Download Pharmacotherapy for Smoking Cessation

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
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42 nicotine receptor blocker
antidepressants
nicotine replacement therapy (NRT)
Pharmacotherapy
for Smoking Cessation - 2
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Evidence for effectiveness
Tolerability
Key prescribing information
Practical issues
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how to choose
combinations
cost
Deaths Attributed to Smoking
Tobacco
Combined
Preventable Deaths
Suicides
Car Accidents
Alcohol
Murders
0
5000
10000 15000 20000 25000 30000 35000 40000 45000 50000
varenicline (Champix)
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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
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42 receptor
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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
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designed to be a selective 42
receptor partial agonist & partial
antagonist
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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
So what…?
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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
But does it work…?
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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…?
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primary end point;
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4-week continuous abstinence rate for
weeks 9 – 12
secondary end points
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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?
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abstinence = not a single puff within
the measurement period; confirmed by
expired CO </= 10 ppm
Continuous Abstinence rates
Gonzales, D. et al. JAMA 2006;296:47-55.
Copyright restrictions may apply.
7-Day Point Prevalence Abstinence
Gonzales, D. et al. JAMA 2006;296:47-55.
Copyright restrictions may apply.
Effects on Craving, Withdrawal & Smoking
Satisfaction
Craving
 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
Withdrawal
 Both reduced the negative affect
associated with quitting about equally
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varenicline reduced restlessness (small
effect size)
varenicline increased appetite cf.
bupropion (small effect size)
Effects on Craving, Withdrawal & Smoking
Satisfaction - 3
Smoking Satisfaction
 varenicline & bupropion both had a
moderate effect on reducing smoking
satisfaction & psychological reward
after smoking while taking the drug
Tolerability
Varenicline
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nausea (28.1%)
headache (15.5%)
insomnia (14.0%)
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abnormal dreams (10.3%)
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Bupropion
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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
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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
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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
Tolerability - 2
bupropion
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nortriptyline
insomnia
dry mouth
nausea
about 1 in 1000 risk
of seizures
risk of suicide is
unproven
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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
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evidence of a small additional benefit from using the
patch in combination with ad lib use of the gum
or inhaler
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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
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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
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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
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
smoking
varenicline
bupropion
nortriptyline
nicotine gum
nicotine patch
nicotine inhaler
nicotine lozenge
Dose for 12 wks
1 pack/day
1 mg BID
150 mg BID
75-100 mg daily
2 or 4 mg PRN
1 OD x 10 weeks
6 – 12 cart. OD PRN
1 or 2 mg PRN
Approx. Cost
$670
$325
$180
$50 - 84
$115 - 210
$230 - 300
$280 - 550
$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…
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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;
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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