The essentials of The essentials of smoking cessationsmoking cessation

Dr Alex BobakDr Alex Bobak

GP and GPSI in Smoking Cessation GP and GPSI in Smoking Cessation Wandsworth, LondonWandsworth, London

More than 50% of More than 50% of long term smokers long term smokers die prematurely of die prematurely of smoking related smoking related

diseasesdiseases

What’s in a cigarette?What’s in a cigarette?

NicotineNicotine TarTar ArsenicArsenic

CarbonCarbonmonoxidemonoxide

CadmiumCadmiumHydrogenHydrogenCyanideCyanide

Cigarette smoke contains more than 4,000 chemicals,Cigarette smoke contains more than 4,000 chemicals,including over 60 known carcinogens and metabincluding over 60 known carcinogens and metabolic poisonsolic poisons

Ginzel KH. What’s in a cigarette?http://www.acsh.org/publications/priorities/0102/nicotine.html

AmmoniaAmmonia TolueneToluenePhenolPhenol

NitrosamineNitrosamineNaphthaleneNaphthaleneButaneButane

DDTDDT

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 The dopamine triggered by inhaled nicotine rapidly gets inhaled nicotine rapidly gets

reabsorbed which leads to…..reabsorbed which leads to…..

low mood and craving low mood and craving which leads to…..which leads to…..

Regular smoking leads to a Regular smoking leads to a 300% increase in brain nicotine 300% increase in brain nicotine

receptorsreceptors

On stopping smoking:On stopping smoking:

It takes 24-48 hours for nicotine to leave the It takes 24-48 hours for nicotine to leave the bodybody

It takes 8-12 weeks for the nicotine receptors It takes 8-12 weeks for the nicotine receptors to down-regulateto down-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

A number of tools to aid smoking A number of tools to aid smoking cessation are availablecessation are available

Combination of both methods?

Non-pharmacological methods

• Counselling• Lifestyle changes (e.g. increased exercise)

Pharmacological methods

• NRT• Bupropion SR

• Varenicline

NRT = nicotine replacement therapy; SR = sustained release

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 Nicotine replacement therapytherapy

Nicotine replacement therapyNicotine replacement therapy

Available in six different formsAvailable in six different forms

Based on nicotine weaningBased on nicotine weaning11

Significantly reduces withdrawal symptoms Significantly reduces withdrawal symptoms

and cravings vs placeboand cravings vs placebo22

Significantly increases smoking cessation Significantly increases smoking cessation

rate vs placebo (odds ratio = 1.77)rate vs placebo (odds ratio = 1.77)33

Treatment lasts 8–12 weeks with gradual Treatment lasts 8–12 weeks with gradual withdrawalwithdrawal

1. Thompson GH, et al. Ann Pharmacother 1998;32:1067–752. Henningfield JE, N Engl J Med 1995;333:1196–203

3. Silagy C, et al. Cochrane Database Syst Rev 2004. CD000146CNS = central nervous system

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

BupropionBupropion(Zyban)(Zyban)

Bupropion SRBupropion SR

Non-nicotine prescription tablet originally Non-nicotine prescription tablet originally developed to treat depressiondeveloped to treat depression11

Modifies dopamine levels and Modifies dopamine levels and noradrenergic activitynoradrenergic activity11

Significantly increases smoking cessation Significantly increases smoking cessation rate vs placebo (odds ratio = 1.94)rate vs placebo (odds ratio = 1.94)22

1.Bupropion (Zyban) prescribing information. Available athttp://us.gsk.com/products/assets/us_zyban.pdf

2.Hughes et al. Cochrane Database Syst Rev 1996. CD000031

VareniclineVarenicline(Champix)(Champix)

• 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.

VareniclineVarenicline

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 Varenicline- partial nicotine agonistagonist

Gonzales D, et al. JAMA 2006;296:47–55

60

50

40

30

20

10

00 4 8 12 16 20 24 28 32 36 40 44 48 52

Po

int

pre

vale

nce

ab

stin

ence

(%

)

Time (weeks)

Varenicline (n=352)

Bupropion SR (n=329)

Placebo (n=344)

Drug treatment

‘‘Recruitment’ to abstinenceRecruitment’ to abstinence

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

52 week quit rate52 week quit rate

26.120.3

0

10

20

30

40

50

60

70

80

Varenicline (n=376) NRT patch (n=370)

Resp

onse

rate

(%

) OR 1.40, 95% CI: 0.99-1.99; p=ns (0.056)

The real world!The real world!

2007/08 English Stop 2007/08 English Stop Smoking Services DataSmoking Services Data

English Stop Smoking Services English Stop Smoking Services 2007/2008:2007/2008:

No. Setting Quit No. Setting Quit DateDate Quit at 4 WeeksQuit at 4 Weeks Quit RateQuit Rate

NRTNRT 474,311474,311 231,601231,601 49%49%

ZybanZyban 22,34822,348 11,92311,923 53%53%

ChampixChampix 97,25997,259 60,86460,864 63%63%

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

Can use anti-emetics ?prochlorperazine (Stemetil)Can use anti-emetics ?prochlorperazine (Stemetil)

Adjust doseAdjust dose

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 = OR = 1.34 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)

Breast feeding Breast feeding 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

Withdrawal SymptomsWithdrawal Symptoms

Compared to placebo varenicline Compared to placebo varenicline significantly reduced :significantly reduced :

Depressed moodDepressed mood

Irritability, frustration or angerIrritability, frustration or anger

AnxietyAnxiety

Difficulty concentratingDifficulty concentrating

Gonazales D Gonazales D et alet al. . JAMAJAMA 2006;296:47-55; Jorenby DE 2006;296:47-55; Jorenby DE et alet al. . JAMAJAMA 2006;296:56-63. 2006;296:56-63.

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

NICE Guidance on varenicline NICE Guidance on varenicline July 2007July 2007

““Varenicline is recommended, within its Varenicline is recommended, within its licensed indications, as an option for smokers licensed indications, as an option for smokers who have expressed a desire to quit smoking”who have expressed a desire to quit smoking”

“…“….should normally be provided in conjunction .should normally be provided in conjunction with counselling and support”with counselling and support”

…….but if such support is refused, or not .but if such support is refused, or not available, this should not preclude treatment available, this should not preclude treatment with vareniclinewith varenicline

Numbers Needed to Treat (NNT) to Numbers Needed to Treat (NNT) to Obtain 1 Long-Term Quitter?Obtain 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)

Varenicline = 8Varenicline = 8(2)(2)

1. West (2006) 2. Cochrane Review. 1. West (2006) 2. Cochrane Review. (2007)(2007)

Numbers Needed to Treat (NNT) to Numbers Needed to Treat (NNT) to Prevent a Premature Death?Prevent a Premature Death?

Brief advice (<5 mins) = 80Brief advice (<5 mins) = 80

AddingAdding medication to medication to behavioural support…..behavioural support…..

NRT = 40NRT = 40

Bupropion = 30Bupropion = 30

Varenicline = 16Varenicline = 16