Tobacco Smoking as an Addiction Karl Fagerstrom Ph.D. Smokers Information Centre

1. Tobacco Smoking as an Addiction Karl Fagerstrom Ph.D. Smokers Information Centre Helsingborg, Sweden karl,.fagerstrom@swipnet.se

2. Addiction to Nicotine or Tobacco ? WHO-ICD prefers Tobacco, APA Nicotine. Tobacco contains many more pharmacologically active substances than nicotine. No addiction in history to pure nicotine. Parallells with pure caffeine and coffee?

3. Nicotinic acethylcholine receptors • The most abundant form is a pentameric receptor made of 4-2 units • 7 forms robust, homomeric nAChR Nicotine is reaching the Brain in a few seconds 7 7 7 Leonard & BertrandNicotine Tob Res, 2001; 3:203-223 7 7

4. Nicotine modulates Neurotransmitters Le HouezecAIM N°25, 1995 Nicotine acts both pre- and post- synaptically

5. The Dopaminergic mesolimbic system Nicotine acts particularlyon dopamine The DA system is of key importance in animals. Also in humans?

6. Nicotine activates the brain London et al 1991

10. Smoker Non Smoker C-11Nikotine Nordgerg Pers comm

12. TOLERANCE Short term: Related to the status of the receptor Long term: Related to number of receptors

13. Withdrawal Symptoms Irritation, anger Weight gain Insomnia Concentration difficulties Anxiety Restlessness Dysphoria Decreased heart rate Performance deficits Craving Headache Fiore MC et al. JAMA 1992; 268: 2687–2694.

14. Time Course of Withdrawal Symptoms Can occur after a few hours Usually peaks within 2 weeks Energy expenditure and mood effects not true withdrawal symptoms

15. WHO ICD-10 Criteria for Tobacco Dependence A Strong desire to smoke B. Difficulties to control the amount C. Continued use despite harmful concequences D. Influencing priorities of other activities E. Increased tolerance F. Physical withdrawal Three need to be present for a diagnosis

16. Very Difficult to Give Up 2-3% succeeds long term Hughes 1999 75% of addicts to other drugs find it at least as difficult to give up smoking Kozlowski et al 1983

19. Jarvis et al 2000

20. With treatment Probability to quit Without Tx Dependence

21. SMOKERS COPD N=153 HEALTHY N=870 DEPENDENCE 4.8 3.1 p<.001 (FTND) CARB. MONOX. 19.7 ppm 15.4 ppm p<.000 Jimenéz-Ruiz et al. 2001

22. Is the role of nicotine over empahzised • No epidemic use of pure nicotine • No misuse of nicotine replacement • Nicotine not a strong reinforcer in animals (McDonald et al 1997). • Human i.v. self-administration studies not very convincing (Henningfield & Goldberg 1983, Henningfield et al 1983). • Human self-administration ofNR not very convincing (Patch, e.g. Benowitz et al. 1998, Gum, e.g. Hughes et al 2000, Spray,e.g. Perkins et al 2001). • Other pharmacoligically active sustances in tobacco, CO, MAO-inhibitors (Fowler et al 2003), Acetaldehyde (Castagnoli 2001).

23. Available drugs tested for smoking cessation • Naltrexone Opioid anatgonist • Selegeline MAO-B inhibitor • Nortriptyline Anti-depressant • (Glucose) • Under investigation • Benoxatone MAO inhibitor • Rimonabont CB-1 blocker • Varenicline Part nic rec agon • Dianicline ” • Nicotine vaccines • Under pre-clinical testing • Glutamate receptor 5 antagonist, GABA enhancers

24. Rimonabant and The Endocannabinoid System • The Endocannabinoid System(EC System) • A natural physiological system believed to play a role in maintaining energy balance through the regulation of food intake and energy expenditure. • The EC system also plays a role in tobacco dependence. • Over-activity of the EC System is associated with obesity and tobacco dependence • Rimonabant • First selective CB1 Blocker. • Selectively blocks CB1 receptors and helps to normalize the disrupted EC System.

25. Treatment Procedure 2 weeks of Rimonabont and smoking Quitting at day 15 8 weeks on Rimonabont

26. Smoking cessation results, in percent, at 8 weeks from quit day. USA Europe Placebo N=261 16 20 5 mg N=262 16 24 20 mg N=261 28 25 Antionelli et al 2004

27. Weight change from baseline to end of treatment (10 weeks) in non obese Placebo 3,0 kg 5 mg 2,5 kg 20 mg 0,7 kg Antionelli et al 2004

28. Most frequent side effects Nausea Diarrea Vomiting Insomnia Urinary tract infections Antionelli et al 2004

29. VareniclineMode of Action It was developed specifically as a Partial Agonist at the 42 nicotinic acetylcholine receptor combining agonist and antagonist properties in one compound.

30. Blocks reward Rationale Partial Agonist: Antagonist Effect Full agonist 100% Partial agonist Effect 50% Craving and withdrawal relief 0% Dose, exposure • A partial agonist has the potential to block the reward associated with smoking and provide relief from craving

31. Any 4-week Continuous Quit Rate Oncken et al 2005

32. CO-confirmed non-smoking Oncken et al 2005

33. Studies I & II: CO-Confirmed Continuous Abstinence Rates Wks 9-52 100 OR=3.13p<0.0001 OR=2.66p<0.0001 40 OR=1.45p=0.064 OR=1.72p=0.0062 Response Rate (%) 20 23.0 22.1 16.4 15.0 10.3 8.4 0 N=340 N=340 N=349 N=329 N=344 N=343 Study I Study II Varenicline Zyban Placebo OR = odds ratio

34. Side effects (in percent) Placebo Varenicline Bupropion Nausea 9 28 10 Headache 12 14 11 Abnormal dreams 4 11 5 Flatulence 2 5 3 Tonstad et al 2005

35. Scientific Rationale The nicotine molecule itself is too small to be recognized by the immune system. Therefore it is coupled to a carrier protein to form an immunoconjugate The immunoconjugate will elicit a humoral immune response generating nicotine selective antibodies The antibodies will bind nicotine, thus, preventing it from reaching the brain and thereby inhibiting the occurrence of nicotine’s central nervous stimulating and addictive pharmacological effects

36. Drug Linker Carrier Protein IMMUNOGEN

37. Important criteria for a nicotine vaccine • Induction of high antibody titres against nicotine and a prolonged immune response. • The antibodies induced should have a high specificity for nicotine and low/no specificity for metabolites from nicotine • Possible to administer parenteral and nasal/oral

38. Brain Blood +

39. NICOTINE DISTRIBUTION in RATS ** Nicotine (ug/g) ** Pentel et al., Pharmacol. Biochem. Behavior 65: 191-198, 2000

40. Immunisations day 0 and 14. KLH-nicotine hapten and FCA, 100 or microgram /dose. Voltametri 3-87 days after last immunisation

42. Animal Studies: Effects of Immunotherapy • Reduces response to nicotine • Physiological: blood pressure • Behavioral: locomotor activity • Reduces • Nicotine relief of nicotine withdrawal • Nicotine discrimination • Acquisition of nicotine self-administration • Reinstatement

43. Immune Response to NicVAX 30 200 ug Nicotine Specific Antibody (ELISA Units) 20 100 ug 10 50 ug Placebo 0 0 50 100 150 200 250 Day Days

44. Vaccines: Summary of early development * Quit rate among actively vaccinated was related to antibody response.

45. Vaccines against nicotine a promising • new tool that can be used for • achieving abstinence • prevent relapse

46. Summary In a few years we will have more and probably also more efficacious treatments to offer the smokers.

47. Thank you for the attentıon

48. ”Cancers of the respiratory tract are responsible for one death in 20 in the EU. These cancers are mainly due to Nicotine poisoning”. EUROSTAT. Mortality in the EU 2004.

49. Prefrontal cortex Nucleusaccumbens Ventral Tegmental Area (VTA) Nicotine addiction: Anatomy of Reinforcing Behavior Nicotine’s reinforcing effects are likely due to its effects on the mesolimbic dopamine (DA) system • Nicotine activates DA neurons in the Ventral Tegmental Area (VTA) • Systemic nicotine stimulates DA release in the nucleus accumbens DA DA X DA • Locomotor effects produced by systemic nicotine, or local nicotine injection into VTA, are blocked by lesions of the VTA • Nicotinic antagonists infused into the VTA block self-administration