1. Nicotine Dependence Laurie Zawertailo, PhD Adjunct Research Scientist Clinical Neuroscience, CAMH

2. Objectives 1.To review the main physiological and pharmacological aspects of nicotine use, abuse, and dependence. 2.To discuss the different treatments available for nicotine dependence.

3. Cigarette Smoking (Statistics) 47% worldwide 47% men 12% women 25% North America 1/3 - 1/2 of adolescents daily smoking 15% - 25% success rate to quit smoking –Spontaneous quit rates in adults 6-7%

4. Costs of Tobacco Dependence 30% (males) and 17% (females) of all cancer deaths in Canada are due to smoking. Over 25% of cancer burden in Canada is attributable to lung cancer. 80 - 90% of lung cancers are directly attributable to smoking Smoking is also directly linked to –Diabetes –Heart disease –Stroke –Respiratory diseases –CV disease

5. Factors Associated With Smoking Biological hereditary, psychiatric, psychological Environmental parties, bars Social predisposition family, friends, cultural Easy access Socially acceptable? Peer pressure

6. Factors ENVIRONMENT HOSTAGENT VECTOR

7. Release of catecholamines increasing sympathetic tone (GI motility, cardiac stimulation), arginine- vasopressin, beta endorphins, ACTH, cortisol, GH, PL, etc. Enhanced memory, task performance, concentration, attention, and anxiety reduction. ?

8. Clinical conditions associated with smoking: Respiratory Cardiovascular Comorbidity: Psychiatric disorders Schizophrenia, depression, anxiety Other drugs of abuse Alcohol abuse/dependence

9. Nicotine Psychoactive drug contained in tobacco Likely responsible for the addictive properties of cigarettes Self-administered by animals and humans Reinforcing and rewarding Following continuous administration the reinforcing effects of nicotine become prominent and the control over its use is lost

10. Nicotine content in cigarettes: 6 – 11 mg (1-3 mg are absorbed) Pack a day = 20 – 40mg Smokers adjust their nicotine intake High yield nicotine – less cigarettes Low yield nicotine – more cigarettes

11. Pharmacology of Nicotine Absorption Buccal and nasal mucosa, skin, GI tract Blood flow, membrane permeability, surface area, and pH Other factors known to modify the rate of absorption: Degree and depth of inhalation Number, duration, and volume of puffs Use of a filter Number of cigarettes smoked Time spent smoking each cigarette

12. Distribution 19 seconds to reach the brain Half-life: 2 hours Metabolism and elimination Liver and kidneys Main metabolite: cotinine (70% - 80%) CYP 2A6 Peak nicotine concentrations are reached after completion of cigarette smoking

13. Pharmacokinetics of Nicotine After Smoking

14. Neuropharmacology of Nicotine Dependence nAChR’s Dopaminergic system (reward) Tolerance, physical dependence MAO A and B

15. Cigarette Active nAChRs Dopamine release Smoking initiation Desensitized nAChRs Nicotine Reward Pathological learning Inactive nAChRs Acute tolerance Smoking continuation Hyper excitable nAChRs Chronic tolerance Smoking discontinuation Withdrawal Drive for the next cigarette Increased no. of AChRs Smoking relapse Perpetuation of smoking behaviour

16. Tobacco as a Drug of Abuse DRUG% ever used% addiction% risk Tobacco75.624.131.9 Alcohol91.514.115.4 Illicit Drugs51.07.514.7 Cannabis46.34.29.1 Cocaine16.22.716.7 Anxiolytics12.71.29.2 Analgesics9.70.77.5 Psychedelic10.60.54.9 Heroin1.50.423.1 Goodman and Gilman, 2001

17. Nicotine Withdrawal Syndrome  Psychological Irritability Anxiety Aggressiveness Inability to concentrate Depressed mood  Physical Difficulty sleeping Increased appetite Headache

18. Drug (Nicotine) Dependence DSM IV Criteria 1.Inability to stop using the drug 2.Preoccupation about drug use 3.Use despite harmful consequences 4.Presence of symptoms accounting for brain adaptation resulting in persistence use of the drug 5.Use despite significant drug-related problems

19. Fagerström Test for Nicotine Dependence

21. Treatments for Nicotine Dependence Behavioural Intervention Therapies Individual behavioural counseling Nicotine fading Aversion treatments Acupuncture Hypnosis

22. Nicotine Replacement Therapies Patch (7, 14, 21, 22mg) 6-12 wks Gum (2 and 4mg) 8-12 wks Inhaler (4mg/cartridge) 6 – 16/day 3-6 mo Nasal spray (1-2/hr; 0.5mg each; max 40mg/day) 3-6mo Low yield cigarettes

23. Bupropion 150mg twice/day 8-12 wks Risk of seizures (>300mg) Nortriptyline Clonidine Nicotine Blockade Therapy Mecamylamine Experimental approaches GABA agonists (vigabatrin)

24. Factors Associated With Low Quitting Success Rate Comorbid psychiatric conditions Alcohol or substance abuse High nicotine dependence Lack of social support for quitting Low self-confidence in ability to quit

25. Pharmacokinetics of NRT

26. Treating Tobacco Dependence Smoking is a complex human behaviour Often takes several quit attempts before one is successful NRT is most successful when combined with supportive care. Lapse and relapse is very common.