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Future pharmacological treatments on stopping smoking

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1 Future pharmacological treatments on stopping smoking
VI Brazilian Congress on Asthma II Brazilian Congress on COPD II Brazilian Congress on Smoking Belo Horizonte, August 22-25, 2007 DURATA: 1 ORA Future pharmacological treatments on stopping smoking Giovanni Viegi, MD . Director of Research, Italian National Research Council, Head, Pulmonary Environmental Epidemiology Unit, CNR Institute of Clinical Physiology, Pisa – Italy . Professor of “Health Effects of Pollution”, School of Environmental Sciences, University of Pisa - Italy Past-President, European Respiratory Society (ERS)

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3 7. Psychological and behavioural interventions
8. Pharmacological treatment for smoking cessation 9. Other interventions 10. Smoking reduction 11. Organisational anchorage and education 12. The costs of smoking and economics of smoking cessation 13. Research prospects 14. References

4 7. Psychological and behavioural interventions
Three interventions can be included as psychological and behavioural strategies to aid smoking cessation: self-help interventions, brief advice and counselling.

5 7.1. Self-help programmes Self-help is defined as structured programming for smokers trying to quit, without intensive contact with the therapist. tailored self-help materials can be recommended for smoking cessation (Evidence A).

6 7.2. Brief advice Brief advice given by physicians or nurses can be defined as routinely providing smokers with brief information to help them quit smoking and increase their motivation to make quit attempts. It can be recommended that physicians give brief advice on smoking cessation to smokers, including respiratory patients who smoke. Nurses should do the same (Evidence A). However, when dealing with most pulmonary patients brief advice cannot stand alone, and much more intensive intervention is required.

7 7.3. Counselling There are three types of counselling - individual, group and telephone – which vary in terms of the manner of providing counselling and the time taken. Individual counselling is defined as a face-to-face encounter between a patient and a trained smoking cessation counsellor. There is a strong dose-response relation between the session length of person-to-person contact and successful treatment outcomes. Intensive interventions are more effective than less intensive interventions (Evidence A).

8 Group counselling Group therapy offers individuals the opportunity to learn behavioural techniques for smoking cessation and to provide each other with mutual support. Using this kind of support allows more people to be treated by one therapist and could be more cost-effective than individual counselling. Part I of II

9 There is no evidence about the efficacy of group therapy in respiratory patients.
Group counselling is effective for smoking cessation (Evidence A). It is unclear whether group counselling is more or less effective than individual counselling (Evidence A). Part II of II

10 7.3.2. Telephone counselling
In the proactive approach, the counsellor initiates the calls to provide the smoker with support to make an attempt at quitting (OR 1.41; 95% CI ). Reactive counselling is provided via help-lines or hotlines that take calls from smokers (OR 1.33; 95 % CI ) [129]. The findings suggest that proactive telephone counselling is effective compared to other minimal interventions (Evidence A).

11 7.4. Behavioural therapy

12 Aversive smoking Aversion therapy pairs the pleasurable stimulus of smoking a cigarette with some unpleasant stimulus. There is insufficient evidence to support the use of aversive smoking to quit [133]. Exercise therapy There is insufficient evidence to support exercise for smoking cessation. [138].

13 7.5. Procedures for psychological and behavioural interventions in smoking cessation
The following visit schedule can be recommended: Weeks 1, 2, 4, 8, and 12 and 6 and 12 months after quit day. Some considerations should be taken into account in order to provide the smoker with the best help during the follow-up period: - At times, ex-smokers feel that they need to smoke again even more than during the first days after quitting. Part I of II

14 - Sometimes abstinent smokers can suffer from withdrawal symptoms for long periods.
- Coinciding with special situations (social occasions, eating and drinking, meeting friends, etc.), smokers can feel confident enough to try smoking just one cigarette. - Smokers who continue smoking daily 2-3 weeks after receiving adequate treatment for their addiction should be considered unsuccessful. Part II of II

15 8. Pharmacological treatment for smoking cessation

16 8.1. First-line treatment Nicotine replacement therapy and/or sustained-released bupropion, in conjunction with behavioural intervention, are recommended as first-line pharmacotherapy in current guidelines for smoking cessation [10, ]. Except in the presence of contraindications, these drugs should be used in almost all patients attempting to quit smoking. Part I of II

17 Smokers of 10 or more cigarettes a day who are ready to stop should be encouraged to use NRT or bupropion to aid cessation. Health professionals who deliver smoking cessation interventions should give smokers accurate information and advice on these products. Part II of II

18 8.1.1. Nicotine replacement therapy (NRT)
This treatment aims to replace the nicotine obtained from cigarettes, thus reducing withdrawal symptoms when stopping smoking The recommended dosages of NRT vary depending on the degree of dependence. Use should normally be restricted to the licensed duration, but may continue for up to and beyond 3 months in instances of continuing nicotine dependency. Part I of V

19 Nicotine replacement therapy should be discontinued if the user restarts smoking [150,151,153].
There is little direct evidence that one NRT product is more effective than another, so the decision about which product to use should be guided by individual preferences. Combination NRT has been reported to improve outcome but long-term results are conflicting. Part II of V

20 No differences have been found between 16‑hour and 24‑hour nicotine patches and prolongation of treatment for more than 3 months did not increase quit rate Higher doses of nicotine patches have resulted in modest increases in success rates. Tapering of patch dosage is not more effective than abruptly ceasing use. Part III of V

21 Relative contraindications given for NRT are cardiovascular disease, hyperthyroidism, diabetes mellitus, severe renal or hepatic impairment and peptic ulcer. NRT has been shown to be safe in patients with coronary heart disease and it should be used in these patients for whom quitting smoking is one of the most important factors influencing prognosis. Part IV of V

22 A risk-benefit assessment should be made as to using NRT in breastfeeding or pregnant women taking into account the fact that continuing smoking will deliver more nicotine than NRT. Nicotine replacement is generally well tolerated. The most common adverse effects are localised irritation from nicotine, such as local skin irritation with the patch, or with oral preparations mucous menbrane irritation in the mouth and throat, that generally lessen or disappear due to development of local tolerance after a few days. Part V of V

23 Table 4. Available nicotine replacement therapy (NRT) formulations
Marketed product Nicotine transdermal patches 5 mg, 10 mg, 15 mg/16 h (Nicorette, Pfizer) 7 mg, 14 mg, 21 mg/24 h (Nicotnell TTS 10, TTS 20, TTS 30, Novartis) 7 mg, 14 mg. 21 mg/24 h (NiQuitin CQ, GlaxoSmithKline (GSK) Part I of II

24 Table 4. Available nicotine replacement therapy (NRT) formulations
Nicotine chewing gum 2 mg, 4 mg (Nicorette, Pfizer; Nicotinell, Novartis) Nicotine oral tablets 2 mg sublingual tablet (Nicorette Microtab, Pfizer) 1 mg lozenge (Nicotinell, Novartis) 2 mg and 4 mg lozenge (NiQuitin CQ, GSK) Nicotine “oral” inhaler 10 mg inhalation cartridge, plus mouthpiece (Nicorette Inhalator, Pfizer) Nicotine nasal spray 0.5 mg per spray into each nostril (Nicorette Nasal Spray, Pfizer) Part II of II

25 NRT vs. placebo Odds ratio (95% CI) Abstinence rate Control
Table 5. Cochrane meta-analysis of effect of NRT formulations as odds ratio of abstinence with NRT versus controls. A total of 39,503 subjects were included in the analysis [139] Smoking cessation therapy NRT vs. placebo Odds ratio (95% CI) Abstinence rate NRT Abstinence rate Control All NRT formulations 1.77 ( ) 17% 10% Nicotine gum 1.66 ( ) Nicotine patch 1.81 ( ) 14% Nicotine inhaler 2.14 ( ) Nicotine nasal spray 2.35 ( ) 24% *Data from ref 140 Part I of II

26 NRT vs. placebo Odds ratio (95% CI) Abstinence rate Control
Table 5. Cochrane meta-analysis of effect of NRT formulations as odds ratio of abstinence with NRT versus controls. A total of 39,503 subjects were included in the analysis [139] Smoking cessation therapy NRT vs. placebo Odds ratio (95% CI) Abstinence rate NRT Abstinence rate Control Nicotine sublingual tablet/lozenge 2.05 ( ) 17% 4 mg gum vs. 2 mg gum 2.20 ( ) Fixed gum vs. ad libitum gum 1.29 ( ) Combination of two NRT vs. single NRT 1.42 ( ) Bupropion SR* 2.06 ( ) *Data from ref 140 Part II of II

27 8.1.2. Efficacy of NRT in smokers with respiratory diseases

28 Hospitalised patients Campbell (1990) 111 20 (+NRT/placebo) 20 NS
Table 6. One-year success rates from smoking cessation studies in patients with respiratory diseases who smoke. Modified from reference 163. Reference No of patients Sustained success (%) P value Intervention Control / Usual care Hospitalised patients Campbell (1990) 111 20 (+NRT/placebo) 20 NS Campbell (1996) 234 21 (+NRT/placebo) 14 Miller (1997) 1,4021 14 (+NRT) 13 1,4822 19 (+NRT) <0.01 Lewis (1998) 1853 6.5 (+Placebo) 4.9 9.7 (+NRT) 1Low intervention and 2high intervention in same study 36‑month success rate 4 5 mg nicotine patch used as ‘placebo’ Part I of II

29 Reference No of patients Sustained success (%) P value Intervention
Table 6. One-year success rates from smoking cessation studies in patients with respiratory diseases who smoke. Modified from reference 163. Reference No of patients Sustained success (%) P value Intervention Control / Usual care Ambulatory patients BTS I (1983) 1,550 9.8 (+NRT/placebo) 8.9 NS Lung Health Study (1994) 5,887 28 (+NRT) 7 <0.001 Tønnesen I (1996) 446 5.6 (+NRT/placebo4) 1.8 <0.01 Taskin (2001) 4043 23 (bupropion/placebo) 16 Hand (2002) 245 15 (+NRT) 14 Tønnesen II (2006) 370 17 (+NRT/placebo) 10 1Low intervention and 2high intervention in same study 36‑month success rate 4 5 mg nicotine patch used as ‘placebo’ Part II of II

30 Indication for smoking reduction
Smoking reduction indication is approved in: Europe: Austria, Belgium, Czech Rep., Denmark, France, Iceland, Italy, Netherlands, Russia, Switzerland, Sweden, UK. Rest of the world: Brazil, Malaysia, New-Zealand, Philippines.

31 Bupropion SR Bupropion hydrochloride is an antidepressive drug (an aminoketone) which has been shown to be an effective aid to cessation in smokers who smoke more than 10 cigarettes/day and who are motivated to stop. Bupropion inhibits neuronal reuptake of noradrenaline and dopamine, with minimal effect on the re-uptake of serotonin and no inhibitory effect on monoamine oxidase. Part I of V

32 It has been shown to reduce the activity of these dopamine-releasing neurones and thereby may deactivate the reward circuit and reduce craving. Sustained-release (SR) bupropion is considered a useful option for smokers attempting to stop smoking for the first time, especially those who cannot tolerate NRT, who prefer non-nicotine treatment or who have failed to quit with NRT [2-6,16-19]. For smoking cessation the recommended dose of bupropion SR is 150 mg/day for the first week, thereafter increasing to 300 mg/day (150 mg twice daily). Part II of V

33 Smokers using bupropion SR are advised to continue to smoke until the target quit day which usually is set after 1 week of treatment. A reduced maintenance dose—that is, 150 mg daily—is recommended in elderly smokers, or those with liver or renal impairment or below 45 kg in body-weight. The recommended duration of treatment for smoking cessation is 7–12 weeks. Part III of V

34 Bupropion SR is a prescription-only medicine.
The most common side effects are sleep disturbances and dry mouth. A serious but rare side effect is seizures (<1:1000).[140]. The drug is contraindicated in patients with current or past epilepsy, and should be used with extreme caution in smokers with conditions predisposing to a low threshold for seizure, such as history of head trauma, or alcohol abuse. Part IV of V

35 Caution is needed regarding the dose in patients with diabetes treated with hypoglycaemic agents or insulin, and in patients taking drugs that lower the seizure threshold (e.g, antipsychotics, antidepressants, theophylline and systemic corticosteroids). Bupropion is also contraindicated in patients with a history of anorexia nervosa and bulimia, severe hepatic necrosis, or bipolar disorder. Bupropion should not be used with a monoamine oxidase inhibitor, and at least 14 days should elapse between stopping such treatment and starting bupropion [9,139, ]. Part V of V

36 8.1.4. Efficacy of bupropion in patients with COPD who smoke
Very few studies have used bupropion SR for smoking cessation in patients with chronic diseases such as COPD. These abstinence rates are much lower than those observed in similar studies with bupropion SR in healthy subjects, suggesting that COPD patients may be relatively “hard core.”

37 8.2. Second-line smoking cessation treatments
Nortriptyline, a tricyclic antidepressant, is the only other antidepressant that has demonstrated evidence of efficacy for smoking cessation. The dose of nortriptyline for smoking cessation is 75–150 mg daily. There are many contraindications with nortriptyline, including common anticholinergic side effects and particularly cardiac conduction disturbances and orthostatic blood pressure drop. Part I of II

38 Clonidine, has been recommended as a second-line therapy in US smoking cessation guidelines [10].
Adverse effects associated with clonidine, such as drowsiness, fatigue and dry mouth, may limit its use [177], and we consider it to be obsolete today. Part II of II

39 SMOKING CESSATION New Medication Treatment Ch Gratziou
Ass.Prof Pulmonary and Crit Care Medical Schools, Athens University

40 Nicotine Addiction Addiction Dopamine release Blood Nicotine REWARD
Blood Brain Barrier Nicotine Achetylocholine Brain receptors Dopamine release

41 X X X Medication Treatment Addiction Dopamine release
Nicotine in Blood X Reward Blood brain Barrier X X Nicotine Ach Receptors Dopamine release

42 New Medications for Smoking Cessation
Cannabinoid Receptor Antagonists

43 Cannabinoid Receptors CB1
Rewarding stimulies (including palatable food ) and other abuse substances produce dopamine release in the nucleus accumbens CB1 Glu GABA DA CB1 CB1 plays an important role in Nac dopamine release by inhibition of GABA release

44 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

45 Cannabinoids Receptors
CB1-receptor CB2-receptor Appetite Pain Brain Lung CB1 are associated with the intake of food and smoking addiction Blocking the CB1 may reduce food craving . Blocking the CB1 may reduce tobacco depedence by less motivation to take nicotine possibly due to impairment of dopamine release by the nucleus accumbens

46 Rimonabant : a CB1- cannabinoid receptor antagonist Pharmacological Characteristics
T ½ : 8-15 days Metabolised by oxidation in the liver

47 Why Rimonabant has a place for Smoking Cessation
Animal Studies Endocannabinoids are released by chronic nicotine administration (Gonzalez et al, 2002) Rimonabant blocks nicotine –induced reinforcement and nicotine self - administration(Cohen et al, 2002) Rimonabant produces loss of weight

48 Weight and Smoking !!

49 Rimonabant Clinical trials phase ΙΙΙ ( 7 studies)
Dose 20mg /day for 10 w Weight Control Diabetics, Hyper cholesterolemia Multicentre International study (RIO Europe)

50 Rimonabant 5 or 20 mg/day Prolonged Abstinence (10 weeks)
Placebo Rimonabant 5 mg Rimonabant 20 mg 40 OR= % CI=[1.296; 3.046] P=.004 35 30 27.6 25 Abstinent (%) 20 16.1 15.6 15 10 5 USA study American College of Cardiology 2004 n=261 n=262 n=261 ITT

51 Rimonabant 5 or 20 mg/day Prolonged Abstinence (10 weeks)
Placebo Rimonabant 5 mg Rimonabant 20 mg 40 P= NS 35 30 25 25 24 Abstinent (%) 20 20 15 10 5 European study Lancet 2005; 365: 1389‑1364. ITT

52 Side effects with Rimonabant
Placebo mg rimonbant mg rimonabant 2.3 % % % Dropouts due to Adverse Events 3.8 % % % Cardiovascular Safety Profile No safety issue has been detected through laboratory, vital signs, or ECG data The most frequent side effects reported with rimonabant were nausea, diarrhoea, vomiting, urinary tract infections, anxiety and upper respiratory tract infections.

53 Rimonabant Not APPROVED for Smoking Cessation Treatment
Drug for a specific target group ? Hypertension , cardiovascular diseases Diabetes, Hypercholesterolemia, Overweight

54 Rimonabant Prevention of weight gain . Relative low abstinence rate
Long term results? Prevention of weight gain . Modification to the molecule might give better efficacy

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

56 Nicotine Addiction and n ACh Receptors
Endogenous nACh Rs are found throughout the central and peripheral nervous system. The most abundant form of nACh receptors is a pentameric made of a4b2 units Leonard & Bertrand Nicotine Tob Res 2001;3 Cholinergic action nACh –Receptor Pre-synaptic Synapsis Meta-synapsic membrane Cellular Body of Dopaminergic neuron The a4b2 receptor is critical for self administration of nicotine Picciotto et al 1998, Tanner et al 2004

57 Varenicline: New Molecule
Developed specifically for targeting the main nicotinic receptor responsible for nicotine addiction : a4b2 n ACh receptors Not a substitute for nicotine Not an antidepressant H N NH Varenicline N S-(-)-Nicotine N N

58 Varenicline New mechanism of Action
Varenicline was developed as Partial agonist of 42 nicotinic acetylcholine recptors combining agonist and antagonist properties in one compound

59 Varenicline : New Mechanism of Action
A selective nicotinic receptor partial agonist evokes a reduced level of response, while antagonizing the response of a full agonist 50 100 Response level (%) a b The nicotinic AcHR is a ligand-gated pentameric ion channel; downstream effects include DATO Full agonist (nicotine) Antagonist (meca- mylamine) Full agonist + antagonist Partial agonist Partial agonist + nicotine Dopamine turnover (DATO)

60 Varenicline: A Partial Agonist
Maximum effect 0% 100% 50% Full agonist Blocks reward Effect Partial agonist Craving; withdrawal relief Dose, exposure

61 Varenicline a Partial Agonist
How Varenicline helps to overcome nicotine addiction As Partial agonist minimises the withdrawal symptoms ( agonist effect) blocks the pathway that is associated with reward system after nicotine intake ( antagonist effect )

62 Varenicline Pharmacological Characteristics
Highly absorbed 99 % Half life 17h Absorption Low Protein binding Distribution Non metabolised No drug interaction with c Ρ450 Metabolism Excreted as unchanged in the urine Renally cleared >90 % Excretion No interaction with Food No interaction with other Medications

63 Varenicline: Clinical Studies
JAMA July 2006 : 3 randomised trials Gonzales D, Rennard SI, Nides M, et al. Varenicline, an a4b2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial JAMA. 2006;296:47-55. 2. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an a4b2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial JAMA. 2006;296:

64 Varenicline Clinical Studies: Design
Treatment Phase Nontreatment Phase Varenicline 1mg bid Bupropion 150 mg bid Placebo Wk 1 9 12 52 Primary Endpoint: CO- confirmed 4-wk continuous quit rate wks 9-12 Screening Visit Baseline Randomization Target Quit Date Secondary Endpoint: CO-confirmed continuous abstinence rate wks 9-52

65 Continuous abstinence rates (confirmed by CO )
44% P.001 Randomised double blind 19 centres in USA 1025 smokers (P=.007), 29.5% 29.5% (P=.057), 21.9% 20.7% 17.7% P.001 16.1% 10.5% (P=.001) 8.4% Treatment 12w Follow-up 40 w Gonzales et al. JAMA. 2006;296:47-55.

66 Continuous abstinence rates (confirmed by CO )
P.001 43.9% 29.8% 29.7% Randomised double blind 14 centres 1413 smokers 23% 20.2% 17.6% 14.6% 13.2% 10.3% Jorenby et al. JAMA. 2006;296:56-63. Treatment 12w Follow-up to 52 w

67 Side effects Jorenby et al. JAMA. 2006;296:56-63.

68 Maintenance treatment with varenicline
Tonstad S, Tønnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial JAMA. 2006;296:64-71. To determine whether smokers who quit after 12 weeks of treatment with varenicline, maintain greater continuous abstinence rates than placebo controls during an additional 12 weeks of treatment and until 52 weeks after treatment initiation.

69 Maintenance of Abstinence: Study Design
OPEN-LABEL DOUBLE-BLIND NONTREATMENT FOLLOW-UP Varenicline 1mg bid Varenicline 1mg bid 12 weeks Quitters randomized Placebo Wk12 24 52 Primary Endpoint: CO-confirmed continuous abstinence rate wk 13–24 Secondary Endpoint: CO-confirmed continuous abstinence rate wk 13–52

70 Maintenance treatment : 7 day point prevalence abstinence
1st phase Open study 12w 2nd phase Randomised double blind additional 12w 14 centres smokers 63 % participate in 2nd phase Tonstad et al . JAMA. 2006;296:64-71

71 Maintenance of Abstinence Study: CO-confirmed Continuous Abstinence Rates
Wks 13–24 Wks 13–52 Wks 24-52 OR=2.47 (95% CI 1.95, 3.15) p<0.0001 OR= 1.35 (95% CI 1.07, 1.70) p=0.0126 N=602 Varenicline N=604 Placebo N=602 Varenicline N=604 Placebo OR = odds ratio

72 Continuous abstinence rates
From baseline therapy plus additional 12 w maintenance therapy and during follow-up period to 52 weeks Tonstad et al . JAMA. 2006;296:64-71

73 Side effects Tonstad et al . JAMA. 2006;296:64-71

74 Varenicline: Published Studies
Varenicline is an efficacious, safe, and well-tolerated smoking cessation pharmacotherapy. Varenicline’s short-term and long-term efficacy exceeded that of both placebo and bupropion SR. Gonzales et al. JAMA. 2006;296:47-55. Jorenby et al. JAMA. 2006;296:56-63. Extended use of varenicline helps recent ex-smokers to maintain their abstinence and prevent relapse Tonstad et al . JAMA. 2006;296:64-71

75

76 Part I of II Cahill et al, Cochrane Database of SR, 2007

77 Part I of II Cahill et al, Cochrane Database of SR, 2007

78 New Medications for Smoking Cessation
Modifiers of nicotine metabolism

79 Modifiers of nicotine metabolism
Inhibitors of CYP2A6 Nicotine CYP2A6 Cotinine CYP2A6 3-hydroxycotinine

80 Cytochrome CYP2A6 CYP2A6 Polymorfism (26 alleles) is Related with
Nicotine metabolism Lower smoking initiation rate and lower smoking dependence Lower smoking habit Reduced risk for lung cancer

81 CYP2A6 Inhibitors Enhance the action and effectiveness of NRTs.
Reduce the number of cigarettes consumption Control the desire for smoking Reduce the activation of pre-carcinogens to carcinogens Reduce the risk for Lung Cancer

82 CYP2A6 Inhibitors Μethoxsalen 10mg , 30 mg
Tranylcypromine (MAO inhibitor) 2.5mg, 10mg Increase plasma level of nicotine Reduce smoking desire and cigarette consumption Sellers et al.Research focus2003 Zhang et al. Drug Metab. Dispos.2001

83 Other New Approaches for Smoking Cessation
Vaccination ????

84 Vaccine : Mechanism of Action
Addiction Nicotine in Blood X Reward Blood brain Barrier Nicotine Ach Receptors Dopamine release

85 Vaccine : Mechanism of Action
Addiction Nicotine in Blood X Reward Blood brain Barrier X Nicotine Ach Receptors Dopamine release

86 Possible place for Vaccine
Relapse prevention Advantages No daily use No action in CNS Combination with other therapies Preparation of heavy smokers for smoking abstinence Early prevention of Smoking Dependence ??

87 Vaccines against Smoking
ΤΑ-ΝΙC (Xenova research Ltd, UK) NicVAX ( Nabi , USA) Nicotine –Qbeta ( Cytos, Switzerland) Successful clinical trials phase Ι and II Few Side Effects More ongoing studies

88 1: Curr Opin Investig Drugs. 2007 Jan;8(1):71-7.
Drug evaluation: CYT-002-NicQb, a therapeutic vaccine for the treatment of nicotine addiction. Heading CE. The Open University in the North, Faculty of Science, Eldon House, Regent Centre, Gosforth, Newcastle upon Tyne NE3 3PW, UK. Cytos Biotechnology AG is developing an intramuscular therapeutic vaccine, CYT-002-NicQb (also known as nicotine-Qbeta), based on its Immunodrug (formerly known as alpha vaccine) nicotine-specific antibody-generating technology, for the potential treatment of nicotine addiction. A phase II trial was initiated in Switzerland in January 2005 and in February 2006, Cytos Biotechnology announced that it planned to begin a phase IIb/III trial in 2007.

89 Vaccines against Smoking Questions !!
More clinical studies in smokers Safety ( long term use) Cost of Therapy Duration of action and effectiveness Use Frequency Ethical issues Prevention of tobacco use in adolescents , Use in pregnancy ??

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

91 8.3. New medications

92 Varenicline Varenicline is a partial agonist at the subtype of neuronal nicotinic receptors composed of α4 and β2 subunits. Varenicline initially stimulates the α4β2 receptors that mediate the effects of the nicotinic agonist on dopamine release in the nucleus accumbens (the agonist function). If nicotine is added to varenicline treatment no increase in dopamine response is seen (the antagonist function). Part I of II

93 As varenicline combines both agonist and antagonist function it can reduce nicotine dependence and can also attenuate the effects of nicotine withdrawal [179,180]. Smokers are asked to up-titrate their dose to varenicline 1 mg twice daily during the first 7 days of treatment, the stop smoking on day 8, and continue treatment for 12 weeks. We expect that with more documentation and experience varenicline will be a first-line drug in smoking cessation. Part II of II

94 Table 7. Continuous quit rates, in percent, from week 9 to 52 in two phase III trials of varenicline for smoking cessation Study Placebo Varenicline 2 mg/day Bupropion SR 300 mg/day P value Gonzalez [179] Study 1 8.4 22.1 16.4 varenicline vs placebo p<0.001 varenicline vs bupropion p<0.07 bupropion vs varenicline p<0.001 Jorenby [180] Study 2 10.3 23.0 15.0 varenicline vs bupropion p<0.001 bupropion vs placebo p<0.001

95 Rimonabant The stimulation of CB1 receptors by endocannabinoids within the brain plays an integral role in the development and maintenance of nicotine and tobacco dependence, and rimonabant exerts its effects in addicted individuals by inhibiting this role of the endocannabinoid system [182]. The most frequent side effects reported with rimonabant were nausea, diarrhoea, vomiting, urinary tract infections, anxiety and upper respiratory tract infections. Part I of II

96 Rimonabant’s effects do not seem to be significantly better than currently available cessation treatments. With its better-documented efficacy on obesity treatment [184], one might speculate that rimonabant could be useful in overweight smokers for whom weight gain is a major barrier to quitting. Part II of II

97 8.4. Key points: Pharmacotherapy and smoking cessation
- NRT and bupropion SR are first-line treatments for smoking cessation (Evidence A) - Smokers attempting to quit should be encouraged to use these drugs to aid cessation, except in the presence of contra-indications (Evidence A). - NRT (gum, patch, inhaler, nasal spray, lozenge and sublingual tablets) are equally effective as smoking cessation treatments (Evidence A). Part I of II

98 Combining the nicotine patch with a self-administered form of NRT can be more effective than a single form of NRT (Evidence B). - NRT should be used to aid cessation in all smokers with COPD, regardless of disease severity and number of cigarettes smoked (Evidence B). - Combined treatment with bupropion SR and NRT might be more effective in heavy smokers (Evidence C) Part II of IV

99 - Both NRT and bupropion SR are effective and well tolerated in smokers with stable cardiovascular disease and in COPD patients.(Evidence A) - Nortriptyline may be used as second-line medication to treat tobacco dependence (Evidence B). - There is no evidence that selective serotonin reuptake inhibitors (SSRIs) have any effect in smoking cessation. Part II of IV

100 - Varenicline might have additional therapeutic effect as smoking cessation treatment and are considered a second-line agent until more documentation and experience occur (Evidence B) - Regular follow-up visits are important and are linked with longer-term successful outcome (Evidence B). Part IV of IV

101 first-line interventions
Figure 2. An illustration of the recommended smoking cessation steps and approved first-line interventions Figure 2. An illustration of the recommended smoking cessation steps and approved first-line interventions Yes No No Yes Part I of II

102 NRT= nicotine replacement therapy
Successful quitter Relapse NRT= nicotine replacement therapy Part II of II

103 9. Other interventions 9.1. Acupuncture and laser therapy 9.2. Hypnotherapy There is no evidence that hypnosis, acupuncture or laser therapy has any effect in smoking cessation

104 11. Organisational anchorage and education
Smoking cessation services should be an integral part of a chest unit, offering advice and help to all smokers with respiratory diseases independently of the smoker’s motivation, but focusing primarily on those who want to try to quit. As a minimum, chest departments should offer smoking cessation support, NRT and/or bupropion SR and at least four follow-up visits to all smokers. The precise details of each service are likely to depend on local factors and national differences, taking into account the fact that individual clinicians fail to intervene with more than one-third of smokers [9].

105 11.1. Systematic identification of smokers
Focusing on hospitals - either inpatients or outpatients – there should be an organisational plan for identifying smokers, documenting smoking data in patients’ records, and delivering brief advice with an offer of referral to the smoking cessation service [9,198].

106 11.2. Equipment and staffing
Certain requirement and expertise should be available in each clinic unit to perform the assessments described previously. It should be possible to assess CO level, nicotine dependence and motivation to quit [80,199,200]. If the clinic cannot offer smoking cessation there should be written flow-charts stating where to refer the patients. It is also important to engage GPs in smoking cessation, as many COPD patients consult their GP frequently.

107 - Education by physician “opinion leaders”
The following tools have been shown to alter physicians’ behaviour [202]: - Education by physician “opinion leaders” - Computerised concurrent feedback on clinical decisions, - Academic detailing i.e. one-on-one education, often by a pharmacist, - Physician incentives, but also patient education or information and patient incentives. Part I of III

108 Guidelines should be simple, pragmatic, usable and flexible with an increasing focus on implementation [201,203]. Smoking cessation should be part of the core curriculum of the undergraduate and postgraduate education and training of physicians. Part II of III

109 As smoking plays so large an aetiological role for a majority of pulmonary disorders, the pulmonary clinician must know about smoking cessation at a level similar to the knowledge about other respiratory therapies e.g. bronchodilators and inhaled steroids. Formal training courses are needed to educate smoking cessation counsellors, and courses must be repeated to take account of turn-over among staff members. It would be optimal if all pulmonary clinicians participated in the above education. There should also be postgraduate smoking cessation courses at the annual ERS conference. Part III of III

110 11.4. Smoke-free health care
Smoking should be banned in hospitals, both for hospitalised and ambulatory patients and for staff. The European Smoke-Free Hospital Network consists of 16 membership countries and this organisation has created implementation guidelines for turning a hospital smoke-free, as well as training guidelines and material for health care workers [205].

111 12. The costs of smoking and economics of smoking cessation

112 13. Research prospects Examine the efficacy of NRT and bupropion SR and combinations for smoking cessation in patients with respiratory diseases, particularly COPD and asthma. Smoking cessation studies are also needed for smokers with several other respiratory disorders such as tuberculosis, alpha 1 antitrypsin deficiency, histiocytosis X, and candidates for lung transplantation. 2) Examine the efficacy of different re-treatment interventions as well as long-term treatment for smoking cessation in patients with respiratory diseases. Part I of IV

113 3) Examine the efficacy of smokeless tobacco as a smoking cessation tool in recalcitrant smokers.
4) Examine the efficacy of lung function screening in asymptomatic and symptomatic smokers, combined with different smoking cessation approaches. 5) Explore the characteristics of tobacco dependence/nicotine addiction and barriers and motivation to quit in patients with respiratory diseases. Part II of IV

114 6) Examine whether reduced smoking in patients not motivated to give up can increase self- confidence and motivation to quit. 7) Examine the relationship between COPD and depression and evaluate whether treatment for depression can help dependent respiratory patients to quit. Part III of IV

115 8) Evaluate the efficacy of new drugs for smoking cessation in respiratory patients.
9) Evaluate the efficacy of smoking cessation programs in rehabilitation courses. 10) Evaluate the efficacy of web-based programmes, quit-lines and other “mass-media” methods for smoking cessation. Part IV of IV

116 2. Key points of recommendations
1. Patients with respiratory disease have a greater and more urgent need to stop smoking than the average smoker. They should be encouraged to stop but many often find it more difficult to do so (B). Respiratory physicians must take a proactive and continuing role with each smoker in motivating him or her stop, and provide treatment to achieve smoking cessation, however long this might take, and deal with relapses when these occur. Smoking cessation treatment must be considered integral to the management of the patient’s respiratory condition. Part I of IV

117 The role includes: • regularly assessing smoking status using methods that can objectively detect smoking, such as expired-air carbon monoxide (CO) tests. (C) • pharmacological treatment for nicotine dependence including bupropion and/or where necessary using high-dose and/or prolonged nicotine replacement therapy (NRT); it could also include giving combinations of different forms of NRT (A). Varenicline is a promising second-line agent (B). • behavioural support, which should be intensive and multi-sessional, and provided by someone who has been appropriately trained (B). Part II of IV

118 3. To carry out this role effectively, respiratory physicians must have adequate knowledge and appropriate attitudes and skills; this requires training and continuing medical education which should be provided according to professional standards, and be accredited (C). 4. The cost of this strategy will partly be offset by a reduction in attendance for exacerbations etc., but a budget must be established to enable implementation of treatment protocols and provide medication and behavioural support (A). Part III of IV

119 5. It is important to check lung function regularly in order to chart disease evolution and use this as a motivational tool (C). 6. Smokers not motivated to stop should be offered NRT to reduce smoking as a gateway to cessation (B). 7. Smokers who are not interested in stopping or reducing should be advised that the physician will return to the question at a later visit (C). Part IV of IV

120 Treatments for Smoking Cessation
Smokers will never be able to “take just a pill” that will make them in a magic way to stop smoking !!!

121 Smoking Cessation Treatment
Smokers must want to stop smoking and must be willing to work hard to achieve the goal of smoking abstinence. Brief Clinical Advice & Intensive Smoking cessation Programs

122 Thank you!


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