1. Smoking Cessation !! How to become a real option ????
Dr. Assem Fouad El Esssawy
Lecturer of Chest Diseases
Fayoum University.

2. Why people smoke/ Is smoking a life style choice?
Smoking a cigarette for a beginner is a symbolic act of rebellion
Smoking is not a life style choice
Creates a dependent state
Nicotine addiction is a complex process
Quitting smoking leads to decrements in attention and cognition
Impaired concentration, thinking, and performance associated with nicotine deprivation are strong motivating factors to smoke
For much of the 20th century, smoking was regarded as a socially learned habit and as a personal choice or as a lifestyle choice
Experimenting with smoking usually occurs in the early teenage years and is driven mainly by psychosocial motives. For a beginner, smoking a cigarette is a symbolic act conveying messages of adulthood or rebelliousness. Children who are attracted to smoking tend to come from backgrounds that favor smoking (high levels of smoking in parents, schools where smoking is common). They also tend not to be succeeding according to their own society rules (they have low self esteem, impaired psychological wellbeing, are overweight or poor achievers at school).
By age of 20, 80% of cigarette smokers regret that they ever started, but as a result of their addiction to nicotine, many will continue to smoke for a substantial proportion of their lives.
Nicotine addiction is a complex process, involving biological, psychological, cultural and behavioral factors. Smokers who try to quit experience decreased attention and cognition. It has been shown that impaired performance can be seen within 4 hours of enforced discontinuation of tobacco use, and impaired concentration, thinking, and performance brought on by nicotine deprivation are strong motivating factors to smoke a cigarette.
M.J Jarvis, BMJ 2004;328:
Heishman SJ. Nicotine Tob Res. 1999;1:S144

3. Mechanism of Action of Nicotine in the Central Nervous System
1/Picciotto, p. S121, para 1 a4 b2
4b2
Nicotinic Receptor
Key Point
Nicotine stimulates dopamine release in areas of the brain which is believed to result in the reward and satisfaction effect associated with smoking.
Background
After inhalation, nicotine preferentially binds to nicotinic acetylcholinergic (nACh) receptors located in the mesolimbic-dopamine system of the brain within a matter of seconds. Nicotine specifically activates 4β2 nicotinic receptors in the Ventral Tegmental Area (VTA) causing an immediate dopamine release at the Nucleus Accumbens (nAcc).1 The dopamine release is believed to be a key component of the reward circuitry associated with cigarette smoking.1
Reference
1. Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S
1/Picciotto, p. S121, para 1
Nicotine binds preferentially to nicotinic acetylcholinergic (nACh) receptors in the central nervous system; the primary is the 42 nicotinic receptor in the Ventral Tegmental Area (VTA)
After nicotine binds to the 42 nicotinic receptor in the VTA, it results in a release of dopamine in the Nucleus Accumbens (nAcc) which is believed to be linked to reward

4. Given tobacco’s carcinogenic properties, smoking has been an identified risk factor across an array of diseases and is causally linked to a host of cardiovascular, respiratory, reproductive, and other conditions, as well as many types of cancer. This includes its link to the top 3 smoking attributable causes of death in the United States 1) lung cancer, 2) ischemic heart disease, and 3) chronic obstructive pulmonary disease (COPD), respectively. Mortality from these conditions is considerable. For example, from 1995–1999, the top 3 smoking-attributable causes of death in the United States, respectively, were cancers of the lung, trachea, and bronchus (n=124,800 annually), ischemic heart disease (n=82,000 annually), and COPD (n=64,700 annually)1.
Further details include:
Ischemic stroke risk doubles for cigarette smokers, and hemorrhagic stroke risk increases 2 to 4 times vs nonsmokers. There is a synergistic effect of smoking on stroke risk in women using oral contraceptives. Passive cigarette smoke confers a doubling of risk for stroke approaching that of active smoking, and an "exposure threshold" rather than a dose-response relationship is observed4.
There is a less obvious link, yet still a risk factor for smokers in areas such as osteoporosis, wound healing, peptic ulcers, metabolic syndromes, etc. The clear takeaway is that the risks of smoking posed on the body are not confined to any one system.
References
CDC. Surgeon General’s Report. The Health Consequences of Smoking: Executive Summary
CDC. US Department of Health and Human Services. The Health Consequences of Smoking. A Report of the Surgeon General. Atlanta, Ga: Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004.
Weitzman M, Cook S, Auinger P, et al. Tobacco smoke exposure is associated with the metabolic syndrome in adolescents. Circulation. 2005;112(6): Epub 2005 Aug 1.
Goldstein LB, Adams R, Alberts MJ, et al. Primary Prevention of Ischemic Stroke. A Guideline from the American Heart Association/American Stroke Association Stroke Council. Cosponsored by the Outcomes Research Interdisciplinary Working Group Physical Activity, and Metabolism Council; and the Quality of Care and Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group. Stroke. 2006;37;

5. Smoking is a Chronic disease
The therapeutic approach is based on:
Motivation of patients and their willingness to quit
Reinforce the motivation of the patient to initiate smoking cessation
Ease the withdrawal period and
Prevent relapse
Success is often obtained only after several attempts
Clinicians should adopt the same attitude as they would with other chronic disorders.

6. Efficacious approaches for smoking cessation
Two types of approaches have demonstrated their efficacy for smoking cessation:
Counseling
Pharmacotherapy
The best results are obtained by combining the two approaches
Fiore MC. Treating tobacco use and dependence. Resp Care 2000;45:1200
West R. Smoking cessation guidelines for health professionals: an update. Thorax 2000;55:987
Simon JA. Smoking cessation counseling (intensive vs minimal). Am J Med 2003;114(7):555

7. Practical steps

8. “1” Ask: The smoking history
Age started smoking
Number of cigarettes smoked daily
How soon after waking does the patient smoke
Previous attempts/success/aides used
Previous withdrawal symptoms experienced
Reasons for failure
Any smokers in the home
Motivation e.g. health, finance

9. “2” Assess: measurements of smoking intensity
(Modified) Fagerstr̈om Test for Nicotine Dependence
Biochemical serum, urine or salivary cotinine - exhaled carbon monoxide
CO measure is useful
for reinforcing patient’s motivation to quit

10. Modified Fagerstrom
1991

11. Preparing the quitting day
A personalized action plain must be
prepared in association with the patient
Potential causes to relapse and how to
cope with them
A smoking cessation date should be prepared, allowing arrangements for follow-up
It is important to see the patient the first day
or week of smoking cessation
Most relapse occurs within a few days of cessation
Provide behavioral support
Adjust the pharmacological treatment

12. Arrange
Arrange follow-up session within 7 days

13. For patients unwilling to quit
Clinicians should provide a brief intervention that is designed to promote the motivation to quit (the 5Rs)
Relevance
Risks
Rewards
Roadblocks
Repetition
Anderson J. Treating Tobacco Use and Dependence. An evidence-based clinical practice guideline. Chest 2002; 121:932-41

14. Pharmacological therapy
C.I.= contraindication

15. Nicotine Replacement Therapy
Transdermal systems
Acute systems

16. NRT prescribing advice for 6 weeks
Side effects
Local (skin, mouth,nose)
GIT
Rarely AF, sleep disturbances
Indications
Reduction of withdrawal symptoms
Temporary abstinence
Reduced smoking to quit
NOT
Relapse prevention (yet?)
Long term maintenance
Contraindications
NONE
Cautions
Unstable CVS
Pregnancy / breastfeeding

17. 150mg twice daily thereafter
Antidepressants
Bupropion SR: dopaminergic and noradrenergic profile
Mechanism of action for smoking cessation unknown
Possibly works via multiple mechanism
Efficacy comparable to NRT or even slightly superior
Nortriptylline
A tricyclic antidepressant with mostly noradrenergic properties
Effective but the limited number of trials and the side effects make it second-line intervention
Grade A
Dose: 150mg/day (3-6 days)
150mg twice daily thereafter
SOS : never >300mg/day
Bupropion may assist in helping patients to quit smoking because it reduces symptoms of depression associated with withdrawals.
It is now considered first line therapy for smoking cessation while the strength of the evidence merits a rating A (Grade A)
The target dose of this agent in nicotine dependence is 300 mg/day. Bupropion is started at least 7 days before the target quit day (TQD) at a dose of 150 mg once a day, and increased to 150 mg twice daily after 3-6 days so that steady-state levels are achieved before the quit attempt.
The most serious adverse effect of Bupropion SR is seizure in 0.1% of users. common side effects include insomnia, ,agitation, dry mouth, headache, skinrash, pruritus, hypersensitivity and dizziness. The use of the drug is contraindicated in patients with history of epilepsy or in patients with seizure or under medication predisposing to a low threshold for seizure as well as in patients with a history of anorexia or bulimia, uncontrolled hypertension or severe hepatic necrosis.
See next slide for smoking cessation rates (point prevalence) with placebo and Sustained-release Bupropion in different doses. (Hurt RD. A comparison of sustained-release Bupropion and placebo for smoking cessation. N. Engl J Med 1997;337(17):
A Cochrane review reveals that nortriltylline is an effective smoking cessation adjunct, with approximately equivalent efficacy to Bupropion.
The efficacy of the drug is independent of its antidepressant effects. In studies of its use as an antidepressant, nortriptylline sometimes caused sedation, constipation, urinary retention and cardiac problems (an overdose can be fatal).
Grade B
75mg/day

18. Bupropion prescribing
Side effects
Insomnia (40%)
Dry mouth (12%)
Hypertension
Urticaria
Seizure (1 in 1000)
Indications
Reduction of withdrawal symptoms
Reduced smoking to quit
NOT
Relapse prevention (yet?)
Long term maintenance
Contraindications
Eating disorder
Seizure (FH)
Many drugs (steroids, theophyllines, antidepressants)
Pregnancy
Breast feeding

19. New Medications for Smoking Cessation
Nicotine Acetylcholine Receptors n-ACh antagonists

20. Varenicline: A Highly Selective 42 Receptor Partial Agonist
Nicotine
Chantix
Key Point
Champix™ (varenicline) was deliberately designed for the 42 receptor, as an 42 nicotinic receptor partial agonist (with dual agonist and antagonist properties) and physically prevents nicotine from binding as an aid in smoking cessation.
Background
The initial view of the mesolimbic system identifies the VTA where the 42 receptors predominate, as well as the nAcc. The release of dopamine at the nAcc from the axons of the dopamine cells of the VTA is believed to produce a reward response. When nicotine binds at the 42 nicotinic receptor in the VTA, it is believed to cause release of dopamine at the nAcc. Champix™ (varenicline) was deliberately designed for the 42 receptor, as an 42 nicotinic receptor partial agonist (with dual agonist and antagonist properties) and physically prevents nicotine from binding and releases intrinsically less dopamine at the nAcc.
References
Coe JW, Brooks PR, Wirtz MC, et al. Varenicline (CP-526, 555): A novel, potent, and selective nicotinic receptor partial agonist for the treatment of smoking cessation: Rationale, discovery, and mode of action. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco, March 20–23, 2005, Prague, Czech Republic.
Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-S125.
Binding of nicotine at the 42 nicotinic receptor in the VTA is believed to cause release of dopamine at the nAcc
Champix is an 42 nicotinic receptor partial agonist, a compound with dual agonist and antagonist activities. This is believed to result in both a lesser amount of dopamine release from the VTA at the nAcc as well as the prevention of nicotine binding at the 42 receptors.
1. Coe JW et al. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco Prague, Czech Republic. 2. Picciotto MR et al. Nicotine Tob Res. 1999; Suppl 2:S121-S125.

21. Varenicline prescribing for 12 weeks
Indications
Reduction of withdrawal symptoms
Relapse prevention in abstinent individuals
Side effects
GIT
Sleep disturbances
Abnormal dreams
Contraindications
Pregnancy
Cautions
Psychiatric
Renal impairment

22. Varenicline prescribing
500mcg1
500mcg2
1mg2*
3 days
4 days
11 weeks
quit
reassess
*reduce to 500 mcg2 if side-effects but avoid abrupt withdrawal

23. 4-Week Continuous Abstinence Response Weeks 9–121OR
VAR vs Pbo 3.91 P<0.0001
VAR vs BUP 1.96 P<0.0001 OR
VAR vs Pbo 3.85 P<0.0001
VAR vs BUP 1.89 P<0.0001
Study 1
Study 2
1/Champix Summary of Product doc/p. 7/¶7 /Table 60 60 50 50
44.4%
44.0% 40 40 CA
Response
rate (%)
Key Point
In both studies, varenicline resulted in continuous abstinence (CA) rates at weeks 9 through 12 that were significantly higher than for placebo or bupropion.
Background
For the primary end point of carbon monoxide (CO)–confirmed, 4-week CA rates were defined as patient report and exhaled CO <10 ppm. 4-week CA rates with varenicline treatment were significantly higher compared with bupropion treatment or placebo.1 In study 1, 44.4% of participants in the varenicline group were continuously abstinent from smoking during weeks 9 to 12 compared with 29.5% of participants in the bupropion group and 17.7% of participants in the placebo group (both P<0.0001). This translated to an abstinence OR of 3.91 for varenicline vs placebo and an OR of 1.96 versus bupropion.1 Similarly, in study 2, 4-week abstinence rates for varenicline, bupropion, and placebo were 44.0%, 30.0%, and 17.7%, respectively. Varenicline was significantly more effective compared with placebo (OR, 3.85; P<0.0001) and bupropion (OR, 1.89; P<0.0001).1 Subjects were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counseling at each clinic visit in accordance with Agency for Healthcare Research and Quality Guidelines.
Reference
1. Champix Summary of Product Characteristics. Pfizer Ltd, Sandwich, UK
29.5%
30.0% CA
Response
rate (%) 30 30 20
17.7% 20
17.7%
1/Champix Summary of Product doc/p. 7/¶7/Table 10 10
VAR 1 mg bid (n=344)
BUP 150 mg bid (n=342)
Pbo (n=341)
VAR 1 mg bid (n=352)
BUP 150 mg bid (n=329)
Pbo (n=344)
Nausea was reported by 28.6% of patients treated with varenicline 1 mg bid. The discontinuation rate for this adverse event was 2.7%. Nausea was generally described as mild or moderate.
VAR=varenicline, Pbo=placebo, BUP=bupropion; OR = Odds ratio.
1. Champix Summary of Product Characteristics. Pfizer Ltd, Sandwich, UK

24. New Treatments for Smoking Cessation
Cannabinoids Receptors Inhibitors (rimonaband ??)
Modifiers of nicotine metabolism (CYP2A6 inhibitors)
Nicotine Vaccines

25. New Medications for Smoking Cessation
Cannabinoid Receptor
Antagonists

26. Cannabinoid Receptors
The primary psychoactive constituent of marijuana, is related to the action on two cannabinoid receptors :
CB(1) and CB(2)
THE NECTAR OF DELIGHT

27. Weight and Smoking !!

28. Rimonabant is a CB1 receptor antagonist
Blocks nicotine-induced reinforcement and self admin in animals (Cohen 2002)

29. New Medications for Smoking Cessation
Modifiers of nicotine metabolism

30. Modifiers of nicotine metabolism
Inhibitors of CYP2A6
Nicotine
CYP2A6
Cotinine
CYP2A6
3-hydroxycotinine

31. Cytochrome CYP2A6 CYP2A6 Polymorfism (26 alleles) Is Related with
Nicotine metabolism
Lower smoking initiation rate and lower smoking depedence
Lower smoking habit
Reduced risk for lung cancer

32. Other New Approaches for Smoking Cessation
Vaccination ????

33. Vaccines Antibodies bind to nicotine Prevent nicotine passing the
blood-brain barrier

34. Vaccines contd TA-NIC, NicVax, Nicotine-Qbeta
Phase I and II complete, phase III expected 2008
Advantages: Not daily, few SEs, can be given alongside other medications?
But
Cost, variability, frequency dosing, slow onset, need high antibody titres, immune adaptation, ethical issues

35. Further Questions on New Treatments
More clinical trials and real phase studies to assess :
Effectiveness
Long term use
Relapse Prevention
Weight gain
Combined use

36. Nicotine Addiction Treatment
Sunrise in
Nicotine Addiction Treatment

37. ‘True hope is like the crouched tiger, which will jump only when the moment for jumping has come.’ Erich Fromm
For global tobacco control movement in every country of the world, the moment for jumping has come!