Smoking and TobaccoPart 2

© 2009 University of Sydney

Images used with permission

Treatment Options

Learning objectives

• To be able to

– Provide brief interventions for people who smoke

– Recognise tobacco dependence– Manage tobacco dependence using

pharmacotherapy and psychological approaches

John, aged 39, presents with his third chest infection in 12 months. He reports that despite two attempts to quit, he is still smoking a pack a day. He now requests a prescription for antibiotics.

• Is John addicted to nicotine?

• How important is it for John to stop smoking?

• Do you think John really wants to stop smoking?

• Is John suitable for nicotine replacement therapy?

• How would you manage him?

Nicotine dependence

Smoking Cessation

• Successful cessation may take a number of attempts

• Most former smokers report a history of several relapses

• The most effective cessation interventions combine behavioural support with drug treatment

Scollo, M & Winstanley, M [eds] (2008).Tobacco in Australia: Facts and Issues. Third Edition.

Behavioural Interventions

• Rationale– Dependence is only partly pharmacological

– Benefit related to intensity of counselling

– Interacts positively with other treatments

• Effectiveness – Unassisted quit rate 2 to 3%– Brief advice increases quitting by a further 1 to 3%1

– More intensive advice and follow up may increase quit rates slightly1

1Stead LF, et al (2008) Cochrane Database Syst Rev. Apr 16;(2):CD000165.

Recommendations for Australian General Practice

• Identify and document tobacco use in all patients

• Offer brief advice to quit to all smokers• Offer relapse prevention advice and follow

up to all smokers attempting to quit– Use 5 “A’s” guideline for smoking cessation

Zwar N, et al (2004). Smoking Cessation Guidelines for Australian General Practice.

5 “A’s”• Ask

• Assess

• Advise

• Assist

• Arrange follow-up

Zwar N, et al (2004). Smoking Cessation Guidelines for Australian General Practice.

5 “A’s”: Ask

• Ask all patients: "Do you smoke?" and "Have you ever smoked?“

• Take a brief smoking history– Number of cigarettes per day/week– The year of starting smoking – Previous quit attempts and what

happened – Presence of smoking related disease

5A’s: Assess

• Assess a person's readiness to change– Not ready/Pre-contemplation– Unsure/Contemplation– Ready/Preparation– Action– Maintenance

Assessment of dependence

Major Diagnostic criteria• Unable to stop despite trying (loss of

control)• Continued smoking despite evident harm

(e.g. health, financial)• Tolerance • Withdrawal

- How soon after waking is 1st cigarette smoked?

Questions to ask• How soon after waking do you have your first

cigarette?• How many cigarettes do you smoke each day?• Have you had cravings and withdrawal symptoms

when you have tried to quit?

• Indicators of nicotine dependence– Smoking within 30 minutes of waking– smoking more than 15 cigarettes/day– a history of withdrawal symptoms in previous

attempts to quit

Zwar N, et al (2007) Smoking cessation pharmacotherapy: an update for health professionals.

5 “A’s”: Advise• Advise to stop smoking

– Advise firmly, but in a non-confrontational manner

• e.g. “The best thing you can do for your health is to quit smoking”

– Emphasise the personal benefits of cessation, e.g.

• Improved health

• Not exposing others to tobacco smoke

• Positive role model for children and adolescents

• Financial benefits

Zwar N, et al (2004)

5 “A’s”: Assist • Assist according to patient’s readiness to

change– Not ready

• Encourage patient to think about their smoking, offer help, offer written material, offer referral

– Not sure• Encourage patient to contemplate and help to

reflect on pros and cons of smoking, plus offer help as above

– Ready/Action• Affirm and encourage the decision to quit

• Help the patient to develop a quit plan

• Help set a Quit Date

Zwar N, et al (2004)

5 “A’s”: Arrange

• Arrange follow up– This increases the effectiveness of

intervention

– Suitable times are 1 week and 1 month after a quit date

– Follow-up can be in person or by telephone

– At follow-up provide support according to circumstances (i.e. not smoking, relapsed, not attempted)

Zwar N, et al (2004)

Cognitive strategies• Keeping a diary for one or several days prior to

the Quit Day– More aware of their smoking pattern and risk

situations

• Consider benefits of quitting• Challenge the perceived benefits of smoking• Coping with cravings

– Thought stopping• Conscious decision not to think about smoking

– Thought substitution• Deciding to think about something else

Zwar N, et al (2004)

Behavioural strategies• Suggest 4Ds

– Delay acting on the urge to smoke. After five minutes the urge to smoke weakens and your resolve to quit will come back.

– Deep breathe. Take a long slow breath in and slowly release it out again. Repeat three times.

– Drink water slowly holding it in your mouth a little longer to savour the taste.

– Do something else to take your mind off smoking. Doing some exercise is a good alternative.

Zwar N, et al (2004)

Behavioural strategies (cont.)

• Encourage to engage social supports. If limited suggest Quit program

• Suggest avoiding major triggers for smoking early in the quit attempt – Alcohol, coffee and smoking friends

• Suggest removing environmental cues where possible (e.g. ashtrays)

• Ask to remember that thinking "I can have just one" can lead to relapse

Zwar N, et al (2004)

First Line Pharmacotherapies

• Pharmacotherapy for dependent smokers is proven to double quit rate

• Substitution for nicotine present in tobacco smoke– Nicotine Replacement Therapy

• Transdermal patch• Chewing gum• Lozenge• Inhaler• Nasal spray

• Partial nicotinic receptor blockade– Varenicline

• Substitution for some stimulant effects– Bupropion

Zwar N, et al (2004)

Nicotine Replacement Therapy

• Aims– To decrease exposure to tobacco smoke– To reduce withdrawal intensity, including

craving– To facilitate abstinence from tobacco smoking

• All forms of NRT are slow delivery devices when compared to cigarettes

• Separation of nicotine delivery from context and rituals and slow onset makes dependence unlikely

Other medications

• Second line– Nortriptylline

• Potential therapies– Cannabinoid receptor antagonists

• Rimonabant

– Nicotinic receptor partial agonist• Cytisine

– Nicotine Vaccines

Nicotine plasma levels

• 1 cigarette= ~ 20-40ng/ml (range 10-80)

N.B. unrelated to brand concentration or numbers smoked.

• 1 x 2mg nicotine gum = 7ng/ml

• 1 x 4mg nicotine gum = 15ng/ml

• 1 x 21 mg nicotine patch = 10ng/ml

Plasma nicotine levels

• Cigarettes – High levels – Arterial >> venous– Rapid rise and fall

• NRT – Moderate levels – Slower rise and fall

Molyneux (2004) BMJ 328:454-456.

Effectiveness of NRT

• All NRT forms increase quit rates at 6-12 months by 50-70% compared with placebo regardless of setting.

• No significant difference between the NRT forms

• In highly dependent smokers 4mg gum is more effective than 2mg gum

• No strong evidence of a benefit from higher doses of patch

• The intensity of additional advise and support does not increase the effectiveness of NRT

Stead LF, et al (2008) Cochrane Database Syst Rev. Jan 23;(1):CD000146.

Combination or high-dose NRT• Wide safety margin• Psychological gain from PRN use• Combining a nicotine patch with a more rapid delivery

form of NRT is more effective than a single type of NRT

• Most effective combination is– Lozenge or gum supplementing 16 hour patch1

• Suitable patients:– Unable to remain abstinent or continue to experience

withdrawal symptoms using one type of therapy2.

• A combination approved in Australia is Nicorette patch plus 2mg gum

1Stead et al (2008) Cochrane Database of Systematic Reviews, Issue 1, CD000146.2Piper ME et al (2009) Arch Gen Psych 66(11):1253-1262.3Zwar N, et al (2004). Smoking Cessation Guidelines for Australian General Practice.

Cut Down Then Stop (CDTS)

• An effective approach for smokers who find it difficult to stop abruptly

• Use of NRT to reduce– Number of cigarettes smoked– Intensity of smoking– Then quit

• Data available for – Gum– Nicotine inhaler

• Doubles the 12-months abstinence rate compared to placebo in this population

• Note: also called Cut Down To Quit in RCTs Wang D, et al. (2008) Health Technol Assess. Feb;12(2)

Two CDTS Approaches

• Use NRT and try to smoke as few cigarettes as possible

• Use NRT and smoke as you feel you need or want to

• Outcomes are similar

Cut Down then StopSummary of outcomes

• Little change in plasma nicotine• 50% reduction in cigarettes smoked• 30% reduction in smoke exposures

• Increase in quit attempts• 8.5% absolute annual quit rate

– Approximately doubled compared to placebo

Wang D, et al. (2008) Health Technol Assess. Feb;12(2)

CTDS – which smoker?

• Smokers unwilling or unable to stop smoking in the short term

• Smokers uninterested in quitting but happy to try something else to reduce harm

• To encourage a smoker to ‘put a toe in the water’ in relation to smoking cessation

• Eventual aim should be cessation

• Must not be seen as a strategy equivalent to a formal quit attempt

Zwar N, et al (2007) Smoking cessation pharmacotherapy: an update for health professionals.

CDTS Australian Guidelines• NRT formulation approved for CDTS in

Australia are Nicorette Gum and Nicorette Inhaler

‘Step When Goal’

1. 0-6 weeks - cut down to 50% of baseline cigarette consumption

2. 6 weeks to 6 months - continue to cut down; stop completely by 6 months

3. 6 to 9 months - stop smoking completely, continue NRT

4. within 12 months - stop using NRT by 12 months

ASH (2007) Available at : http://www.ashaust.org.au/pdfs/NRTguide0702.pdf

NRT use in Heart Disease

• All forms of NRT can be used by patients with cardiovascular disease

• Whenever smoking is the alternative NRT is safe

• NRT safe in stable cardiac disease

• In unstable disease

– Probably no access to smoking

– Consider NRT to palliate withdrawal

Zwar N, et al (2007) Smoking cessation pharmacotherapy: an update for health professionals. RACGP.

Smoking in Pregnancy• Young female smokers anticipate cessation prior to

planned pregnancy• It is hard to quit and relapse rates are high during

and after pregnancy – 70%• NSW 1998-20021

– Fewer smoking in pregnancy • 19.3% to 16.8% • ATSI 58% (unchanged)

– 4% of smokers quit before 20 weeks• 1.7% of ATSI women

• NSW 20062

– 12.5% smoking in the second half of pregnancy

1Centre for Epidemiology and Research, NSW Department of Health (2003) New South Wales Mothers and Babies 2002. NSW Public Health Bull; 14(S-3).2Centre for Epidemiology and Research. NSW Department of Health (2009) New South Wales Mothers and Babies 2006. NSW Public Health Bull; 20(S-1).

NRT use in Pregnancy (cont.)• NRT can be used during pregnancy and

lactation

– Much safer than smoking

– No excess of birth defects

• Benefits of NRT without cessation

– Higher birth weight

• No other pharmacotherapy treatment is proven to be

– Safe (or unsafe)

– Effective (or ineffective)

• Intermittent dosing forms are preferableZwar N, et al (2007) Smoking cessation pharmacotherapy: an update for health professionals. RACGP.

Bupropion (‘Zyban’)• Inhibitor of neuronal reuptake of

noradrenaline and dopamine– Limits craving (substitution for some of the

stimulant effects of nicotine)

• Marketed as an antidepressant and decreased desire to smoke observed in depressed patients

• Doubles the success rate of quitting compared to placebo

• Equally effective in patients who are not depressed

Cox LS et al (2004) J Gen Intern Med. 19(8):893-5.

* p 0.001 versus placebo30

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Based on: Hurt RD et al. (1997) N Engl J Med 337:1195–1202.

Bupropion efficacyContinuous abstinence at EOT (7 weeks)

Bupropion: Patient issues• Adverse effects

– Insomnia– Dry mouth– Tremors– Rashes– Weight loss– Seizures– Hypertension

• Lowers seizure threshold• Important contraindications to use

– Past seizures– Drugs that alter seizure threshold

Combinations: Bupropion with NRT

• Combining bupropion with a nicotine inhaler has been shown to increase smoking abstinence rates1

• However, combination with a lozenge may not increase effectiveness2

1Croghan IT et al. (2007) Mayo Clin Proc. 82(2):186-95. 2Piper ME et al (2009) Arch Gen Psych 66(11):1253-1262.

Relative effectiveness of pharmacotherapies

Piper ME et al (2009) Arch Gen Psych 66(11):1253-1262. Copyright © 2009 American Medical Association. All rights reserved.

Varenicline (‘Champix’)• High-affinity partial agonist at 42 AChR

specifically designed for smoking cessation1

• Alleviates symptoms of craving and withdrawal, but produces much weaker effect than nicotine

• Prevents inhaled nicotine from a cigarette activating the α4β2 receptor and blocks the pleasurable effect of smoking2

1Coe JW. (2005) J Med Chem; 48:3474-3477. 2Dani JA, Harris RA. (2005) Nature Neuroscience, 8:1465-1470.

Varenicline: effectiveness

• Existing data indicate that varenicline is more effective than bupropion and some forms of NRT in achieving abstinence and is recommended for use as a first line therapy1

• More efficacy and safety evaluation in the general population is needed, particularly in those with comorbid conditions2

1Zwar N, et al (2007) Smoking cessation pharmacotherapy: an update for health professionals. RACGP. 2Garrison GD, Dugan SE. (2009) Clin Ther. 31(3):463-91.

Point prevalence quit rate & trend

Jorenby et al, 2006, JAMA, 296(1): 56-63. Copyright © 2006 American Medical Association. All rights reserved.

PPQR = no cigarette for 7 days – CO confirmed at visits

Point prevalence quit rate

PPQR = no cigarette for 7 days – CO confirmed at visits

Gonzalez et al, 2006, JAMA, 296(1): 47-55. Copyright © 2006 American Medical Association. All rights reserved.

Effect of longer treatment period

Tonstad et al, 2006, JAMA, 296(1): 64-71. Copyright © 2006 American Medical Association. All rights reserved.

Major adverse events

Gonzalez et al, 2006, JAMA, 296(1): 47-55. Copyright © 2006 American Medical Association. All rights reserved.

Combinations:Varenicline with NRT

• Not sensible based on pharmacology

• When used together there is prohibitive nausea – efficacy undeterminable

• Suggests that there are receptors other than 42 involved in nausea

Combinations: Varenicline with bupropion1

• Potentially useful

• In an open-label study patients (n=38) achieved smoking abstinence rates of 71% at 3 months and 58% at 6 months.

• The most common side effects were sleep disturbance (26%) and nausea (24%).

• No significant weight gain (change in weight 1.6 kg on average)

• No increase in depressive symptoms was observed and no subjects reported suicidal ideation.

1Ebbert JO et al (2009) Nicotine Tob Res.11(3):234-9

Vareniclinein patients with mental illness

• Lack of safety data• Previous mild depression

– Use with caution and with due warning

• Active depression– Consider other options including closely supervised

bupropion

• Unstable severe depression– Address this first then smoking; NRT safe

• Psychotic illnesses (schizophrenia/bipolar)– Use only with close active supervision ideally with

treating psychiatrist

Zwar N, et al (2007) Smoking cessation pharmacotherapy: an update for health professionals. Melbourne: The Royal Australian College of General Practitioners. © Australian Family Physician. Reproduced with permission. Permission to reproduce must be sought from the publisher, The Royal Australian College of General Practitioners.

Effectiveness of all pharmacotherapies

• Abstinence rates at 6 and 12 months compared to placebo– Odds ratio (OR) for cessation for all forms

of NRT and bupropion is ~ 2.0– OR for varenicline is 2.4

• Varenicline is twice as efficacious as bupropion– OR 2.18

Eisenberg et al. (2008)CMAJ. 179(2):135-44.

Data source: Eisenberg et al (2008) CMAJ 179(2): 135-144.

Effectiveness of pharmacotherapies

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Second line treatment• Nortryptylline1, 2

– Tricyclic antidepressant– Mechanism of action in smoking cessation is likely

to be separate from antidepressant effects – Dose is 75mg/day for 12 weeks– 3 clinical trials show OR 2.8 over placebo– Quit rates in one study vs bupropion

• 29% bupropion; 23% nortryptylline; 13% placebo– Side-effects and risks of tricyclic antidepressants

• Dry mouth, sedation, overdose risks– Not registered for smoking cessation in Australia

1Wagena EJ, et al (2005) Addiction,100:317–26.2Hughes JR, et al (2007) Cochrane Database Syst Rev 1: CD000031.

Second line treatment

• Clonidine– Antihypertensive agent, centrally

acting alpha-agonist– Minimal use for this indication in

Australia

Possible future options

• Nicotinic receptor partial agonist – Cytisine

• Cannabinoid receptor antagonist– Rimonabant

• Nicotine Vaccine

Rimonabant• Endocannabinoid receptor CB1 antagonist

• Showed promise for obesity treatment and smoking cessation1

• Smoking cessation effect less than with NRT – ~1.5 times the placebo rates1

• Obesity indication limited by CNS toxicity– Convulsions, tremor, anxiety, depression1

• Increased risk of suicide (0.4% vs 0.2% in placebo group)2

• Not approved by the FDA for use in smoking (in 2006) and for use in obesity (in 2007) – Insufficient safety data– No further information as to whether development for these

indications is continuing3

1Cahill K and Ussher M (2007)Cochrane Database Syst Rev. Oct 17;(4):CD005353.2Hughes JR (2008) Drug Alcohol Depend. 98(3):169-178. 3Nides M.(2008) Am J Med. 121:S20-31.

Cytisine• Similar chemical structure to nicotine and

varenicline• Partial agonist at nicotinic ACh receptors • Evidence from old placebo-controlled studies that

it may be effective in aiding smoking cessation even with minimal behavioural support

• Little current studies of efficacy, safety and abuse liability but renewed interest

• It is inexpensive to make - if effective and safe, it could potentially save many lives

Etter JF, et al (2008) Drug Alcohol Depend. Jan 1;92(1-3):3-8.

Nicotine Vaccine

• Rationale– to stimulate production of nicotine-

specific antibodies

• Principle– antibodies bind to nicotine in the

bloodstream and prevent it from crossing the blood-brain barrier (no or reduced nicotine effect)

– after vaccination antibodies may persist in the blood for months

Cornuz J (2008) PLoS One 25;3(6):e2547.

Nicotine Vaccine (cont.)

• Preliminary clinical trials (Phase II):– The vaccine is safe

– Sufficiently high levels of antibodies needed to promote continuous abstinence (~doubles the placebo rates)

– Low levels are ineffective

Cornuz J (2008) PLoS One 25;3(6):e2547.

Smoking cessation: ineffective treatments

• Acupuncture and related techniques1

– Insufficient evidence for acupuncture, acupressure, laser therapy or electrostimulation

• Hypnotherapy2

– No consistent evidence that it is more effective than other interventions or no treatment

• Anecdotal evidence exists for both approaches– Smokers choosing these treatments should not

be discouraged provided they are informed of the state of the evidence2.

1White AR, et al (2006). Cochrane Database Syst Rev. Jan 25;(1):CD000009.2Villano LM and White AR (2004). Med Clin North Am.88(6):1607-1621.

Management issues

• Nicotine dependence is a chronic, relapsing condition– Long history– Some remissions– Relapse is common

Relapse• Even motivated smokers relapse.• 50% relapse within the first week of quitting• ~ 10% in the second week• Relapse rates decrease after the second

week

• It often takes a number of attempts to quit smoking successfully.

• Smokers should be encouraged to keep trying to quit even if they have returned to smoking.

• Three months of abstinence leads to increased long-term abstinence

Relapse (cont.)

• Predictors of relapse– Severity of withdrawals– Living with a smoker or having

more than 50% of friends who smoke

– Alcohol consumption– Other substance use– Significant weight gain

Weight gain• Nicotine suppresses appetite and

increases metabolic rate• Smoking cessation often causes

craving for sweets• Body weight returns to non-smoking

levels in 6-12 months after quitting• For some smokers this triggers

relapse to smoking

Dani JA, et al (2009) The Pharmacology of Nicotine and Tobacco. In: Principles of Addiction Medicine. 4th edition

Interventions to reduce weight gain

• Simple behavioural interventions– e.g. general advice only

– Not effective and may even provoke relapse

• Individualized interventions– e.g. very low calorie diets and CBT

– May be effective in reducing weight gain

– Less likely to reduce abstinence rate

• Exercise interventions– Not effective in reducing weight gain at the end of

treatment

– May lead to worthwhile reductions in weight gain in the long term

1Parsons AC et al (2009) Cochrane Database Syst Rev. Jan 21(1):CD006219.

Pharmacotherapies: effect on weight gain

• Bupropion and NRT– reduce weight gain during treatment and

possibly long-term

• Varenicline– does not reduce weight gain as much as

bupropion

• Not enough data at present to make recommendations for effective weight reduction programs

1Parsons AC et al (2009) Cochrane Database Syst Rev. Jan 21(1):CD006219.

Best practice• Smoking cessation treatment should address:

– Behaviour

– Biology

– Social context

• All available first line medicines for stopping smoking at least double the chance of quitting (varenicline > NRT = bupropion)

• Integrating behavioural therapy increases the quit rate

– Face-to-face, internet and telephone counselling and coaching

• More frequent follow-up leads to better long-term outcome

Self-test case

• Jane is 46 years of age. She smokes 30 cigarettes per day

• Has had no previous quit attempts

• Currently feeling ‘down’ about loss of job

How would you manage tobacco use in this case?

Self-test answers

• Assess current motivation to quit

• If not ready, aim to increase motivation for a later quit attempt; make offer of future support if needed

• Make aware of NRT, varenicline and bupropion

• Arrange follow-up

Conclusions• Clinical success in smoking cessation rests upon

applying the simplest clinical principles of identifying smokers, then advising and aiding cessation

• 5 “A’s” is a useful screening and intervention approach

• Pharmacotherapies for smoking cessation (NRT, bupropion and varenicline) are effective in aiding smoking cessation

• Combining pharmacological therapy and psychological/behavioural support is best management

ContributorsDr Olga Lopatko

University of Sydney

Clinical A/Professor Matthew Peters

Concord Hospital & University of Sydney

All images used with permission, where applicable