Successful SMOKING CESSATION

Dr. Sallehudin Bin Abu BakarMD (M’sia); MPH (Philippines); M.Epid.(Johns Hopkins)

The integrated approach to successful smoking cessation

Professional Professional involvementinvolvement

Behavioural Behavioural supportsupport

Proven Proven pharmacotherapypharmacotherapy

Non-Physiological Reasons for Smoking Peer pressure Mass media Pleasure and relaxation Nature of work Improved thinking and performance Relief from negative moods (anxiety, stress,

anger, irritability and depressed mood) Weight control

Physiological Reasons for Smoking

Physical dependence on nicotine Relief from withdrawal symptoms

Effects of Nicotine Withdrawal When nicotine levels drop, most smokers

report physiological withdrawal symptoms such as :AnxietyIrritabilityRestlessnessDifficulty in concentratingStomach problemsCravingDrowsiness

Nicotine Circulation in the Body When the smoker inhales

Nicotine first enters the lungs Quickly enter the pulmonary circulation

and is pumped into the heartThe heart pumps the nicotine-laden blood

throughout the bodyReaches the brain only 7 to 10 secs after

inhalation

Effects on the Nervous System Nicotine acts on the central and autonomic

nervous systems by stimulating the brain’s nicotinic receptors

Changes in mood, learning, concentration, alertness and performance

Physical changes such as up-regulation of the brain (increase in no. of nicotine receptors)

Change in metabolism and energy utilisation in the brain, similar to other addictive drugs

EEG changes Alteration of the endocrine system functioning

Effects on the Nervous System

These changes in the physical make-up and functioning of the brain and nervous system may contribute to the development of :Nicotine TolerancePhysical Dependence

Health Benefits

Within days of quitting, carbon monoxide from smoking begins to leave the body

Within weeks, ex-smokers begin to breathe easier and enjoy improved senses of taste and smell

One year after quitting, risk of death from coronary heart disease decrease by 50% and continues to decline with time

Risk of stroke and lung cancer are also reduced significantly over time

Health Benefit

Overall, fifteen years after quitting, the overall risk of death is about the same as for those who have never smoked.

Health Benefits

One-fourth of smokers die early because of smoking

A 25 year-old heavy smoker’s life expectancy may be shortened by more than 25% compared to a non-smoker

Smoking Finances

Assuming a smoker spends RM8.00a day on cigarettes (1 pack of 20’s), quitting will save RM2,920.00 a year.

The Cessation Reality

74% of current smokers want to quit Only 25% of those who manage to quit remain

abstinent for longer than 1 year 1.3 million (6.5%) experience long term

success

Obstacles to Cessation

Nicotine addiction Stress / anxiety Fear of gaining weight Peer pressure Many have tried and failed!

Addiction Triangle

Physical (Neurochemistry)Physical (Neurochemistry)

Emotional (Psychological)

Emotional (Psychological)

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FACTORS FACTORS AFFECTING AFFECTING ADDICTIONADDICTION

Nicotine Addiction Brain disease Compulsive need for and use of a habit-

forming substance characterised by tolerance and by well-defined physiological symptoms upon withdrawal

Dependence Occurs when body becomes accustomed to the

presence of nicotine and is altered in such a way that it needs nicotine in order to function normally

To feel stabilised, heavy smokers need to maintain a high level of nicotine in their brains and will unconsciously regulate their puff rate until this requirement is met

Addiction and Dependence are used interchangeably despite that “dependence” does not

incorporate the compulsive use aspect

Two Types of Addiction

Interplay of the two types of addiction that make smoking so addicting and so difficult to give up

Ingestive addiction Process addiction

Ingestive Addiction Excessively and compulsively taking into

the body artificially refined or produced mood-altering substances such as specific foods, drugs, gases, alcohol or tobacco

Process Addiction “Hooked” on a set of neutral actions,

interactions, or behaviours that become overused to the point where they lose their original value, meaning and purposeHighly addictive - gambling, working,

exercising, spending money, or eating

Physiology of Nicotine Addiction

Cigarette smoking is being reinforced by both positive and negative processes

Nicotine affects both reward and withdrawal pathwaysDopaminergic effects in nucleus accumbens

involved in rewardNoradrenergic effects in locus ceruleus

involved in withdrawal

Anatomy of Reward and Withdrawal

MesolimbicDopamine

System

Nucleus Accumbens

Prefrontal Cortex

Locus Ceruleus

Physiology of AddictionDopaminergic pathway Also known as the reward pathway or mesolimbic

pathway Between the ventral tegmental area to the

nucleus accumbens These contain high density of nicotinic receptors Responsible for motivational behaviour - the need

to reproduce and survive Produces pleasurable effects and positive

reinforcement

Dopamine surge in the nucleus accumbens is thought to produce the same positive motivational state associated with food and sex

The Reward Pathway

While all highly addictive drugs activate the mesolimbic pathway, nicotine is a particularly reinforcing drug because it is inhaled and nicotine levels in the brain rise very rapidly (within 10 secs), producing a more powerful effect than drugs taken orally

The Reward Pathway

Physiology of Nicotine Addiction

The combination of heightened arousal with pleasure trigger creates a sense of cyclical satisfaction

Each time a smoker smoke, these states are being reinforced.

Reinforcing message “You will only continue to feel well if you continue smoking” is the foundation of lifelong nicotine addiction.

Smoker’s Withdrawal Withdrawal is mediated by norepinephrine in the

locus ceruleus Approximately 80% of individuals who quit smoking

experience physiological withdrawal effects such as Irritability - Increased taste of sweetsDifficulty concentrating - Weight gainRestlessness - Gastrointestinal

problemsCravings - constipationAnxiety - Increased hungerDrowsiness

Smoker’s Withdrawal Withdrawal symptoms begin 6 to 12 hours after

cessation Most intense within the first 3 days May last from a few days to many months About 25% of those who quit smoking relapse

within 48 hours 50% relapse within the first 7 days 75% relapsed in 1 year

The Reality of Nicotine Addiction The smoker experience positive

reinforcement every time he lights a cigarette and stimulates the reward pathway

He also receives negative reinforcement through withdrawal symptoms and must light another cigarette to relieve them

Healthcare Provider Strategies The Agency for Health Care Policy and Research

(AHCPR) Clinical Practice Guidelines :

1. Every person who smokes should be offered smoking cessation treatment at every visit

2. Ask and record the tobacco use status of every patient

3. Clinician intervention, even as brief as 3 mins, is effective

4. The more intensive the treatment, the more effective it is in producing long-term abstinence from tobacco

5. Nicotine-replacement therapy, social support, and skills training are effective components of smoking cessation treatment

“5 A’s” for Smoking Cessation

ASK 1. Systematically identify ALL tobacco users at every visit

ADVISE 2. Strongly urge all smokers to quit ASSES 3. Asses smokers willingness

to make a quit attempt ASSIST 4. Aid the patient with a quit plan ARRANGE 5. Follow-up to monitor progress

Assisting Patient in Quitting Help the patient set a quit date and prepare

for quitting Encourage pharmacotherapy except in

special circumstances Give key advice on successful quitting Provide supplementary materials

A Quit Plan Setting a quit date - within 2 weeks of the

decision to quit Should inform family, friends, co-workers of

quitting and request for understanding and support

Remove cigarettes from the environment and, prior to quitting, avoid smoking in places where they spend a lot of time, e.g. the car

Review previous quit attempts to determine what was helpful and what led to relapse

Key Advice on Successful Quitting Abstinence - “Not even a single puff after quit

date” Alcohol - associated with relapse Other smokers in the household- developing

specific plans to deal with their abstinence in a household where others still smoke

Patient Types5 Stages of smoking cessation readiness : Pre-contemplation

Not seriously considering quittingClinicians should put their effort towards

motivating the patients to consider quitting Contemplation

Seriously considering quittingClinician should help to develop a quit plan

Patient Types Action

Actively trying to quit or has recently quitClinicians should advise smokers on coping

strategies to reduce withdrawal symptoms and at the same time discuss specific treatment options

MaintenanceHas quit and is attempting to avoid relapseClinicians should follow-up and advise them on

relapse prevention strategies

Patient Types Relapse

Very common and most difficultHelp patients realise that relapse is part of

cessation process not a failureAble to learn from the causes of relapseDevelop a more intensive treatment on the next

attempt

Intervention Strategies Non-pharmacological

Self-helpBehaviouralGroup supportHypnosisAcupuncture

PharmacologicalNicotine

replacementBupropionVerinicline

Management

Researchers and clinicians view nicotine addiction as a brain disease embedded in a social context

Effective treatment should incorporate both :Behavioural TherapyMedication

Self-help Programmes Smoking Cessation Clinics

Counselling supportBehavioural programmesIf the above programmes are inadequate,

then pharmacological therapies are sought

Behavioural Programmes Self-management strategies Aversion conditioning techniques Relapse-prevention methods Nicotine fading

Self-Management Strategies Most commonly used Make smokers more aware of their smoking

patterns and cues Self-monitoring

Record when, where, and why they smokePromote a behavioural change and design a treatment

plan Stimulus control (Cue extinction)

Done before quitting to reduce the strength of the smoking cue

Avoiding dominant cues (talking on the phone, finishing a meal

Aversion Conditioning Techniques Should only be administered by trained

smoking cessation specialists Used to decrease a smoker’s urge to smoke

before quit dates or upon relapse Techniques include rapid smoking and satiation Rapid smoking :

Smokers puff cigarettes every 6 to 8 seconds until the cigarette is gone or nausea occurs

Satiation :Smokers double or triple their daily cigarette

consumption for brief periods of time

Relapse-Prevention Methods Designed to prevent smokers from returning

to smoking behaviour Avoidance :

Minimising exposure to temptations, e.g. stress, other smokers

Coping Strategies :Techniques such as deep breathing or use of

relaxation tapes, to deal with withdrawal symptoms

Contingency management :Rewards and punishments

Nicotine Fading Gradual reduction of nicotine intake :

Tapering the number of cigarettes smokedSwitching to brands containing less nicotine

Disadvantage :Smokers can compensate by inhaling more deeply

and longerFurther reinforce each episode of smoking

Results are inconsistent and thus not recommended for routine use

Group Smoking Cessation Programmes Most smokers are unwilling to attend such

programmes Option for smokers who have failed to respond to

less intensive cessation methods Done in small group with multiple sessions Incorporate various types of behavioural

approaches

Hypnosis and Acupuncture Appeal to smokers who want rapid cessation with

little effort Claims to have high cure rates up to 95% No clinical data to support efficacy of these

methods

Nicotine Replacement Therapies

Gum Transdermal patches Nasal Spray Oral Inhaler Lozenges

Nicotine Gum Administered on an as-desired basis Most people chew 8 to 15 pieces a day; Each piece

is chewed for 20 to 30 mins Approximately 50% of nicotine is released Providing 8 to 15mg of nicotine per day from the 2-

mg form and 16 to 30mg from 4-mg form Approx. one-third or one-half of the usual daily intake

of a person who smokes 30 cigarettes daily Recommended use for 4 to 6 months and patients

should be encouraged to wean from nicotine gum, but the optimal duration of use is unknown

Efficacy of Nicotine Gum Successful only accompanied by intensive

behavioural programmes Acidic drinks, such as coffee or soda, decrease

acidity of saliva and may interfere with the effects of nicotine gum

One should never smoke and chew

Safety and Adverse Effects of Nicotine Gum

Flatulence Indigestion Nausea Unpleasant taste Hiccups Sore mouth, throat and jaw

Nicotine Patches

Delivering a steady amount of nicotine to the body right through the skin (usually on an arm, abdomen)

Easy to use Once a day (changing the location each time)

Start with TTS 30 or TTS 20 depending on no. of cigarettes smoked/dayThose smoking >20 sticks/day start with TTS 30Those smoking <20 sticks/day start with TTS 20

Use 30, 20 and 10 cm2 to allow gradual withdrawal

Use over 3-4 weeks treatment Treatment > 3 months and doses > 30 cm2

have not been evaluated

Nicotine Patches

Safety and Adverse Effects of Nicotine Patches

Skin irritation at the patch site Insomnia Headache Cold and flu-like symptoms Nausea Myalgia Dizziness Less common : Sleep disturbance, GI side effects -

diarrhoea, upset stomach

Safety of Replacement Therapies NRTs should be used with extra caution in

patients with cardiovascular disease Smoking while using patch or gum therapy may

increase the risk of cardiovascular and toxic effects of nicotine

Patients should stop smoking completely when starting treatment

In addition, many smokers see such therapy as simply prolonging their dependence or fear becoming dependent on the replacement itself

Works on the biology of nicotine addictionBy enhancing dopamine levels in the

reward pathwayAffect noradrenergic neurons in the

locus ceruleus to reduce craving and withdrawal symptoms

Bupropion

Dosage & Administrationfor Bupropion

Start with 150mg/day for the first 3 days Follow by a dose increase to 300mg/day given as

150mg b.d. (at 8-hourly interval) Maximum dose : 300 mg/day Doses above 300mg/day should not be used due

to dose-dependent risk of seizures

Dosage & Administration Patients should start taking bupropion BEFORE they quit smoking They should set a “target quit date” during the 2nd week of

treatment with bupropion as it takes about 1 week to reach steady-state blood levels

Treatment with bupropion should be continued for 7-12 weeks Dose tapering is not necessary when discontinuing bupropion Important that patients continue to receive counselling and

support throughout treatment with bupropion, and for a period of time thereafter

Individualization of Therapy Need for education/counseling/support

Discontinue if patient has not made significant progress toward abstinence by the seventh week of therapy

If unsuccessful, re-evaluate later for retrial of therapy

Bupropion should be used as a part of a comprehensive smoking cessation treatment program

Bupropion in Clinical Practice Bupropion is indicated for the treatment of

nicotine dependence as an aid to smoking cessation in subjects aged 18 years and over.

Adult smokers who are motivated to stop could benefit from treatment with bupropion.

For the majority of patients, the recommended dosage is 150mg once daily for 3 days, increasing to 150mg twice daily.

Combination Therapy for the Heavily Addicted Smoker—Mayo Clinic Style

Nicotine patch

Strongest dose, can use more than one

Shorter acting nicotine replacement

Bupropion SR

Varenicline Tartrate (Champix®) Indicated for smoking cessation in adults Oral administration (tablet) Non-nicotine a partial agonist selective for the α4β2

nicotinic acetylcholine receptorDual action with dual benefitsPartial agonist activity:

○ Reduces craving and withdrawal symptomsAntagonist activity:

○ Produces a reduction of the rewarding and reinforcing effects of smoking ()

1. Champix Prescribing Information

Champix® (Varenicline): A Highly Selective 42 Receptor Partial Agonist

1. Coe JW et al. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco. 2005. Prague, Czech Republic. 2. Picciotto MR et al. Nicotine Tob Res. 1999; Suppl 2:S121-S125.

Binding of nicotine at the 42 nicotinic receptor in the VTA is believed to cause release of dopamine at the nAcc

Champix is an 42 nicotinic receptor partial agonist, a compound with dual agonist and antagonist activities. This is believed to result in both a lesser amount of dopamine release from the VTA at the nAcc as well as the prevention of nicotine binding at the 42 receptors.

Nicotine Champix

Nicotine Part Ag Part ag

Varenicline: 42 nAChR Partial Agonists

442 nAChR2 nAChR

Dual action of a partial agonistDual action of a partial agonist

Agonist

ResponseResponse 100%

Nicotine

SmokingSmokingNo Partial AgNo Partial Ag

No SmokingNo SmokingPartial AgPartial Ag

SmokingSmoking+ Partial Ag+ Partial Ag

AntagonistAntagonist

50%50% Potential to block Potential to block reinforcing effectsreinforcing effects when smoking when smoking

Partial AgonistPartial Agonist

50%50%Potential to relievecraving and withdrawalwhen quitting

Varenicline (Champix®): Dosage

Treatment period is 12 weeks An additional course of 12 weeks of treatment may

be considered for patients who have successfully quit at end of 12 weeks

Varenicline is supplied for oral administration in 2 strengths: 0.5 and 1.0 mg; titration is as below:

Days 1 – 3:Days 1 – 3: 0.5 mg once 0.5 mg once dailydaily

Days 4 – 7:Days 4 – 7: 0.5 mg twice 0.5 mg twice dailydaily

Day 8 – End of Day 8 – End of treatment:treatment:

1 mg twice 1 mg twice dailydaily

1. Champix Prescribing Information

Pharmacokinetics of Varenicline Half-life ~24 hours Cmax within 3 to 4 hours Steady state reached within 4 days Oral bioavailability unaffected by food 92% of drug is excreted unchanged No inhibition of cytochrome P450 enzymes No clinically meaningful drug interactions identified No dose restrictions in patients with hepatic insufficiency Dose adjustment required for severe renal impairment,

may be considered for moderate renal impairment No dosage adjustment is necessary for elderly patients

absent renal impairment

1. Champix Prescribing Information

Adverse Effects During clinical trials, approximately 4000

individuals were exposed to varenicline Most frequently reported AEs (≥10%) associated

with varenicline 1 mg vs placebo were: Nausea Abnormal dreams Insomnia Headache

The percentage of participants who discontinued treatment due to adverse events receiving varenicline treatment was comparable; 11.4% vs 9.7%

1. Varenicline Prescribing Information

Contraindications & Interactions Contraindications:

hypersensitivity to the active substance or to any of the excipients

No clinically meaningful drug interactions have been identified with varenicline

1. Champix Prescribing Information

Precautions There are no adequate data from the use of varenicline in

pregnant women Varenicline should not be used during pregnancy

It is unknown whether varenicline is excreted in human breast milk Animal studies suggest varenicline is excreted in breast

milk A decision whether to discontinue varenicline or

discontinue breastfeeding should consider the benefits of breastfeeding to the child and varenicline to the woman

Varenicline may have minor or moderate influence on the ability to drive and use machines Patients are advised not to engage in potentially hazardous

activities until it is known whether their ability to perform these activities is affected

1. Champix Prescribing Information

Dose Adjustment in Special Populations

Patients with hepatic impairment No dosage adjustment necessary

Patients with renal insufficiency No dosage adjustment necessary for patients with mild to

moderate renal impairment For patients with moderate renal impairment who experience

adverse events that are not tolerable, dosing may be reduced to 1 mg once daily

For patients with severe renal impairment, the recommended dose is 1 mg/d. Dosing should begin at 0.5 mg once daily for the first 3 days then increase to 1 mg once daily.

In patients with end-stage renal disease, treatment is not recommended

1. Champix Prescribing Information

Comparative Daily Costs of Pharmacotherapy

Cost per day, in U.S. dollars0 2 4 6 8

Nasal spray

Patch

Varenicline

Cigarettes (1 pack/ day)

Lozenge

Bupropion SR

Gum

Inhaler $6.07$5.81

$5.73$5.26

$3.91$3.67

$4.22$4.26

New Medications in the Pipeline Rimonabant

Cannabinoid receptor inhibitorBlocks reinforcing effects of nicotineAlso suppresses appetiteIn phase III trialsNot approved for smoking cessation by FDA

Nicotine VaccineProduces antibodies to nicotineReduces nicotine levels in animals

CYP246 InhibitorsCYP246 is a hepatic enzyme that metabolizes nicotineHigher blood nicotine levels per cigarette smokedCould also increase potency of NRT

Smoking Cessation: A Very Powerful Intervention…Intervention Reduction in Mortality

Smoking Cessation 36%

Statin Therapy 29%

Beta-Blockers 23%

ACE Inhibitors 23%

Aspirin 15%

Critchley JA, Capewell S. JAMA;2003;290:86-97

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1.0 1.1(0.9,1.3)

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2.2(1.5,3.2)

n = 29 studiesType of clinician

Fiore et al. Treating Tobacco Use and Dependence. Clinical Practice Guideline. USDHHS, PHS, 2000.

Effects of Clinician Interventions

Compared to smokers who receive no assistance from a clinician, smokers who receive such assistance are 1.7–2.2 times as likely to quit successfully for 5 or more months.

Power of Intervention

⅓ to ½ of the 44.5 million smokers will die from the habit. Of the 31 million who want to quit, 10 to 15.5 million will die from smoking.

Increasing the 2.5% cessation rate to 10% would save 1.2 million additional lives.

If cessation rates rose to 15%, 1.9 million additional lives would be saved.

No other health intervention could make such a difference!