1. 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

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

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

4. 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, July 14, http//

5. 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

6. 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

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

8. 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

9. 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

10. 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

11. 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

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

13. 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.
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14. 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.
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15. 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

16. 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)

17. 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

18. 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)

19. 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)

20. 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

21. 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

22. 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

23. 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

24. 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)

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

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

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

33. 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

34. 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, )
placebo 49.6%
NNT 5
continuous abstinence from weeks 13 to 52.
Varenicline 43.6% (OR, 1.34; 95% CI, )
Placebo 36.9%
NNT 15
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35. 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

36. 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
mg daily $
nicotine gum
2 or 4 mg PRN $
nicotine patch
1 OD x 10 weeks $
nicotine inhaler
6 – 12 cart. OD PRN $
nicotine lozenge
1 or 2 mg PRN $

37. 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 cigarettes a day

38. 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