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