smoking cessation treatments and clinical practice dr alex bobak gp and gpsi in smoking cessation...
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Smoking Cessation Smoking Cessation Treatments and Clinical Treatments and Clinical
PracticePracticeDr Alex BobakDr Alex Bobak
GP and GPSI in Smoking Cessation GP and GPSI in Smoking Cessation WandsworthWandsworth
More than 50% of long More than 50% of long term smokers die term smokers die
prematurely of prematurely of smoking related smoking related
diseasesdiseases
Why do people keep smoking?Why do people keep smoking?
NICOTINENICOTINE
ADDICTIONADDICTIONHABIT
SOCIAL
Mechanics of nicotine Mechanics of nicotine addictionaddiction
α4β2Nicotinic Receptor
α4β2
α4β2β2
NIC NicotineDopamine
NucleusAccumbens(NAcc)
VentralTegmentalArea(VTA)
NIC
The dopamine triggered by inhaled The dopamine triggered by inhaled nicotine rapidly gets reabsorbed which nicotine rapidly gets reabsorbed which
leads to…..leads to…..
low mood and craving low mood and craving which leads to…..which leads to…..
Regular smoking leads to a 300% Regular smoking leads to a 300% increase in brain nicotine receptorsincrease in brain nicotine receptors
On stopping smoking:On stopping smoking:
It takes 24-48 hours for nicotine to leave the bodyIt takes 24-48 hours for nicotine to leave the body
It takes 8-12 weeks for the nicotine receptors to It takes 8-12 weeks for the nicotine receptors to down-regulatedown-regulate
Smokers want to stopSmokers want to stop
AllAllsmokerssmokers
~2–3%~2–3%succeed insucceed instoppingstopping
each yeareach year33
~~70%70%want to stopwant to stop11
~~30%30%try each yeartry each year22
1. Bridgwood et al, General Household Survey 1998. 2. West, Getting serious about stopping smoking 1997. 3. Arnsten, Prim Psychiatry 1996.
Stopping smoking:Stopping smoking:What works, what doesn’tWhat works, what doesn’t
Long term cessation ratesLong term cessation rates
No No PharmacotherapyPharmacotherapy
PharmacotherapyPharmacotherapy
(eg NRT)(eg NRT)
Willpower aloneWillpower alone 2-3%2-3% 4-6% 4-6%
Support (trained Support (trained adviser)adviser) 10-15%10-15% 20-30%20-30%
Nicotine replacement therapyNicotine replacement therapy
Nicotine replacement therapyNicotine replacement therapy
Based on nicotine weaningBased on nicotine weaning11
Well toleratedWell tolerated
Significantly reduced withdrawal symptoms and cravingsSignificantly reduced withdrawal symptoms and cravings
Treatment lasts 8–12 weeks with gradual withdrawalTreatment lasts 8–12 weeks with gradual withdrawal
1. Thompson et al., 1998.2. Henningfield, 1995.
NRT-Dosage and useNRT-Dosage and use GumGum upto 15 or 25/day upto 15 or 25/day 2mg or 4mg 2mg or 4mg
PatchPatch 16 or 24 hours 16 or 24 hours 3 strengths 3 strengths
S/L tabsS/L tabs upto 40/day upto 40/day 2mg 2mg
Lozenges min 9 max 15/dayLozenges min 9 max 15/day 2mg or 4mg 2mg or 4mg
InhalatorInhalator 6-12 cartridges/day 6-12 cartridges/day
Spray Spray upto 64 sprays/day upto 64 sprays/day
Plasma nicotine levels Plasma nicotine levels – – contrast contrast between cigarettes and NRTbetween cigarettes and NRTP
lasm
a n
icot
ine
(n
g/m
l)
25
20
15
10
5
0100 20 4030 50 60
Cigarette
Spray
Gum/Inhalator/Tablet/lozenge
Patch
Time (minutes)
Adapted from: Tobacco Advisory Group of the Royal College of Physicians 2000.
ConsiderationsConsiderationsfor patients using NRTfor patients using NRT
USE ENOUGH!USE ENOUGH! Avoid under-Avoid under-dosing and irregular use. dosing and irregular use.
LONG ENOUGH! LONG ENOUGH! Don’t Don’t stop early, continue 8-12 weeks. stop early, continue 8-12 weeks.
NOT A PUFF!NOT A PUFF! Slower Slower and less efficient source of nicotine than cigarettes and less efficient source of nicotine than cigarettes so can not compete.so can not compete.
BupropionBupropion
Background to Bupropion (Zyban) Background to Bupropion (Zyban)
Non-nicotine prescription tablet Non-nicotine prescription tablet
Modifies dopamine levels and Modifies dopamine levels and noradrenergic activity noradrenergic activity
Used by approx. 15 million people Used by approx. 15 million people
worldwide for smoking cessation worldwide for smoking cessation (incl. > 700,000 smokers in UK)(incl. > 700,000 smokers in UK)
Well established safety profileWell established safety profile
Bupropion Bupropion treatment regimetreatment regime
150 mg o.d.for 6 days
150 mg b.d.for remainder of 120
tablet treatment course
Patients should choose a quit date in the second Patients should choose a quit date in the second week, for example day 11, or earlier if the patient week, for example day 11, or earlier if the patient feels ready to stopfeels ready to stop
Adverse events on bupropion in smokers with CVD. McRobbie 2001
24
1211 11
18
10
13
6
0
5
10
15
20
25
Insomnia Headache Dry mouth Nausea
Bupropion Placebo
VareniclineVarenicline
• Specifically designed
• Oral prescription medicine
• Targets the 42 nicotinic acetylcholine receptor
1. Coe JW. J Med Chem 2005; 48:3474-3477. 2. Dani JA, Harris RA. Nature Neuroscience 2005; 8:1465-1470.
Varenicline (Champix)Varenicline (Champix)
Part Stimulating • Relieves craving and withdrawal symptoms1-3
1. Coe JW. J Med Chem 2005; 48:3474-3477. 2. Gonzales D et al. JAMA 2006; 296:47-55. 3. Jorenby DE et al. JAMA 2006; 296:56-63. 4. Foulds J. Int J Clin Pract 2006; 60:571-576.
Part blocking
• Reduces the pleasurable effects of smoking and potentially the risk of full relapse after a temporary lapse1-4
Varenicline- partial nicotine agonistVarenicline- partial nicotine agonist
““Recruitment” to Abstinence:Recruitment” to Abstinence:Gonzaleset al. JAMA. 2006;296:47-55.
22.5%
15.7%
9.4%
0%
5%
10%
15%
20%
25%
Varenicline 1mg bd†
Bupropion 150mg bd
Placebo
1. Gonzales DH et al. Presented at 12th SRNT, 15-18th Feb, 2006, Orlando, Florida. Abstract PA9-2.
Co
nti
nu
ou
s ab
sti
nen
ce r
ate
wee
ks 9
- 5
2 (%
)
52 week quit rates52 week quit rates
varenicline vs. bupropion OR = 1.56 (95% CI 1.19, 2.06) †p<0.0013varenicline vs. placebo OR = 2.82 (95% CI e.06, 3.86), †p<0.0001
Secondary endpoint –Pooled Analysis Comparator Studies 1 & 2 (n=2,045)
n=692 n=669 n=684
The real world!The real world!
Early UK DataEarly UK Data
Leeds Stop Smoking Service Leeds Stop Smoking Service 4 week Quit rates (%):4 week Quit rates (%):
NRTNRT ZybanZyban VareniclineVarenicline
Specialist advisers:Specialist advisers: 68.668.6 68.668.6 77.177.1
Registered advisers:Registered advisers: 61.461.4 61.561.5 66.366.3
East Lancashire Stop Smoking Service East Lancashire Stop Smoking Service 1/1/07-30/9/07:1/1/07-30/9/07:
NRTNRT VareniclineVareniclineSet a quit date:Set a quit date: 21212121 789789
Quit at 4 weeks:Quit at 4 weeks: 12831283 703703
% Quit at 4 weeks:% Quit at 4 weeks: 60%60% 89%89%
Maudsley (London) study of Maudsley (London) study of varenicline v NRT in routine treatment varenicline v NRT in routine treatment of tobacco dependence of tobacco dependence (Stapleton et al Addiction Oct (Stapleton et al Addiction Oct
2007)2007)
NRTNRT VareniclineVareniclineSet a quit date:Set a quit date: 204204 208208
Quit at 4 weeks:Quit at 4 weeks: 125125 150150
% Quit at 4 weeks:% Quit at 4 weeks: 61.3%61.3% 72.1%72.1%
29
9
15
12 12
5
14 13
0
5
10
15
20
25
30
Nausea Headache AbnormalDreams
Insomnia
Varenicline
Placebo
Adverse events on varenicline compared with placebo
What about nausea?What about nausea?
Warn before prescribingWarn before prescribing
Usually self limitingUsually self limiting
Take with food or waterTake with food or water
Adjust doseAdjust dose
Can use anti-emetics ?prochlorperazine (Stemetil)Can use anti-emetics ?prochlorperazine (Stemetil)
1. Tonstad S et al. JAMA 2006; 296:64-71.
Extended therapy studyExtended therapy study1927 smokers
Initial phase
12 weeks varenicline treatment
Inclusion criteria: participants adherent to drug and with CO confirmed abstinence during week 12 n=1236
Randomised double-blind phase n=1,210
Primary endpoint
Secondary endpoint
24 week continuous quit rate
52 week continuous quit rate
Follow-up phase
12 weeks placebo n=607Additional 12 weeks varenicline
treatment n=603
20
40
60
80
100
12 16 20 24 28 32 36 40 44 48 52 56
Week
% of Patients
12 vs 24 Weeks Use: Results12 vs 24 Weeks Use: Results
Tonstad S, et al. JAMA. 2006;296:64-71.
43.6%43.6%
36.9%36.9%
P=0.02 P=0.02 OR = 1.34 OR = 1.34
Varenicline 24 wksVarenicline 24 wks Varenicline 12 wksVarenicline 12 wks
70.5%70.5%
49.6%49.6%
Who Can Use It?Who Can Use It?
ContraindicatedContraindicated::
–Hypersensitivity to VareniclineHypersensitivity to Varenicline
Not RecommendedNot Recommended::
–PregnancyPregnancy
–Under 18 yrsUnder 18 yrs
–End stage renal diseaseEnd stage renal disease
Cautions for UseCautions for Use
Severe renal disease as primarily Severe renal disease as primarily excreted via kidneys (unchanged)excreted via kidneys (unchanged)
Epilepsy (not tested)Epilepsy (not tested) Psychiatric illness (not tested) Psychiatric illness (not tested)
Quitting smoking may exacerbate Quitting smoking may exacerbate underlying conditionunderlying condition
Breast feedingBreast feeding
Pharmacological Properties:Pharmacological Properties:
Steady-state reached within 4 daysSteady-state reached within 4 days
Elimination half-life of ~24 hoursElimination half-life of ~24 hours
No significant hepatic effectsNo significant hepatic effects
No clinically meaningful drug interactionsNo clinically meaningful drug interactions
Dose of varenicline
Days 1 – 3:Days 1 – 3: 0.5mg once daily0.5mg once daily
Days 4 – 7:Days 4 – 7: 0.5mg twice daily0.5mg twice daily
Days 8 – 14: Days 8 – 14: 1mg twice daily1mg twice daily
Days 15+Days 15+ 1mg twice daily1mg twice daily
Quit date
Comparative NNTsComparative NNTs
1. Bandolier 2. Gates, Am Fam Phys 2001.
InterventionIntervention OutcomeOutcome NNTNNTStatin (as primary Statin (as primary prevention)prevention)
Prevent one death (from MI, stroke or Prevent one death (from MI, stroke or other cause) over 5 yearsother cause) over 5 years
10710711
Antihypertensive Antihypertensive therapy in mild therapy in mild hypertensionhypertension
Prevent one stroke, MI or death over 1 Prevent one stroke, MI or death over 1 year year
70070011
Screening for Screening for cervical cancercervical cancer
Prevent one death over 10 years Prevent one death over 10 years 1,1401,14022
Numbers Needed to Treat (NNT) to Obtain Numbers Needed to Treat (NNT) to Obtain 1 Long-Term Quitter?1 Long-Term Quitter?
Brief advice (<5 mins) = 40Brief advice (<5 mins) = 40(1)(1)
AddingAdding medication to behavioural medication to behavioural support…..support…..
NRT = 20NRT = 20(2)(2)
Bupropion = 15Bupropion = 15(2)(2)
1. West (2006) 2. Cochrane Review. (2007)1. West (2006) 2. Cochrane Review. (2007)
Varenicline = 8Varenicline = 8(2)(2)
Numbers Needed to Treat (NNT) to Prevent Numbers Needed to Treat (NNT) to Prevent a Premature Death?a Premature Death?
Brief advice (<5 mins) = 80Brief advice (<5 mins) = 80
AddingAdding medication to behavioural medication to behavioural support…..support…..
NRT = 40NRT = 40
Bupropion = 30Bupropion = 30
Varenicline = 16Varenicline = 16
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