Treating Tobacco Dependence Revised 2

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%


Varenicline-adverse effects


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


Nausea All causes

Varenicline 2.6% 8.6%

Bupropion 1.8% 15.2%

Placebo 0.3% 9.0%


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 Placebo

Nausea 40% 8%

Dreams 23% 7%

Insomnia 19% 9.5%

Disgeusia 11% 2%

Dizziness 8% 5%

Any adverse effect 96% 83%

Varenicline-cessation


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.

Health & Medicine

Treating Tobacco Dependence Revised 2