1. 니코틴의존의 새로운 약물치료 니코틴의존의 새로운 약물치료 가톨릭대학교 성가병원 신경정신과 금연클리닉 김 대 진

4. 금연 성공 ‘ 의지 ’ 만으론 부족하다 - 한겨례. 2005. 5. 3. -

6. 니코틴 의존에 관한 이해  중독  약물남용/의존  갈망  뇌보상회로

8. N EUROBIOLOG Y  Why Smoke?  Addiction  Dopamine  VTA, nAcc  Withdrawal Symptoms

9. Why Do People Smoke?  Since at least the 1988 US Surgeon General’s Report 1 –Addiction defined as compulsive use despite damage to the individual or society and drug-seeking behavior can take precedence over important priorities –Addiction persists despite a desire to quit or even repeated attempts to quit  Most people smoke primarily because they are addicted to nicotine 2  There is a clear link between smoking, nicotinic receptors, and addiction 2 Addiction – Habitual psychological and physiological dependence on substance or practice which is beyond voluntary control – Stedman’s Medical Dictionary 1. Centers for Disease Control and Prevention. The Health Consequences of Smoking: Nicotine Addiction; A Report of the Surgeon General. Washington DC: US Department of Health and Human Services; 1988. 2. Jarvis MJ. BMJ. 2004;328:277-279.

10. 뇌보상회로 뇌보상회로  뇌 안에 존재하는 긍정적인 보상 또는 강화시스템  양성강화시스템 – 뇌의 자극을 통해 행동의 반복을 유발 – 먹는 것, 성행위 등 생존과 종족 보존을 위한 기본적인 생 물학적 기능들은 반복적으로 일어나게 하기 위한 것 – 일생을 통하여 이들 중추들을 자극하는 경험을 배우게 됨  그러나 인위적으로 이들 뇌보상회로를 활성화시킬 수 있음

11. Natural Rewards and then…  Food  Water  Sex  Nurturing

12. NA VTA PFC prefrontal cortex NA nucleus accumbens VTA ventral tegmental area A amygdala C cingulate gyrus H hippocampus

14. 44 22 22 22 44  4  2 nicotinic ACh receptors nicotine Nicotine Addiction: Reinforcin g Behavior Dopamine GLU GABA  Nicotine activates nAChRs on Dopamine neurons in the VTA  Enhanced DA release in the n. accumbens (‘reward system”) Rollema et al (2007) TiPS 28(7): 316-325

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

19. Smoker Non Smoker C-11 Nicotine Nordberg Pers com

21. Enhanced dopamine release in smokers STRIATAL DOPAMINE RELEASE FOLLOWING NICOTINE ADMINISTRATION BP reduction in the striatum SmokersNon-smokers nicotine Takahashi et al Int J Neuropsychoparmacol 2007

22. Positive correlation between FTND score and BP reduction Nicotine dependence and dopamine release FTND The more you dependent, the more you release dopamine Takahashi et al Int J Neuropsychoparmacol 2007

23. Rationale:  4  2 nAChR partial agonists for smoking cessation Theoretical paper by Jed Rose & Edward Levin*: “Improved efficacy by combining nicotine (an agonist) with mecamylamine (an antagonist)” * Rose and Levin (1991) Concurrent Agonist-Antagonist Administration for the Analysis and Treatment of Drug Dependence. Pharmacol Biochem Behav 41: 291-226

24. Hypothetical effects of smoking without and with NRT on mesolimbic DA release Time Response to nicotine Smoking NRT = cigarette smoked + smoking Rollema et al (2007) TiPS 28(7): 316-325

25. Instead of nicotine + mecamylamine, better if: 1. Agonist and antagonist properties can be combined in 1 drug, i.e. a partial agonist 2. Such a drug is selective for the receptor that mediates addictive effects of nicotine, i.e.  4  2 Therefore: design a  4  2 selective partial agonist 1992: Dr. Jim Heym (Pfizer Neuroscience) Rationale:  4  2 nAChR partial agonists for smoking cessation

26. Hypothetical effects on mesolimbic DA release of smoking with NRT or with Nicotinic Partial Agonist Time Response to nicotine Smoking NRTPartial agonist = cigarette smoked + smoking Rollema et al (2007) TiPS 28(7): 316-325

27. Nicotine Part Ag Part ag Agonist and Antagonist actions of a  4  2 nAChR Partial Agonist  4  2 nAChR Dual action of a partial agonist Agonist Response100% Nicotine Smoking No Partial Ag No Smoking Partial Ag Smoking + Partial Ag Antagonist50% Potential to block reinforcing effects when smoking Partial Agonist50% Potential to relieve craving and withdrawal when quitting Potential to relieve craving and withdrawal when quitting

28. 0% Dose, exposure Agonist Effect 100% 50% Full agonist (nicotine) Partial agonists with 50% efficacy Relieves craving and withdrawal Functional activity and efficacy: Agonist action Rollema et al (2007) TiPS 28(7): 316-325

29. 0% Dose, exposure Antagonist effect 100% 50% Nicotine + weak 50% partial agonist Nicotine + potent 50% partial agonist Nicotine effect Blocks reinforcement Functional activity and efficacy: Antagonist action Rollema et al (2007) TiPS 28(7): 316-325

30. Nicotine Synthesis: Clues from Nature Synthesis: Clues from Nature Tobacco plant Morphine Opium poppy Cytisine Golden Chain

31. Varenicline synthesized Feb 1997 Varenicline Coe et al (2005) J Med Chem 48: 3474-3477

32. Measure concentration of free radio-label: affinity High Binding Affinity = Low K i (in nM) Neurotransmitter or drug: Acetylcholine, nicotine, varenicline Receptor, transporter: a4b2 nAChR radiolabeled ligand compound Properties 1 - Binding to the receptor: Affinity In vitro receptor binding: displacement of labeled ligand

33. Measure the current evoked by drug application: EC 50 = functional potency E max (max effect as % of nicotine) = functional efficacy Neurotransmitter or drug: Acetylcholine, nicotine, varenicline Receptor, transporter: a4b2 nAChR Depolarisation: effect Properties 2 - Effect on the receptor: Activity In vitro electrophysiology (current by patch clamp)

34. (V H = -60 mV, 2 sec. agonist application) Time (s) I, (pA) Nicotine 10 µM Varenicline 0.3 µM Varenicline 1.0 µM Varenicline 3.0 µM Varenicline 10 µM drug on Partial agonist activity in vitro at  4  2 nAChRs expressed in HEK cells 45% partial agonist EC 50 =  3.1  M Rollema et al (2007) Neuropharmacology 52: 985-994

35. Time (sec) Current (pA) 200 0 -200 -400 -600 -800 -1000 0 5 10 15 20 25 Nicotine 10 M Varenicline 0.1 M Varenicline 1.0 M Varenicline 10 M Antagonist activity in vitro at  4  2 nAChRs expressed in HEK cells 55% antagonist IC 50 =  0.8  M Rollema et al (2007) Neuropharmacology 52: 985-994

36. Properties 3 – Effect on DA: Function and Potency In vivo microdialysis in rat nucleus accumbens

37. 75 100 125 150 175 200 -180-120-60060120180240300360 Time (minutes) Dopamine Release in N. Accumbens % of Basal ± SEM Nicotine 0.32 mg/kg Nicotine 0.32 mg/kg sc Varenicline 1 mg/kg po + Nicotine 0.32 mg/kg sc Varenicline 1 mg/kg po Nicotine 0.32 mg/kg Partial agonist and antagonist effects on dopamine release in rat nucleus accumbens Coe et al (2005) J Med Chem 48: 3474-3477

38. Computerized data collection and operant controller Sound-proof enclosure Swivel Tether Valve Drug reservoir Syringe pump assembly Operant system for intravenous self-administration of drugs in mice. Lights for reinforcement response Nose poke holes S.C. saddle Operant chamber Operant system for intravenous self-administration of drugs Properties 4 – Behavior: Animal model of Addiction Nicotine Self-Administration in rats

39.  Potent binding affinity at 42 nAChRs  Highly selective for 42 nAChRs  40-60% partial agonist efficacy at 42 nAChRs  in vitro (HEK cells, electrophysiology)  in vitro ([ 3 H]-DA release)  ex vivo (DA turnover)  in vivo (DA release)  Minimal or no abuse liability  Excellent oral bioavailability Varenicline has the desired properties:

40.  Absorption  Good membrane penetration, highly absorbed  Rapid absorption: median T max = 3 h “Drug-like” pharmacokinetic properties  Distribution  Low protein binding (f u  0.8) and moderate V Distribution (1.9 L/kg)  Not a substrate for the P-glycoprotein efflux transporter  Metabolism  Not metabolized: excreted >90% as unchanged drug in the urine  Does not inhibit cytochrome P450 enzymes  Excretion  Renal clearance (mainly passive diffusion): 2.4 mL/min/kg  Long half life: T 1/2 ~24 hr in man

41. Addictive Nature of Nicotine  The addictive characteristics of nicotine are believed to be a result of its rapid, intense and short-acting effects on dopamine release in the brain –When inhaled, nicotine reaches the brain within 10 seconds –Nicotine's half-life is approximately 2 hours  Similar to addictions associated with cocaine, amphetamines and opiates, nicotine addiction is a chronic, relapsing medical condition and warrants clinical intervention –Nicotine, cocaine, amphetamines and morphine act on different areas in the dopamine reward system that encompasses theme so limbic portion of the bra in. –Among users of alcohol, tobacco, cannabis, and cocaine, tobacco users were more likely to be nicotine dependent (28%) than alcohol (5.2%), cannabis (8.2%) or cocaine (11.6%) users 1. CDC. Surgeon General's Report. The Health Consequences of Smoking. 2004. 2. Foulds J.lntJ Clin Pract. 2006;60:571-576. 3. Fiore MC et al. U.S. DHHS. U.S. Public Health Service, 2000. 4. Changeux JP et al. Brain Research Reviews. 1998;26:1 98-21 6. 5. Kandel D et al. Drug Alcohol Depend. 1997:44:11-29. 18

45. Varenicline - a selective  4  2 receptor partial agonist Partial agonist  Binds with high affinity to the  4  2 receptor, only partially stimulating dopamine release 1  Provides relief from craving and withdrawal symptoms 1-3 Antagonist  Prevents stimulation of the receptor by nicotine 1,4  This reduces the pleasurable effects of smoking and potentially the risk of full relapse after a temporary lapse 1-4 1. Coe JW. J Med Chem 2005; 48:3474-3477. 2. Gonzales D et al. JAMA 2006;296:47-55. 3. Jorenby DE et al. JAMA 2006; 296:56-63. 4. Foulds J. Int J Clin Pract 2006; 60:571-576.

46. Varenicline - the evidence  Meta-analysis 1 of randomised placebo controlled trials shows that varenicline is more effective than –Placebo OR = 3.22; (95% CI: 2.43-4.27) –Bupropion OR = 1.56 (95% CI: 1.19-2.06)  Indirect comparison 2 shows that it is better than NRT (1) Cahill, K., L.F. Stead, and T. Lancaster, Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev, 2007 (2) Wu, P., et al., Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health, 2006. 6

47. Subjective effects  Varenicline: –reduced patient ratings of urges to smoke compared with placebo and bupropion –reduced ratings of mood disturbance compared with placebo –reduced patient ratings of satisfaction and reward from their cigarette in those who smoked a cigarette after the quit date, compared with placebo and bupropion West, R., et al., Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt. Psychopharmacology (Berl), 2007

48. Prescribing information  Contra-indications –Hypersensitivity to varenicline or excipients  Cautions –Pregnancy – not recommended, breast feeding - risk/benefit, age <18 – not recommended (safety not established), renal impairment – reduce to 1mg/day, psychiatric illness (secondary to cessation)  Adverse events –Nausea – experienced by approximately a third of people that use it; mostly mild; dissipates over time –Sleep disturbance (most likely to be an abstinence effect) –Recent concern over relationship with suicidal ideation (most likely to be an effect of stopping smoking)

49. CHAMPIX dosing instructions 1 1. CHAMPIX (varenicline tartrate) Approved Product Information. Pfizer Australia Pty Ltd..

50. The future of treatment  More effective use of existing treatments –combinations –pre-treatment –longer term use if required –wider access  Better treatments –novel medications –cheaper medications –more comprehensive behavioural treatments  A realistic goal –25% of quit attempts that would have failed, lasting for at least 6 months

51. The old way Cold Turkey (aged 22) Self-help bookHypnosisNRT from the pharmacySees Physician (ABC)Meds PLUS supportQUITS (age 55) Problem? M.I. (aged 50) Smokers don’t know of or see the need for treatment Physicians not engaged Adapted from: John Hughes

52. A better way Cold Turkey (aged 22) Sees Physician (ABC) (Meds + Support) RelapsesQUITS (age 30)Sees Physician (ABC) (Meds + Support) Physicians engaged Evidence-based treatments actively promoted Adapted from: John Hughes

53. SummaryInterventionNNT brief advice 40 supporttelephoneindividualgroup302520 pharmacotherapy nicotine replacement therapy bupropionnortriptylinevarenicline1713117

54. Comparative studies: abstinence data Gonzales DH, Rennard SI, Billing CB, et al. A pooled analysis of varenicline: an α 4 β 2 nicotinic receptor partial agonist vs. bupropion for smoking cessation. SRNT Paper sessions PA9-2, PA9-3, 2006. 0 5 10 15 20 25 30 35 40 45 50 Responders (%) Week 1216202428323640444852 0 10 20 30 40 Odds Ratio (95% CI) V vs P2.82(2.06, 3.86; P <0.0001) V vs B1.56(1.19, 2.06; P <0.0013) B vs P1.80(1.29, 2.51; P <0.0004) Varenicline 1 mg bid (n=692) 22.5% Bupropion 150 mg bid (n=669) 15.7% Placebo (n=684) 9.4% CA rate (%) Varenicline Bupropion Placebo

55. Outcomes of Clinical trial- Varenicline (1)  1mg of varenicline twice a day vs. 150mg of bupropion twice a day for 12 weeks. Jorenby et al. JAMA 2006

56. Outcomes of Clinical trial- Varenicline (2)  12 weeks open label, following 12 weeks double blind placebo controlled among the abstainers. Tonstad et al. JAMA 2006

57. Frequent adverse events Jorenby et al. JAMA 2006

58. Meta-analysis data about varenicline 3.22 [2.43, 4.27] 1.66 [1.28, 2.16]

59. Phase III results in Korea (1)

60. Most frequent † adverse events Adverse events Varenicline (N=126) n (%) Placebo (N=124) n (%) Total all-causality AEs109 (86.5)98 (79) Total treatment-related AEs96 (76.2)73 (58.9) Nausea54 (42.9)14 (11.3) Insomnia12 (9.5)9 (7.3) Abnormal dreams7 (5.6)1 (0.8) Fatigue8 (6.3)6 (4.8) † Occurring in ≥5% of subjects in the varenicline treatment group; AEs, adverse events

62. A Simulation of Plasma Concentration Throughout the Day in Relation to Psychoactive Effect

64. 1. Bridgwood et al. General Household Survey 1998; 2. West. Getting serious about stopping smoking 1997; 3. Arnsten, Prim Psychiatry 1996. To Quit Smoking is Easy? All Smoker ~2 – 3% Succeed to quit 3 ~70% Want to quit 1 ~30% Try to quit 2

65. Nicotine Addiction: A Chronic Relapsing Medical Condition  True drug addiction 1  Requires long-term clinical intervention, as do other addictive disorders –Failure to appreciate the chronic nature of nicotine addiction may 2  Impair clinicians’ motivation to treat tobacco dependence long-term  Impede acceptance that condition is comparable to diabetes, hypertension, or hyperlipidemia, and requires counseling, support, and appropriate pharmacotherapy  Relapse is –Common 1,2 –The nature of addiction, not the failure of the individual 3  Long-term smoking abstinence in those who try to quit unaided † = 3%–5%  Most relapse within the first 8 days 1. Fiore MC, Bailey WC, Cohen SJ, et al. Clinical Practice Guideline: Treating Tobacco Use and Dependence. US Department of Health and Human Services. Public Health Service; June 2000. Available at: www.surgeongeneral.gov/tobacco/default.htm. 2. Jarvis MJ. Why people smoke. BMJ. 2004;328:277-279.

66. Multiple Quit Attempts May Be Necessary  More than 70% of US smokers have attempted to quit 1 –Approximately 46% try to quit each year –Less than 5% who try to quit are abstinent 1 year later –Similar percentages in countries with established tobacco control programs (eg, Australia, Canada, UK) 2  30% to 50% try to quit; <5% achieve long-term abstinence  Some smokers succeed after making several attempts 3 –Past failure does not prevent future success –Length of prior abstinence is related to quitting success 1. Fiore MC, et al. US Department of Health and Human Services. Public Health Service. June 2000. 2. Foulds J, et al. Expert Opin Emerg Drugs. 2004;9:39–53. 3. Grandes G, et al. Br J Gen Pract. 2003;53:101–107.

67. Increased plasma BDNF levels after unaided smoking cessation