Pharmacotherapy for Smoking Cessation Dave Davidson B.Sc., M.D.,C.M., C.C.F.P.(EM), F.C.F.P. Department of Family Medicine, University of Ottawa

Pharmacotherapy for Smoking Cessation 42 nicotine receptor blocker antidepressants nicotine replacement therapy (NRT)

Pharmacotherapy for Smoking Cessation - 2 Evidence for effectiveness Tolerability Key prescribing information Practical issues how to choose combinations cost

Deaths Attributed to Smoking Medical Facts In Canada, smoking is the most important cause of preventable illness, disability and premature death. In 1996, greater than 45,200 deaths (29,229 male and 15,986 female were caused by smoking—more than 20% of all deaths among Canadians. In 1996, smoking prematurely killed three times more Canadians than car accidents, suicides, drug abuse, murder and AIDS combined. Accounting for over 45,200 deaths in 1996, smoking far exceeded the second most important preventable cause of death—accidents (over 8,600 deaths). Compared with non-smokers, the risk of premature death is more than double among Canadian men and almost double Canadian women who begin smoking by age 15. Works Cited: Health Canada, Legislation Regulation & Compliance: Each Year, the Equivalent of a Small City Dies from Tobacco Use, February 08, 2002. July 14, 2005. http//www.hc-sc.gc.ca/hecs-sesc/tobacco/legislation/warnings/e_i.html.

varenicline (Champix) approved for use in Canada this year first pharmaceutical agent designed for smoking cessation starting point was cytisine, a plant derived 42 receptor agonist used in Eastern Europe by smokers trying to quit

varenicline 42 receptor acetylcholine (nicotinic) receptor in the reward centre of the brain (nucleus accumbens) when stimulated by smoked nicotine the 42 receptor releases dopamine

The Brain Le Foll, B. et al. CMAJ 2007;177:1373-1380 Copyright ©2007 Canadian Medical Association or its licensors

Varenicline - 2 designed to be a selective 42 receptor partial agonist & partial antagonist varenicline has 35 – 60% of nicotine’s agonist effect on dopamine release in the brain varenicline is a competitive antagonist with more affinity for the 42 receptor than nicotine

Nides, M et al. Arch Intern Med; Vol 16, Aug 14/28, 2006 So what…? through its partial agonist and partial antagonist effect on the nicotine receptor varenicline stimulates enough release of dopamine to decrease craving and withdrawal while also blocking the pleasurable effects of smoked nicotine. Nides, M et al. Arch Intern Med; Vol 16, Aug 14/28, 2006

Gonzales, D et al. JAMA, Vol 296, No. 1, July 5, 2006 But does it work…? 2 identical RCTs varenicline vs. bupropion vs. placebo 1000+ subjects randomized in each study age 40s, 50 – 60% men, ~80% white, ~20 cigarettes per day for 24 years 12 weeks of study drug Gonzales, D et al. JAMA, Vol 296, No. 1, July 5, 2006

Varenicline, does it work…? primary end point; 4-week continuous abstinence rate for weeks 9 – 12 secondary end points continuous abstinence rates weeks 9 – 24 and weeks 9 – 52 weight change measures (questionnaires) of craving, withdrawal, and smoking reinforcement Jorenby, DE et al, JAMA, Vol 296, No. 1, July 5, 2006

Varenicline, does it work? abstinence = not a single puff within the measurement period; confirmed by expired CO </= 10 ppm

Continuous Abstinence rates Continuous abstinence weeks 9 to 12 (Jorenby) Varenicline 44.0% (43.9) OR vs bupropion, 1.93 (1.90); 95% CI, 1.40 – 2.68; P<.001 Bupropion 29.5% (29.8) Placebo 17.7% (17.6) Continuous abstinence weeks 9 to 24 Varenicline 29.5% (29.7) OR vs bupropion, 1.63; 95% CI, 1.14 – 2.33; p=.007 Bupropion 20.7% (20.2) Placebo 10.5% (13.2) Continuous abstinence weeks 9 to 52 Varenicline 21.9% (23.0) OR vs bupropion, 1.46; CI, 0.99 – 2.17; p=.057 Bupropion 16.1% (14.6) Placebo 8.4% (10.3) Gonzales, D. et al. JAMA 2006;296:47-55. Copyright restrictions may apply.

7-Day Point Prevalence Abstinence Varenicline, does it work…? Yes, but… w.r.t. the partial agonist/antagonist mechanism of action; Point prevalence 7-Day abstinence rates increase to week 5. “The trend of increasing quit rates over time for varenicline may indicate decreased reinforcing effects of smoking.” Gonzales, D. et al. JAMA 2006;296:47-55. Copyright restrictions may apply.

Effects on Craving, Withdrawal & Smoking Satisfaction both reduced craving but varenicline had twice the effect (moderate effect size) both reduced urge to smoke but varenicline had twice the effect size

Effects on Craving, Withdrawal & Smoking Satisfaction - 2 Both reduced the negative affect associated with quitting about equally varenicline reduced restlessness (small effect size) varenicline increased appetite cf. bupropion (small effect size)

Effects on Craving, Withdrawal & Smoking Satisfaction - 3 varenicline & bupropion both had a moderate effect on reducing smoking satisfaction & psychological reward after smoking while taking the drug

Tolerability Varenicline Bupropion nausea (28.1%) headache (15.5%) insomnia (14.0%) abnormal dreams (10.3%) Bupropion insomnia (21.9%) headache (14.3%) nausea (12.5%) seizures (n=1)

Antidepressants for Smoking Cessation Effectiveness As sole pharmacotherapy bupropion and nortriptyline both double the odds of cessation bupropion (31 trials; OR 1.94, 95% CI, 1.72 to 2.19) nortriptyline (4 trials; OR 2.34, 95% CI 1.61 to 3.41)

Antidepressants for Smoking Cessation - 2 their effect is not restricted to people with a history of depression or depressive symptoms during smoking abstinence insufficient evidence that adding either bupropion or nortriptyline to NRT provides an additional long-term benefit

Antidepressants for Smoking Cessation - 3 equal in effectiveness to NRT pooled data from 3 trials comparing bupropion to varenicline showed a lower odds of quitting with bupropion (OR 0.60, 95% CI, 0.46 TO 0.78) nortriptyline is not approved in Canada for smoking cessation

Antidepressants for Smoking Cessation - 4 SSRIs 4 trials of fluoxetine 1 trial of sertraline 1 trial of paroxetine none showed significant effectiveness in smoking cessation alone or when pooled Atypical Antidepressants 1 trial of venlafaxine showed no benefit MAOs 1 trial of moclobemide showed no effect

Hughes, JR et al. Cochrane Collaboration, January 2007 Tolerability - 2 bupropion insomnia dry mouth nausea about 1 in 1000 risk of seizures risk of suicide is unproven nortriptyline dry mouth constipation nausea sedation dangerous in overdose Hughes, JR et al. Cochrane Collaboration, January 2007

NRT for Smoking Cessation Pooled odds ratios for abstinence with NRT from 103 controlled trials was 1.77 (95% CI, 1.66 to 1.88) Gum 1.66 (95% CI, 1.52 to 1.81) Patches 1.81 (95% CI, 1.63 to 2.02) Lozenge 2.05 (95% CI, 1.62 to 2.59) Inhaler 2.14 (95% CI, 1.44 to 3.18)

NRT for Smoking Cessation - 2 Gum fixed dose or ad lib heavy smokers (>30 cigarettes/day) benefit from the 4mg pieces side-effects hiccups, GI disturbances, jaw pain, dental problems

NRT for Smoking Cessation - 3 Patches eight weeks of patch therapy is as effective as longer courses no evidence that tapered therapy is better than abrupt withdrawal wearing the patch only during waking hours is as effective as wearing it for 24 hours a day

NRT for Smoking Cessation - 4 Patches evidence of a small additional benefit from using the patch in combination with ad lib use of the gum or inhaler evidence supports using more than one patch at a time in heavy smokers or those who relapse because of craving and withdrawal symptoms on standard dose therapy repeated courses of NRT in those who relapse after using the patch produces a small additional probability of quitting

NRT for Smoking Cessation - 5 Patches side-effects skin irritation in up to 54% but rarely leads to withdrawal of patch use no evidence of increased risk of cardiac events in patients with known CV disease

NRT for Smoking Cessation - 6 Lozenge 1mg if smoking less than 20/day; 2mg if smoking more than 20/day suck & park 10 – 12 per day for most people absorbed through buccal mucosa ad lib use instead of smoking takes about 30 minutes to dissolve

NRT for Smoking Cessation - 7 Inhaler nicotine 10mg/canister 4mg delivered to the throat & oral mucosa 2mg absorbed side-effects throat irritation, coughing, oral burning Silagy, C et al, Cochrane Collaboration, July 2004

Pharmacotherapy for Prevention of Relapse 50 – 60% of initially successful quitters go on to relapse within a year

Pharmacotherapy for Prevention of Relapse - 2 nicotine gum 2 trials found a small effect; (n=2261: OR, 1.30; 95% CI, 1.06-1.61) bupropion no effect when data from two trials pooled: (n=605; OR, 1.25; 95% CI, 0.86-1.81)

Pharmacotherapy for Prevention of Relapse - 3 “Varenicline is the first smoking cessation treatment to demonstrate a (clinically) significant long-term relapse prevention effect.” Tonstad, S et al. JAMA, Vol 296, No.1, July 5, 2006

Seven-Day Point Prevalence of Abstinence 64.1% were smoke-free during week 12 of 12 weeks of open-label treatment with varenicline 1mg BID randomized to 12 more weeks of varenicline (n=603) or 12 weeks of placebo (n=607) main outcome measures continuous abstinence from weeks 13 to 24 varenicline 70.5% (OR, 2.48; 95% CI, 1.95-3.16) placebo 49.6% NNT 5 continuous abstinence from weeks 13 to 52. Varenicline 43.6% (OR, 1.34; 95% CI, 1.06-1.69) Placebo 36.9% NNT 15 Copyright restrictions may apply.

Pills or NRT to Quit? Effectiveness? 3 studies show that varenicline is more effective than bupropion only varenicline helps prevent relapse with an additional 12 weeks of Rx no evidence to choose bupropion or nortriptyline over NRT or vise versa

Pills or NRT to Quit? - 2 Drug Dose for 12 wks Approx. Cost smoking 1 pack/day $670 varenicline 1 mg BID $325 bupropion 150 mg BID $180 nortriptyline 75-100 mg daily $50 - 84 nicotine gum 2 or 4 mg PRN $115 - 210 nicotine patch 1 OD x 10 weeks $230 - 300 nicotine inhaler 6 – 12 cart. OD PRN $280 - 550 nicotine lozenge 1 or 2 mg PRN $110 - 290

Pills or NRT to Quit? - 3 Patient factors? The smoker’s level of dependence on nicotine influences NRT effectiveness heavy smokers (>30 cigarettes/day) benefit from higher doses of nicotine replacement e.g. 4mg gum vs 2mg or combinations of NRT limited evidence of NRT effectiveness in those who smoke less than 10-15 cigarettes a day

Pills or NRT to Quit? - 4 In closing… Most patients will tell you what they want so be guided by their preferences and past experiences with quitting. Varenicline is generally more effective than bupropion or NRT & appears to be safe. Consider the side effect profile; NRT – few SE, none serious bupropion – insomnia (common), seizures (rare) varenicline – nausea (common) To avoid weight gain bupropion might be a better choice between the pills History of seizure disorder or anything that lowers seizure threshold eliminates bupropion