1. Describe the benefits of smoking cessation. 2. List the withdrawal symptoms of quitting smoking. Cessation

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1 Time to Butt Out Adil Virani, BSc (Pharm), Pharm D, FCSHP Objectives After this presentation, participants should be able to: 1. Describe the benefits of smoking cessation 2. List the withdrawal symptoms of quitting smoking 3. List the main treatment options to help people quit smoking and their likelihood of producing abstinence at 6-12 months 4. Describe the advantages and drawbacks of various pharmacological smoking cessation treatment options 5. List the appropriate dosages and duration of treatment of smoking cessation medications 6. Describe the monitoring parameters you would use when initiating a specific smoking cessation treatment Smoking Cessation The single most important step that smokers can take to enhance the length and quality of their lives. US Surgeon General, Guide to quitting smoking. American Cancer Society, 2006 Potential Lifetime Health Benefits of Quitting Smoking 1-2 Cardiovascular heart disease (CHD) risk is similar to never smokers Lung CA risk is 30-50% that of continuing Stroke risk returns to the level of people who have smokers never smoked at 5-15 years post-cessation Lung function starts to improve with cough, sinus congestion, fatigue and shortness of breath CHD risk is by 50% Cessation 3 months 1 year 5 years 10 years 15 years 1. CDC. Surgeon General Report 2004: American Cancer Society. Guide to Quitting Smoking. 2. US Department of Health & Human Services. The Health Benefits of Smoking Cessation: A Report of the Surgeon General Smoking Cessation Stopping smoking may have a greater effect on reducing the risk of mortality among patients with CHD who smoke than the effect of any other intervention or treatment. Critchley JA, Capewell S JAMA;2003;290:86-97 Smoking cessation is considerably more cost effective per life year saved than most pharmacological therapies (e.g., drugs for hypertension, hyperlipidemia). Benowitz NL Prog Cardiovasc Dis 2003;46: Did you know? n ~40% of smokers attempt quitting each year n Most attempts are unaided n 6 mo abstinence rates (unaided) = 3-5% n Most relapse in the first week n Most smokers have several triggers n s half life is <2 hrs n Withdrawal symptoms peak at 1 week and can last months Nides, M. Am J Med 2008:121;S

2 Going smoke free If you had a patient (with your age and medical history) who smoked 1ppd x 4 yrs what method would you use to quit? n Ask, Assess and Assist n Nonpharmacological approaches n Replacement Therapy (NRT) n The patch n Chewing gum, lozenges n Nasal spray n Inhaler n Delayed onset options n Bupropion (antidepressant) n Varenicline (nachr partial agonist/antagonist) n Nortriptyline (antidepressant) 2 nd line [OR = 2.14 ( )] n Clonidine (antihypertensive) 2 nd line [OR = 1.89 ( )] Ask, Assess and Assist Ask: Are you willing to try quitting? YES: Assess Conviction: 1 to 10 S...Set a quit date Assess Confidence: 1 to 10 T...Tell family & friends A...Anticipate challenges R...Remove tobacco items T Tobacco replacements? NO: Here to help if you change your mind. Need a Comprehensive Strategy n Smoking addiction has two main components: n Psychological (behavioural factors) n Physiological (pharmacological treatment) n Advice and behavioural support increase the chances of successfully quitting! Replacement Therapy (NRT) n Delivers nicotine that binds to the nicotinic acetylcholine receptor (nachr) receptors 1 n Does not counter the additional satisfaction from smoking 1 n NRTs does not deliver nicotine to the circulation as fast as smoking 2 n The biggest predictor of success is the number of quit attempts. Jarvis MJ. BMJ 2004;328: Hughes JR. CA Cancer J Clin 2000;50: American Heart Association website. 2. Sweeney CT et al. CNS Drugs 2001;15:

3 Plasma Levels by Cigarettes vs. NRT Products NRT: Gum n polacrilex n (e.g., Nicorette, Thrive gum ) n Method of delivery: n released from gum upon chewing n Bite the gum then, chew, chew until tingle, then park for sec, repeat for 30 min n Start with about pieces/day n Chew regularly for 4-12 wks, then PRN cravings for up to 6 months n Avoid acidic beverages (coffee, alcohol, pop, citrus fruit juice) within 15 min ( absorption) Sweeney CT et al. CNS Drugs 2001;15: NRT: Lozenge Gum or Lozenge: Common Adverse Events n Dehydrated bitartrate n e.g.,thrive Lozenge n released by sucking on lozenge..then park lozenge (when taste is strong); repeat x 30 min n Dosage: n > 20 cigarettes / day = 2mg n < 20 cigarettes / day = 1 mg n 5-15 lozenges/ day for 1-3 months, then PRN cravings Local Jaw pain, tooth disorders Gum sticking to dentures Throat irritation (5%) Stomatitis (4%) Gingivitis (1%) Taste perversion GI Hiccups (10%) Dyspepsia (9%) Nausea (9%) CNS symptoms Headache (11%) Dizziness (4%) Insomnia (2%) Inhaler n is absorbed through oral mucosa n Dose: n 1 cartridge (4mg) n 4-12 cartridges/d X 3 mo, then taper n 20 min/cartridge n Expires within 24 hours if not used n Side effects n Cough n Mouth and throat irritation n Changing the technique might help in these cases (small puffs less irritating than long puffs) n Rhinitis, pharyngitis NRT: Patches n E.g., Habitrol, Nicoderm n New patch (7, 14, 21 mg) applied every 24 hrs, taper dose q 3-4 wks n 3 months therapy n Advantages: n Eliminate variability of GI absorption n Reduce nicotine first-pass metabolism n Enhance patient compliance n Disadvantages: n Local skin irritation n Insomnia n Wears off in hrs 3

4 Comparison Efficacy of NRT vs. Placebo 6 or longer) Trials (n) Participants (n) Pooled OR (95% CI) Gum 52 17, ( ) Patch 37 16, ( ) Nasal spray ( ) Inhaler ( ) Tablets/lozenges ( ) Combination vs. single type ( ) Any NRT vs. control , ( ) 1. Silagy C et al. Cochrane Database Syst Rev 2004;(3):CD Stead L, Lancaster T. Int J Epidemiol 2005;34: Is it withdrawal or too much NRT? Symptoms Withdrawal Overdose Anxiety, irritability Insomnia Headache, dizziness Nausea, vomiting, abdominal pain, diarrhea Salivation Sweating, flushing Palpitations NRT Contraindications n Unstable cardiac condition n 2 weeks following heart attack n Unstable angina n Any unstable cardiac condition n Pregnancy and breastfeeding??? n Patients under 18 years old??? Safety of NRT n NRT delivers nicotine without the toxins associated with smoking 1 n Toxins, not nicotine, cause most tobacco-related health concerns 1 n Tobacco smoke contains >4000 chemicals; at least 50 are carcinogenic 2 n In more than 100 clinical trials, including longterm (>5-yr) data, 3 NRT has not been associated with increased risk of cancer 1 1. Benowitz NL. In: Benowitz NL (ed.). safety and toxicity. Oxford University Press, 1998; pp Health Canada. The facts about tobacco. 3. Murray RP, et al: Chest 1996; 109(2): NRT: Key Messages n Safe and effective for smoking cessation (esp. in conjunction with a behavioural program). n Delivers nicotine (more slowly and at lower levels vs. smoking) to nachr receptors n NNT vs placebo ~11-19 n Acidic beverages affect absorption n NO Carbon monoxide, oxidants or >4000 other chemicals and mutagens! n The use of NRT is not associated with any increase in risk of MI, stroke, cancer or death. Which of the following statements regarding bupropion is/are TRUE? A. Bupropion s efficacy at 6 months is equivalent or slightly better than NRT B. Bupropion s efficacy at 6 months is less effective than NRT C. Bupropion s efficacy at 6 months is superior to nortriptyline D. Bupropion s efficacy at 6 months is equivalent to varenicline Hubbard R et al. Tobacco Control 2005;14: Benowitz NL. safety and toxicity. Oxford University Press, 1998; pp

5 Bupropion SR (Zyban, Wellbutrhin ) n Non-nicotine SR tablet n Blocks reuptake of dopamine and noradrenaline 1,2 n Non-competitive inhibition of brain nicotine receptors n Started 1-2 wks before quit date n 150mg once daily x 3 days, then bid for 7-12 wks n Contraindications n History of head injury, CNS tumour, seizures n Anorexia, bulimia, heavy alcohol use 1. Henningfield JE et al. CA Cancer J Clin 2005;55: Foulds J et al. Expert Opin Emerg Drugs 2004;9: Most Frequent Adverse Events With Bupropion Insomnia 20-40% Dry mouth 10% Disturbed concentration 9% Dizziness 9% Nausea 9% Constipation 8% Discontinuations 8% n Tricyclic antidepressant Nortriptyline n Blocks the reuptake of NA and 5HT n Start 1-3 wks before quit date n 25mg daily and titrate up to 100 mg n Treat for 12 wks n As effective as buproprion n Side effects: n Dry mouth, blurred vision, constipation, sedation, confusion, urinary retention Bupropion & Nortriptyline: Key Messages n >30 RCTs for Bupropion (n>7,000) n Abstinence rates at 12 months: n BUP 19% vs 9% Placebo n Pooled OR ~ 2 n Nortriptyline (75-100mg) as effective as BUP n NNT (for both agents) ~ Hughes JR et al. The Cochrane Library, 2004, Issue 3, Art. NO CD NICE Guidance on the use of NRT and bupropion for smoking cessation. No. 39. March Eisenberg MJ et al. CMAJ. July 2008;179(2): Varenicline (Champix ) n Partial agonist and antagonist at (α4β2) nachr n Health Canada NoC: January 24, 2007 n Start before quit date n 0.5mg 1mg bid x 12 weeks n Though not studied, given the mode of action, there may be limited additional benefit of combo with NRT n May be more effective than NRT or bupropion? Cahill et al, Cochrane Database of Systematic Reviews, 2007 Gonzales D et al. JAMA 2006;296: Jorenby DE et al. JAMA 2006;296: α4β2 nachr α4β2 nachr Partial Agonists Smoking No Partial Ag Part Ag Part ag Agonist Response 100% No Smoking Partial Ag Partial Agonist 50% Potential to relieve craving and withdrawal when quitting Smoking + Partial Ag Antagonist 50% Potential to block reinforcing effects when smoking Dual action of a partial agonist 5

6 Gum/Patch Efficacy Eisenberg MJ et al. CMAJ. July 2008;179(2): n Extensive Meta-analysis of RCTs n 69 trials; n=32,908 pts n Included studies reporting 6-12 mo abstinence rates for 7 pharmacolgical therapies n Objectives: n Summarize the efficacy of approved therapies n Compare varenicline vs. bupropion n Indirect comparison of all 7 approved therapies With Gum or Patch, the odds of abstinence at 6 months or longer is 1.71 or 1.95 Bupropion Efficacy Varenicline Efficacy Bupropion doubles your odds of abstinence at 6 months or longer Varenicline more than doubles your odds of abstinence at 6 months or longer Varenicline vs. Bupropion at 26 wks + Treatment Duration (months) Efficacy of treatments gum patch inhaler Bupropion Varenicline (longer) Bupropion Dosage 2, 4 mg 7, 14, 21mg 6-12 cartridges / day (higher) mg/day mg bid Efficacy at 6-12 month vs Placebo (OR [CI]) Abstinence rates at 6 mo (or longer) +/-3%; Placebo =8% 1.66 [1.65] ( ) 1.81 [1.88] ( ) 2.14 [2.18] ( ) 2.06 [2.12] ( ) [2.55] ( ) 13% 14.5% 17% 16.5% 26% Though quite rates are small, Varenicline increases the odds of abstinence at 6 months over bupropion Cahill et al, 2007 NNTs (vs. Placebo) for abstinence at 6 mo or longer) Hughes JR et al. Cochrane Database Syst Rev 2004; Cahill C et al. Cochrane Database Syst Rev 2007; 6

7 Adverse Effects Common side effects Serious side effects gum/ Lozange Dyspepsia (9%) Nausea (9%) Hiccups (10%) Headache (11%) Jaw pain Denture issues Throat irritation (5%) patch Headache Disturbed sleep Site rash inhaler Throat irritation Sneezing Coughing Rhinitis Pharyngitis Bupropion Insomnia (20%) Dry mouth Disturbed concentration Nausea Seizures Angioedema Varenicline Nausea (30%) Headaches Abnormal dreams Constipation Suicidal ideation Severe allergic reactions Cost/ 3month $ $ (6x/d) $180 (Nortriptyline = $75) $330 Eisenberg MJ et al. CMAJ. July 2008;179(2): Hughes JR et al. Cochrane Database Syst Rev 2004; Cahill C et al. Cochrane Database Syst Rev 2007 Limitations of Current data n Many patients lost to follow up (high drop out rates (30-45%) at 52 wks n No head-to-head trials of varenicline vs. NRT n Limited data for some treatment options n Need to look at a similar time frame n Abstinence data >12 months is sparse n Patient characteristics differ n Publication bias? n No negative studies published n 2 studies dominate varenicline data (published multiple times?) Questions? 7