nicotine and tobacco dependence

Nicotine dependenceTerry Rustin, MD

Nicotine and Tobacco Dependence

Terry A. Rustin, MD, FASAM

Review Course in Addiction Medicine September, 2012

ASAM Disclosure of Relevant Financial Relationships

Content of Activity: ASAM 2012 Review Course

Name Commercial Interests

Relevant Financial

Relationships: What Was Received

Relevant Financial

Relationships: For What

Role

No Relevant Financial

Relationships with Any

Commercial Interests

Terry Rustin Consultant Consultation fees

Developing smoking cessation programs

Physician Salary Assisting patients in quitting smoking

Author Book royalties Author of books on smoking cessation

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6Jean Nicot (1530 – 1600)


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All tobacco products have two things in common:

1. Nicotine

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All tobacco products have two things in common:

2. They kill people


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Tobacco kills

• Over 400,000 Americans die every year from diseases caused by tobacco

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Tobacco kills

• More Americans die from the effects of tobacco than from alcohol, cocaine, heroin, amphetamines, AIDS, suicides, murders, fires, drownings, airplane crashes, car crashes, and the death

penalty… combined

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4,000 chemicalsin tobacco smoke

• hydrogen cyanide

• carbon monoxide

• formaldehyde

• acetaldehyde

• benzene

• nitrosamines

• pyrethrins

• cadmium

• lead

• arsenic

• radon

• polonium-210


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142009 NSDUH survey

Cigarette use and mental health

• Co-occurring smoking and:• Schizophrenia: 85%

• Major depressive disorder: 60%

• Addictions: 75%

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162009 NSDUH survey

172009 NSDUH survey

182009 NSDUH survey


192009 NSDUH survey

202009 NSDUH survey

.

Physicians: less than 3%

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2002 2007 2009

Men 52.1 50.5 50.4

Women 38.4 33.6 33.0

All 45.3 41.8 41.6

Tobacco use in the past month,age 18‐25

2002, 2007, 2009 NSDUH survey


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Tobacco use and ethnicity, 2009

• American Indians, Alaska natives: 41.8%

• Whites: 29.6 %

• Blacks: 26.5 %

• Hispanics: 23.3 %

• Asians: 11.9 %

• “Mixed races”: 36.6 %

2009 NSDUH survey

Pharmacology of nicotine and smoking

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Pharmacology of nicotine and smoking

• What’s so special about nicotine?

• What’s so special about smoking?


At acid pH, most of the nicotine is ionized, and is not readily absorbed. Cigarette smoke is highly acidic.


At physiologic pH, most of the nicotine is still ionized, and is not readily absorbed. Cigarette smoke entering the lungs must be buffered to physiologic pH before being absorbed.

When the pH of the smoke is raised to alkaline levels, most of the nicotine is no longer ionized, and is readily absorbed across biologic membranes.


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Addiction pharmacology

• Tolerance (neuroadaptation)

• Withdrawal

• Mind- and mood-altering effects

• Denial

• Compulsive use

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Tolerance (neuroadaptation)

• Over time, more and more of the drug is required to produce the same effect

• Neuroadaptation to nicotine occurs faster than to most other drugs (10 min)

• Neuroadaptation to the various effects of nicotine occurs at different rates


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Withdrawal

• The set of signs and symptoms that occur when the drug is decreased or stopped, and which are alleviated when the drug is started again

• Specific to the drug, not the individual

• Nicotine: irritability, agitation, anxiety, difficulty concentrating, bradycardia, insomnia, hunger, labile mood

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Fagerström Testfor Nicotine Dependence

• How soon after you wake up do you smoke your first cigarette?

• <5 minutes = 3 points

• 5-30 minutes = 2 points

• 31-60 minutes = 1 point

• How many cigarettes do you smoke each day?

• >30 cigarettes = 3 points

• 21-30 cigarettes = 2 points

• 11-20 cigarettes = 1 point

Heatherton et al (1991). British Journal of Addictions 86:1119-1127

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Fagerström Testfor Nicotine Dependence

• Is it hard to refrain from smoking in situation where you should not smoke? • Yes = 1 point No = 0 points

• Which cigarette do you value the most?• First one = 1 point Any other = 0 points

• Do you smoke more in AM?• Yes = 1 point No = 0 points

• Do you smoke if you are ill?• Yes = 1 point No = 0 points

Heatherton et al (1991). British Journal of Addictions 86:1119-1127


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Mind- and mood-altering

• Pharmacologically active alkaloid

• High potency (10 mg nicotine in the tobacco; 1-2 mg delivered per cigarette)

• Short half-life (100 minutes)

• Releases dopamine, growth hormone, epinephrine, cortisol

• Effects similar to cocaine, amphetamine

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Denial

• The unconscious resistance to accepting the truth• The observation is true

• The conclusion is false


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Denial

• The behavior is perceived as risky or dangerous

• The individual engages in the behavior despite the risk

• A justification is given for engaging in the behavior

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Perception of Great Risk from Substance Use among Persons Aged 12 to 17, by Gender and Age Group:

2007 and 2008

Risk Gender 12 or 13 14 or 15 16 or 17Smoking One or More Packs of Cigarettes Per Day

Male 67.3% 64.5% 64.5%

Smoking One or More Packs of Cigarettes Per Day

Female 72.1% 73.4% 74.3%

Having Five or More Drinks of Alcohol Once or Twice a Week

Male 40.7% 37.2% 32.3%

Having Five or More Drinks of Alcohol Once or Twice a Week

Female 45.9% 41.9% 42.7%

Source: 2007 and 2008 SAMHSA National Surveys on Drug Use and Health

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Compulsive use

• Craving: A drive state in which obtaining the chemical seems essential to survival

• Continued use despite consequences

• Inability to quit easily

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Audrey Flack. Royal Flush


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Smoking cessation treatment

• “Quitting smoking” for individuals who do not have another addiction

• “Recovery from nicotine and tobacco dependence” for individuals who have another addiction




NOT CONTROVERSIAL





HIGHLY CONTROVERSIAL

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• Now or later?

• Quit or switch brands?

• Quit or cut down?

• Medication or no medication?


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• Now or later?




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Setting a Quit Day: The single most important contribution a clinician can make

• The patient must select the date, not the clinician

• Two weeks or more in the future

• Choose a date with significance

• Develop a plan to be successful on the Quit Day

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.


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• Now or later?




62Neal Benowitz

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• Now or later?





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Heavy smokers cut down using the nicotine inhaler. Carbon monoxide levels remained constant.

Hurt et al (2000) Nicotine and Tobacco Research

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Heavy smokers cut down using the nicotine inhaler. Thio-cyanate levels (measure of carcinogenesis) stayed constant.

Hurt et al (2000) Nicotine and Tobacco Research

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• Now or later?





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Medication for smoking cessation

• 85 percent of people who have successfully quit smoking did so without medication

• Use of appropriate medication doubles the success rate in smoking cessation

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Medications for treating nicotine withdrawal

• Nicotine polacrilex

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Fortmann et al (1988)JAMA 260:1575-1580

Nicotine gum vs. placebo gum with no

counseling in a research setting

Point prevalence of abstinence at 6 mos

Placebo gum = 22 percent

Nicotine gum = 31 percent

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Goldstein (1989)AmJPsychiatry, 146:56-60

Nicotine gum with and without counseling in a research setting

Point prevalence of abstinence at 6 mos

Education only = 17.5 percent

Education and counseling = 36.7 percent

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Nicotine polacrilex (Nicorette®)• Reduces withdrawal

• Convenient

• OTC

• Improves quit rates when combined with counseling

• Pregnancy C

• Unpleasant taste

• Must keep saliva in mouth

• Must chew up to 25 pieces daily

• Must avoid acidic beverages, foods


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• Nicotine transdermal systems

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Hurt et al (1994)JAMA 271:595-600

Nicotine patch vs. placebo patch with

nurse counseling in a research setting

Point prevalence of abstinence at 1 year

Placebo patch = 14.2 percent

Nicotine patch = 27.5 percent

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Richmond et al (1997)Addiction 92:27-31

Nicotine patch vs. placebo patch with

counseling in general practice (Australia)

Continuous abstinence for 12 months

Placebo patch = 9 percent

Nicotine patch = 19 percent

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Stapleton et al (1995)Addiction, 90:31-42

Nicotine patch vs. placebo patch, no

counseling in general practice (England)


Placebo patch = 4.8 percent

Nicotine patch = 9.6 percent


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Nicotine transdermal system• Improves quit rates

• Reduces withdrawal

• Steady-state levels

• Unobtrusive

• 0TC

• Apply once daily

• Pregnancy C

• Skin irritation

• Limited dose range

• Smoking + patch may be a danger

• Start after Quit Date

• Nausea, bad dreams

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• Nicotine nasal spray

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Schneider et al (1995)Addiction, 90:1671-1682

Nicotine nasal spray vs. placebo in a

research setting

Continuous abstinence for 1 year

Placebo nasal spray = 8 percent

Nicotine nasal spray= 18 percent


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Nicotine spray (Nicotrol NS®)

• Improves quit rates

• Rapid rise in nicotine levels

• Easy to use

• Pregnancy C

• Addictive potential

• Irritates nasal mucosa

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• Nicotine oral inhaler

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Schneider et al (1996)Addiction, 91:1293-1306

Nicotine oral inhaler vs. placebo oral inhaler, no counseling, research setting

Continuous abstinence for 1 year

Placebo oral inhaler = 8 percent

Nicotine oral inhaler = 13 percent


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Nicotine inhaler (Nicotrol®)

• Improves quit rates

• Moderately rapid rise in nicotine levels

• Easy to use

• Pregnancy C

• Addictive potential

• Looks and feels like a cigarette holder

• Kinetics similar to polacrilex

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Ferry et al (1992)Circulation (abstract supp), 86:I-671

Bupropion 300 mg vs. placebo, treatment for 3 months in a research setting


Placebo = 0 percent

Bupropion = 50 percent

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Hurt et al (1998)NEJM 337:1195-1205

Bupropion (Zyban) in a research setting

Point prevalence of abstinence at 12 months

Placebo = 12 percent

Zyban 100 mg QD = 20 percent

Zyban 150 mg QD = 23 percent

Zyban 150 mg BID = 23 percent


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Hurt et al (1998)NEJM 337:1195-1205

Bupropion (Zyban) in a research setting

Weight gain at six weeks

Placebo = 2.9 kg

Zyban 100 mg QD = 2.3 kg

Zyban 150 mg QD = 2.3 kg

Zyban 150 mg BID = 1.5 kg

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Bupropion (Zyban®)• Improves quit rates

• Reduces withdrawal symptoms

• Reduces craving symptoms

• Reduces depressive symptoms

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Bupropion (Zyban®)• Weight loss more

common than weight gain

• Well-tolerated by both depressed and nondepressed patients

• Pregnancy B


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Bupropion (Zyban®)• Insomnia, dry mouth

• Use caution when combining with antidepressants

• Contraindications: seizure disorders, anorexia/bulimia

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Bupropion (Zyban®)

• Start with patients in Preparation stage

• For most patients: Set a Quit Date 1-2 weeks in the future

• Start Zyban 1-2 weeks before Quit Date

• Initial dose: 150 mg daily

• Maintenance dose: 150 mg BID

• Continue treatment at least 7 weeks

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Jorenby et al (1999)NEJM 340:685-91

Bupropion (Zyban) + NTS in a research setting

Point prevalence of abstinence at 10 wks

Placebo = 27 percent

Nicotine patch 21 mg QD only = 33 percent

Zyban 150 mg BID only = 47 percent

Zyban 150 mg BID + patch 21 mg = 53 percent


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Bupropion (Zyban®) in combination with the patch

• No significant drug-drug interactions

• Higher quit rates than with either product alone

• Well tolerated in combination

• Increased cost

• Potential increase in side effects

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Effective combinations

• Nicotine patch plus nicotine gum

• Nicotine patch plus nicotine nasal spray

• Bupropion plus nicotine gum

• Bupropion plus nicotine patch

• Bupropion plus nicotine nasal spray

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Nicotine

Varenicline

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Varenicline

• Approved May 11, 2006 by FDA (Pfizer)

• Partial agonist at the acetylcholine-N (nicotine) receptor

• High affinity for the α4β2 subtype

• Trade name: Chantix, Champix

• 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

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Varenicline

• Excretion is primarily in unchanged form (81 percent)

• Remainder glucuronidated

• Minimal metabolism

• T ½ excretion = 17 ± 3 hours

Orbach et al (2006) Metabolism and disposition of varenicline, a selective alph4-beta2 acetylcholine receptor partial agonist, in vivo and in vitro.. Drug Metabolism and Distribution http://dmd.aspetjournals.org/cgi/content/abstract/34/1/121


100Orbach et al (2006) Drug Metabolism and Distribution http://dmd.aspetjournals.org/cgi/content/abstract/34/1/121

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Powledge TM (2004) Nicotine as therapy.PLoS Biol 2(11): e404.

Nicotine receptor

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http://www.sdsc.edu/

Nicotine receptor (electron micrograph)


103Foulds (2006) J Clin Pract 60: 571–576

104Foulds (2006) J Clin Pract 60: 571–576

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N

N = Nicotine


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N

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N

Na+

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N V

V = VareniclineN = Nicotine


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NV

V = VareniclineN = Nicotine

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N

V

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N

V


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N

V

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N

V

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N

V


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N

V

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N

V

Na+

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Varenicline

• Partial agonist at the acetylcholine-Nurse site—targets the α4β2 receptor

• Reduced craving and withdrawal symptoms

• The most common adverse effects included nausea, headache, trouble sleeping, and abnormal dreams

Pfizer: data on file


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Varenicline

• Abstinence at 12 weeks of treatment

Varenicline 44 %

Bupropion 30 %

Placebo 17.7 %


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Varenicline

• Abstinence at 12 months of treatment

Varenicline 22.1%

Bupropion 16.4%

Placebo 8.4%


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Varenicline

• November 22, 2007: Early communication on suicidal ideation

• July 1, 2009: Black Box Warning

• Risk of psychiatric symptoms, including depression and suicidal ideation

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WARNING:Serious neuropsychiatric events, including, but not limited to depression, suicidal ideation, suicide attempt and completed suicide have been reported in patients taking CHANTIX. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke. All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking CHANTIX in the post-marketing experience. When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy. These events have occurred in patients with and without pre-existing psychiatric disease. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of CHANTIX and the safety and efficacy of CHANTIX in such patients has not been established. Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. The risks of CHANTIX should be weighed against the benefits of its use. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial. (See WARNINGS/Neuropsychiatric Symptoms and Suicidality, PRECAUTIONS/Information for Patients, and ADVERSE REACTIONS/Post-Marketing Experience)

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Suicidal ideation

• Current smoking is reliably associated with suicide both in case-control and cohort studies. Hypotheses:• Smokers have pre-existing conditions that increase

their risk for suicide• Smoking causes painful and debilitating conditions

that might lead to suicide• Smoking decreases serotonin and monoamine

oxidase levels• Stopping smoking leads to depression in some

smokers; thus, it could induce suicide• Smoking cessation has not been associated with

suicide in the few studies available

Hughes. (2008) Smoking and Suicide: A Brief Overview. Drug Alcohol Depend 98(3): 169–178.

Recovery from nicotine dependence

• Smokers with stable, long-term recovery

• Smokers new in recovery

• Smokers in primary treatment settings



• Smokers with stable, long-term recovery

• Smokers new in recovery

• Smokers in primary treatment settings

Baca (2009) J Subst Abuse Treatment 36:205-219


• Consensus among nicotine dependence experts• Quitting smoking and recovery from nicotine

dependence while in primary addiction treatment is possible, does not interfere with primary addiction recovery, and may be beneficial to recovery

• Addiction treatment episodes are ideal opportunities to address nicotine dependence.

• Becoming a smoke-free treatment environment is necessary but not sufficient to adequately address nicotine dependence during addiction treatment

• The staff will be a bigger problem than the patients


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Nicotine as a therapeutic agent

• Use of nicotine ligand for treatment of schizophrenia

• Nicotine protects against lesions in the striatum in rats (possible protective effect from Parkinson’s disease)

• A nicotine ligand suppresses amphetamine-seeking behavior in rats

• Nicotine reduces Alzheimer’s type degeneration

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Nicotine and sensory gating

• The p50 auditory evoked potential (AEP) attenuates with repeated stimuli in normal humans

• Persons diagnosed with schizophrenia do not attenuate the p50 AEP

• After one cigarette, the AEP in patients with schizophrenia normalizes

• The AEP does not normalize with use of the nicotine patch

Adler (1998) Schizophrenia Bulletin, 24(2): 189-202.


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Environmental tobacco smoke

• Annoying, messy, insensitive

• Acute respiratory illnesses

• Arteriosclerotic heart disease

• Carcinoma

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136Source: Gallup poll

Public health measures

• Increasing the cost of tobacco products• Smokefree buildings and grounds• Decreased availability of cigarettes• Programs to decrease smoking initiation

by children and adolescents• Limiting advertising of cigarettes• Public awareness programs• Information on health risks of smoking


Percentage of smokers quitting each year

Zhu (2012) Tobacco Control 21:110-118

Quit attempts, quit success, use of cessation aidsZhu (2012) Tobacco Control 21:110-118

Thank you for your participation in the Review Course

nicotine and tobacco dependence

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