During medication treatment period 1 year after medication treatment-end Do not give Chantix with nicotine replacement
therapy
Nicotine Liquid in its native state Distilled from burning tobacco and carried on tar
droplets Free (unprotonated) nicotine crosses biological
membranes, therefore pH dependent Inhalation → peak arterial concentrations 2-4 x
venous concentrations Extensive first pass hepatic metabolism Half-life 120 minutes
TreatmentPharmacotherapy First line
Nicotine gum Nicotine patches Nicotine nasal spray Nicotine inhaler Nicotine lozenge Bupropion Varenicline
Second line Clonidine nortriptyline
Nicotine Patch TherapyBackground Placebo-controlled trials show doubling of
stop rates Growing literature showing a dose response -50% median replacement with standard dose Reduced smoking
while using nicotine patch
High Dose Patch TherapyConclusions High dose patch therapy safe for heavy smokers Smoking rate or blood continue to estimate initial
patch dose Assess adequacy of nicotine replacement by patient
response or percent replacement More complete nicotine replacement improves
withdrawal symptom relief Higher percent replacement may increase efficacy of
nicotine patch therapy
High Dose Patch TherapyDosing Based on Smoking Rate
<10 cpd 7-14 mg/d
10-20 cpd 14-22 mg/d
21-40 cpd 22-44 mg/d
>40 cpd 44+ mg/d
2 ppd = 2 patches
Nicotine Patch TherapyClinical Use Individualize the dose and duration Base initial dose on smoking rate or blood
continine Usual length of therapy: 6-8 weeks Return visit or phone call at 1 or 2 week
intervals Adjust dose and determine length of Rx based
on response
BupropionBackground Monocyclic antidepressant Inhibits reuptake of norepinephrine and
dopamine May inhibit nicotinic ACH receptor function Mechanism in helping smokers stop is not
clear May attenuate weight gain in abstinent
smokers
Bupropion for Relapse PreventionResults 58.8% smoking abstinence at week 7 Relapse rate lower in active group through weeks 12
and 24 but not thereafter Median time to relapse 156 d (active) vs. 65 d
(placebo) Smoking abstinence 47.7% (active) vs. 37.7%
(placebo) through week 78 Weight gain 3.8 and 4.1 kg (active) vs. 5.6 and 5.4
kg (placebo) at weeks 52 and 104
BupropionSummary Dose response efficacy in treating smokers Attenuates weight gain May be more effective than nicotine patch
therapy Delays relapse to smoking Can be prescribed to diverse populations of
smokers with expected comparable results
Medication strategies
Partial receptor antagonist Varenicline (Chantix)
Varenicline
Approved May 11, 2006 by FDA (Pfizer) Partial agonist at the nicotine receptor High affinity for the α4β2 subtype nicotine
receptor Trade name: Chantix Derived from natural chemical cytisine, found
in the plant “false tobacco”Foulds (2006) The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. J Clin Pract 60: 571–576
Orbach et al (2006) Drug Metabolism and Distribution http://dmd.aspetjournals.org/cgi/content/abstract/34/1/121
T ½ excretion = 17 ± 3 hours
Nicotine receptor
Nicotine receptor
Nicotine receptor
Powledge TM (2004) Nicotine as therapy.PLoS Biol 2(11): e404.
Foulds (2006) J Clin Pract 60: 571–576
N
N = Nicotine
N
N
Na+
N V
V = VareniclineN = Nicotine
N
V
V = VareniclineN = Nicotine
N
V
N
V
N
V
N
V
N
V
N
V
N
V
Na+
Varenicline
Partial agonist at the N-acetylcholine site—targets the α4β2 receptor
Reduced craving and withdrawal symptoms The most common adverse effects included
nausea, headache, trouble sleeping, and abnormal dreams
No documentation of serious adverse effects
Pfizer: data on file
Varenicline
Continuous abstinence, weeks 9-12
Varenicline 44 %
Bupropion 30 %
Placebo 17.7 %
Gonzales. JAMA 296:47-55
Varenicline
Abstinence at 12 months of treatment
Varenicline 22.9%
Bupropion 16.1%
Placebo 8.4%
Gonzales. JAMA 296:47-55
Varenicline-adverse effects
Gonzales. JAMA 296:47-55
Nausea Dreams Insomnia
Varenicline 28% 10% 14%
Bupropion 12.5% 5.5% 22%
Placebo 8.4% 5.5% 12.8%
Varenicline-study drug discontinuation due to adverse effects
Gonzales. JAMA 296:47-55
Nausea All causes
Varenicline 2.6% 8.6%
Bupropion 1.8% 15.2%
Placebo 0.3% 9.0%
Varenicline-adverse effects
One report: exacerbation of symptoms in a patient with schizophrenia
One report: exacerbation of manic symptoms in a patient with bipolar disorder
One report: exacerbation of depression and psychosis in a patient with depression and a FH of bipolar disorder
One report: mixed episode and psychosis in a patient with depression
One report: cataracts
Varenicline-discontinuation due to adverse effects, 1 year
Williams. 23:793-801
Varenicline Placebo
Adverse effects 26% 10%
Lack of efficacy 0 5%
Protocol deviations 2% 3%
Lost to f/u 10% 15%
Refusal to continue study
5% 16%
All causes 46% 53%
Varenicline-adverse effects
Williams. 23:793-801
Varenicline Placebo
Nausea 40% 8%
Dreams 23% 7%
Insomnia 19% 9.5%
Disgeusia 11% 2%
Dizziness 8% 5%
Any adverse effect 96% 83%
Varenicline-cessation
Williams. 23:793-801
Varenicline Placebo
Abstinence at week 52
37% 8%
Possible explanations for adverse psychiatric effects Varenicline is a dangerous drug
Possible explanations for adverse psychiatric effects Smoking is a dangerous behavior
Nicotine has a prolonged effect on receptor function, causing profound and long-term alterations in mood, cognition, and behavior
Cessation of nicotine use results in poorly understood, but significant effects on mood, cognition, and behavior
Many of the adverse effects seen in patients using varenicline are due to long-term use of tobacco and nicotine, and nicotine withdrawal
Varenicline dosing
Begin while the patient is still smoking “Starter Pack”
Initial dose = 0.5 mg at breakfast x days 1-3 Then 0.5 mg @ breakfast and dinner x days 4-8
“Continuation Pack” 1 mg @ breakfast and dinner
Varenicline dosing
Since varenicline is a partial nicotine agonist, it is illogical to use a nicotine replacement product at the same time
There is inadequate data to advise for or against the simultaneous use of bupropion of nortriptyline for smoking cessation
Simultaneous use of antihypertensives, antidepressants, neuroleptics, and anticonvulsants appears safe
WHAT YOUR PATIENT NEEDS TO HEAR FROM YOU – 1 (At the Start of Treatment)
Effective Treatment Takes Time Mean: 6-9 months Range: 6 weeks to many years 25-35% need lifetime treatment
Goals of Treatment Stop smoking Suppress nicotine withdrawal symptoms
WHAT YOUR PATIENT NEEDS TO HEAR FROM YOU -2 (At the Start of Treatment)
Goals of Tapering Continue to be tobacco-free Continue to blunt nicotine withdrawal symptoms Thus: Medication Tapering is NOT a Down
Escalator Keep Communication Lines Open
Call me, your doctor, if you even think you may be having a problem
Thank you.