Smoking Cessation Treatments and Clinical Practice Dr Alex Bobak GP and GPSI in Smoking Cessation Wandsworth

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

Why do people keep smoking? NICOTINEADDICTION HABIT SOCIAL

Mechanics of nicotine addiction

α4β2 Nicotinic Receptor α4α4 β2β2 α4α4 β2β2 β2β2 NIC Nicotine Dopamine Nucleus Accumbens (NAcc) Ventral Tegmental Area (VTA) NIC

The dopamine triggered by inhaled nicotine rapidly gets reabsorbed which leads to….. low mood and craving which leads to…..

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

On stopping smoking: It takes hours for nicotine to leave the body It takes hours for nicotine to leave the body It takes 8-12 weeks for the nicotine receptors to down-regulate It takes 8-12 weeks for the nicotine receptors to down-regulate

Smokers want to stop Allsmokers ~2–3% succeed in stopping each year 3 ~70% want to stop 1 ~30% try each year 2 1. Bridgwood et al, General Household Survey West, Getting serious about stopping smoking Arnsten, Prim Psychiatry 1996.

Stopping smoking: What works, what doesn’t

Long term cessation rates No Pharmacotherapy Pharmacotherapy (eg NRT) Willpower alone 2-3% 2-3% 4-6% 4-6% Support (trained adviser) 10-15% 10-15% 20-30% 20-30%

Nicotine replacement therapy

Based on nicotine weaning 1 Based on nicotine weaning 1 Well tolerated Well tolerated Significantly reduced withdrawal symptoms and cravings Significantly reduced withdrawal symptoms and cravings Treatment lasts 8–12 weeks with gradual withdrawal Treatment lasts 8–12 weeks with gradual withdrawal 1. Thompson et al., Henningfield, 1995.

NRT-Dosage and use Gum upto 15 or 25/day 2mg or 4mg Gum upto 15 or 25/day 2mg or 4mg Patch 16 or 24 hours 3 strengths Patch 16 or 24 hours 3 strengths S/L tabs upto 40/day 2mg S/L tabs upto 40/day 2mg Lozenges min 9 max 15/day 2mg or 4mg Lozenges min 9 max 15/day 2mg or 4mg Inhalator 6-12 cartridges/day Inhalator 6-12 cartridges/day Spray upto 64 sprays/day Spray upto 64 sprays/day

Plasma nicotine levels – contrast between cigarettes and NRT Plasma nicotine (ng/ml) Cigarette Spray Gum/Inhalator/Tablet/lozenge Patch Time (minutes) Adapted from: Tobacco Advisory Group of the Royal College of Physicians 2000.

Considerations for patients using NRT USE ENOUGH!Avoid under-dosing and irregular use. USE ENOUGH!Avoid under-dosing and irregular use. LONG ENOUGH! Don’t stop early, continue 8-12 weeks. LONG ENOUGH! Don’t stop early, continue 8-12 weeks. NOT A PUFF!Slower and less efficient source of nicotine than cigarettes so can not compete. NOT A PUFF!Slower and less efficient source of nicotine than cigarettes so can not compete.

Bupropion

Background to Bupropion (Zyban) Non-nicotine prescription tablet Non-nicotine prescription tablet Modifies dopamine levels and noradrenergic activity Modifies dopamine levels and noradrenergic activity Used by approx. 15 million people worldwide for smoking cessation (incl. > 700,000 smokers in UK) Used by approx. 15 million people worldwide for smoking cessation (incl. > 700,000 smokers in UK) Well established safety profile Well established safety profile

Bupropion treatment 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 week, for example day 11, or earlier if the patient feels ready to stop Patients should choose a quit date in the second week, for example day 11, or earlier if the patient feels ready to stop

Adverse events on bupropion in smokers with CVD. McRobbie InsomniaHeadacheDry mouthNausea BupropionPlacebo

Varenicline

Specifically designed Oral prescription medicine Targets the  4  2 nicotinic acetylcholine receptor 1. Coe JW. J Med Chem 2005; 48: Dani JA, Harris RA. Nature Neuroscience 2005; 8: Varenicline (Champix)

Part Stimulating Relieves craving and withdrawal symptoms Coe JW. J Med Chem 2005; 48: Gonzales D et al. JAMA 2006; 296: Jorenby DE et al. JAMA 2006; 296: Foulds J. Int J Clin Pract 2006; 60: Part blocking R educes the pleasurable effects of smoking and potentially the risk of full relapse after a temporary lapse 1-4 Varenicline- partial nicotine agonist

“Recruitment” to Abstinence: Gonzaleset al. JAMA. 2006;296:47-55.

1. Gonzales DH et al. Presented at 12th SRNT, 15-18th Feb, 2006, Orlando, Florida. Abstract PA9-2. Continuous abstinence rate weeks (%) 52 week quit rates varenicline vs. bupropion OR = 1.56 (95% CI 1.19, 2.06) †p< varenicline vs. placebo OR = 2.82 (95% CI e.06, 3.86), †p< Secondary endpoint – Pooled Analysis Comparator Studies 1 & 2 (n=2,045) n=692 n=669 n=684

The real world! Early UK Data

Leeds Stop Smoking Service 4 week Quit rates (%): NRTZybanVarenicline NRTZybanVarenicline Specialist advisers: Registered advisers:

East Lancashire Stop Smoking Service 1/1/07-30/9/07: NRTVarenicline NRTVarenicline Set a quit date: Quit at 4 weeks: % Quit at 4 weeks: 60%89%

Maudsley (London) study of varenicline v NRT in routine treatment of tobacco dependence (Stapleton et al Addiction Oct 2007) NRTVarenicline NRTVarenicline Set a quit date: Quit at 4 weeks: % Quit at 4 weeks: 61.3%72.1%

Adverse events on varenicline compared with placebo

What about nausea? Warn before prescribing Warn before prescribing Usually self limiting Usually self limiting Take with food or water Take with food or water Adjust dose Adjust dose Can use anti-emetics ?prochlorperazine (Stemetil) Can use anti-emetics ?prochlorperazine (Stemetil)

1. Tonstad S et al. JAMA 2006; 296: Extended therapy study 1927 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=607 Additional 12 weeks varenicline treatment n=603

Week % of Patients 12 vs 24 Weeks Use: Results Tonstad S, et al. JAMA. 2006;296: % 36.9% P=0.02 OR = 1.34 Varenicline 24 wks Varenicline 12 wks 70.5% 49.6%

Who Can Use It? Contraindicated: Contraindicated: –Hypersensitivity to Varenicline Not Recommended: Not Recommended: –Pregnancy –Under 18 yrs –End stage renal disease

Cautions for Use n Severe renal disease as primarily excreted via kidneys (unchanged) n Epilepsy (not tested) n Psychiatric illness (not tested) Quitting smoking may exacerbate underlying condition n Breast feeding

Pharmacological Properties: Steady-state reached within 4 days Steady-state reached within 4 days Elimination half-life of ~24 hours Elimination half-life of ~24 hours No significant hepatic effects No significant hepatic effects No clinically meaningful drug interactions No clinically meaningful drug interactions

Dose of varenicline Days 1 – 3: 0.5mg once daily Days 4 – 7: 0.5mg twice daily Days 8 – 14: 1mg twice daily Days 15+ 1mg twice daily Quit date

Comparative NNTs 1. Bandolier 2. Gates, Am Fam Phys InterventionOutcomeNNT Statin (as primary prevention) Prevent one death (from MI, stroke or other cause) over 5 years Antihypertensive therapy in mild hypertension Prevent one stroke, MI or death over 1 year Screening for cervical cancer Prevent one death over 10 years 1,140 2

Numbers Needed to Treat (NNT) to Obtain 1 Long-Term Quitter? Brief advice (<5 mins) = 40 (1) Brief advice (<5 mins) = 40 (1) Adding medication to behavioural support….. Adding medication to behavioural support….. NRT = 20 (2) NRT = 20 (2) Bupropion = 15 (2) Bupropion = 15 (2) 1. West (2006) 2. Cochrane Review. (2007) Varenicline = 8 (2) Varenicline = 8 (2)

Numbers Needed to Treat (NNT) to Prevent a Premature Death? Brief advice (<5 mins) = 80 Brief advice (<5 mins) = 80 Adding medication to behavioural support….. Adding medication to behavioural support….. NRT = 40 NRT = 40 Bupropion = 30 Bupropion = 30 Varenicline = 16 Varenicline = 16