Transcript Smoking cessation therapy

VI Brazilian Congress on Asthma
II Brazilian Congress on COPD
II Brazilian Congress on Smoking
Belo Horizonte, August 22-25, 2007
DURATA: 1 ORA
Future pharmacological treatments on stopping smoking
Giovanni Viegi, MD
. Director of Research, Italian National Research Council,
Head, Pulmonary Environmental Epidemiology Unit,
CNR Institute of Clinical Physiology, Pisa – Italy
. Professor of “Health Effects of Pollution”, School of Environmental
Sciences, University of Pisa - Italy
. 2006-07 Past-President, European Respiratory Society (ERS)
7. Psychological and behavioural interventions
8. Pharmacological treatment for smoking cessation
9. Other interventions
10. Smoking reduction
11. Organisational anchorage and education
12. The costs of smoking and economics of smoking
cessation
13. Research prospects
14. References
7. Psychological and behavioural interventions
Three interventions can be included as psychological
and behavioural strategies to aid smoking cessation:
self-help interventions, brief advice and counselling.
7.1. Self-help programmes
Self-help is defined as structured programming for
smokers trying to quit, without intensive contact
with the therapist.
tailored self-help materials can be recommended
for smoking cessation (Evidence A).
7.2. Brief advice
Brief advice given by physicians or nurses can be defined as
routinely providing smokers with brief information to help
them quit smoking and increase their motivation to make quit
attempts.
It can be recommended that physicians give brief advice on
smoking cessation to smokers, including respiratory patients
who smoke. Nurses should do the same (Evidence A).
However, when dealing with most pulmonary patients brief
advice cannot stand alone, and much more intensive
intervention is required.
7.3. Counselling
There are three types of counselling - individual, group and
telephone – which vary in terms of the manner of providing
counselling and the time taken.
Individual counselling is defined as a face-to-face encounter
between a patient and a trained smoking cessation counsellor.
There is a strong dose-response relation between the session
length of person-to-person contact and successful treatment
outcomes. Intensive interventions are more effective than less
intensive interventions (Evidence A).
7.3.1. Group counselling
Group therapy offers individuals the opportunity to
learn behavioural techniques for smoking cessation
and to provide each other with mutual support.
Using this kind of support allows more people to be
treated by one therapist and could be more costeffective than individual counselling.
Part I of II
There is no evidence about the efficacy of group
therapy in respiratory patients.
Group counselling is effective for smoking
cessation (Evidence A). It is unclear whether
group counselling is more or less effective than
individual counselling (Evidence A).
Part II of II
7.3.2. Telephone counselling
In the proactive approach, the counsellor initiates the calls to
provide the smoker with support to make an attempt at quitting
(OR 1.41; 95% CI 1.27-1.57).
Reactive counselling is provided via help-lines or hotlines that
take calls from smokers (OR 1.33; 95 % CI 1.21-1.47) [129].
The findings suggest that proactive telephone counselling is
effective compared to other minimal interventions (Evidence
A).
7.4. Behavioural therapy
7.4.1. Aversive smoking
Aversion therapy pairs the pleasurable stimulus of smoking a
cigarette with some unpleasant stimulus.
There is insufficient evidence to support the use of aversive
smoking to quit [133].
7.4.2. Exercise therapy
There is insufficient evidence to support exercise for smoking
cessation. [138].
7.5. Procedures for psychological and behavioural
interventions in smoking cessation
The following visit schedule can be recommended: Weeks
1, 2, 4, 8, and 12 and 6 and 12 months after quit day.
Some considerations should be taken into account in order
to provide the smoker with the best help during the followup period:
At times, ex-smokers feel that they need to smoke
again even more than during the first days after quitting.
Part I of II
Sometimes abstinent smokers can suffer
from withdrawal symptoms for long periods.
Coinciding with special situations (social
occasions, eating and drinking, meeting friends,
etc.), smokers can feel confident enough to try
smoking just one cigarette.
Smokers who continue smoking daily 2-3
weeks after receiving adequate treatment for their
addiction should be considered unsuccessful.
Part II of II
8. Pharmacological treatment for smoking cessation
8.1. First-line treatment
Nicotine replacement therapy and/or sustained-released
bupropion, in conjunction with behavioural
intervention, are recommended as first-line
pharmacotherapy in current guidelines for smoking
cessation [10,146-149].
Except in the presence of contraindications, these drugs
should be used in almost all patients attempting to quit
smoking.
Part I of II
Smokers of 10 or more cigarettes a day who are
ready to stop should be encouraged to use NRT or
bupropion to aid cessation.
Health professionals who deliver smoking
cessation interventions should give smokers
accurate information and advice on these
products.
Part II of II
8.1.1. Nicotine replacement therapy (NRT)
This treatment aims to replace the nicotine
obtained from cigarettes, thus reducing
withdrawal symptoms when stopping smoking
The recommended dosages of NRT vary
depending on the degree of dependence.
Use should normally be restricted to the licensed
duration, but may continue for up to and beyond 3
months in instances of continuing nicotine
dependency.
Part I of V
Nicotine replacement therapy should be
discontinued if the user restarts smoking
[150,151,153].
There is little direct evidence that one NRT
product is more effective than another, so the
decision about which product to use should be
guided by individual preferences.
Combination NRT has been reported to improve
outcome but long-term results are conflicting.
Part II of V
No differences have been found between 16-hour
and 24-hour nicotine patches and prolongation of
treatment for more than 3 months did not increase
quit rate
Higher doses of nicotine patches have resulted in
modest increases in success rates.
Tapering of patch dosage is not more effective
than abruptly ceasing use.
Part III of V
Relative contraindications given for NRT are
cardiovascular disease, hyperthyroidism, diabetes
mellitus, severe renal or hepatic impairment and
peptic ulcer.
NRT has been shown to be safe in patients with
coronary heart disease and it should be used in
these patients for whom quitting smoking is one
of the most important factors influencing
prognosis.
Part IV of V
A risk-benefit assessment should be made as to
using NRT in breastfeeding or pregnant women
taking into account the fact that continuing
smoking will deliver more nicotine than NRT.
Nicotine replacement is generally well tolerated.
The most common adverse effects are localised
irritation from nicotine, such as local skin
irritation with the patch, or with oral preparations
mucous menbrane irritation in the mouth and
throat, that generally lessen or disappear due to
development of local tolerance after a few days.
Part V of V
Table 4. Available nicotine replacement therapy (NRT) formulations
Formulation
Marketed product
Nicotine transdermal 5 mg, 10 mg, 15 mg/16 h (Nicorette, Pfizer)
patches
7 mg, 14 mg, 21 mg/24 h (Nicotnell
TTS 10, TTS 20, TTS 30, Novartis)
7 mg, 14 mg. 21 mg/24 h (NiQuitin CQ,
GlaxoSmithKline (GSK)
Part I of II
Table 4. Available nicotine replacement therapy (NRT) formulations
Nicotine chewing gum 2 mg, 4 mg (Nicorette, Pfizer; Nicotinell,
Novartis)
Nicotine oral tablets
2 mg sublingual tablet (Nicorette
Microtab, Pfizer)
1 mg lozenge (Nicotinell, Novartis)
2 mg and 4 mg lozenge (NiQuitin CQ,
GSK)
Nicotine “oral” inhaler 10 mg inhalation cartridge, plus mouthpiece
(Nicorette Inhalator, Pfizer)
Nicotine nasal spray
0.5 mg per spray into each nostril
(Nicorette Nasal Spray, Pfizer)
Part II of II
Table 5. Cochrane meta-analysis of effect of NRT formulations as odds ratio
of abstinence with NRT versus controls. A total of 39,503 subjects were
included in the analysis [139]
Smoking cessation
NRT vs. placebo
Abstinence
therapy
Odds ratio (95% CI) rate NRT
All NRT
formulations
1.77 (1.7-1.9)
17%
Nicotine gum
1.66 (1.5-1.8)
17%
Nicotine patch
1.81 (1.6-2.0)
14%
Nicotine inhaler
2.14 (1.4-3.2)
17%
Nicotine nasal
spray
2.35 (1.6-3.4)
24%
*Data from ref 140
Abstinence
rate Control
10%
Part I of II
Table 5. Cochrane meta-analysis of effect of NRT formulations as odds ratio
of abstinence with NRT versus controls. A total of 39,503 subjects were
included in the analysis [139]
Smoking cessation
therapy
NRT vs. placebo
Odds ratio (95% CI)
Abstinence
rate NRT
Nicotine sublingual
tablet/lozenge
2.05 (1.9-3.3)
17%
4 mg gum vs. 2 mg
gum
2.20 (1.5-3.3)
Fixed gum vs. ad
libitum gum
1.29 (0.90-1.9)
Combination of two
NRT vs. single NRT
1.42 (1.1-1.8)
Bupropion SR*
2.06 (1.8- 2.4)
Abstinence
rate Control
*Data from ref 140
Part II of II
8.1.2. Efficacy of NRT in smokers with respiratory diseases
Table 6. One-year success rates from smoking cessation studies in patients
with respiratory diseases who smoke. Modified from reference 163.
No of patients
Sustained success (%)
P value
Reference
Intervention
Control /
Usual care
Hospitalised
patients
Campbell (1990)
111
20 (+NRT/placebo)
20
NS
Campbell (1996)
234
21 (+NRT/placebo)
14
NS
1,4021
14 (+NRT)
13
NS
1,4822
19 (+NRT)
13
<0.01
1853
6.5 (+Placebo)
4.9
NS
9.7 (+NRT)
4.9
NS
Miller (1997)
Lewis (1998)
1Low
intervention and 2high intervention in same study
36-month success rate
4 5 mg nicotine patch used as ‘placebo’
Part I of II
Table 6. One-year success rates from smoking cessation studies in patients
with respiratory diseases who smoke. Modified from reference 163.
No of patients
Sustained success (%)
P value
Reference
Intervention
Control /
Usual care
Ambulatory
patients
BTS I (1983)
1,550
9.8 (+NRT/placebo)
8.9
NS
Lung Health
Study (1994)
5,887
28 (+NRT)
7
<0.001
Tønnesen I
(1996)
446
5.6 (+NRT/placebo4)
1.8
<0.01
Taskin (2001)
4043
23 (bupropion/placebo)
16
<0.01
Hand (2002)
245
15 (+NRT)
14
NS
Tønnesen II
(2006)
370
17 (+NRT/placebo)
10
<0.001
1Low
intervention and 2high intervention in same study
36-month success rate
4 5 mg nicotine patch used as ‘placebo’
Part II of II
Indication for smoking reduction
• Smoking reduction indication is approved
in:
• Europe: Austria, Belgium, Czech Rep.,
Denmark, France, Iceland, Italy,
Netherlands, Russia, Switzerland,
Sweden, UK.
• Rest of the world: Brazil, Malaysia, NewZealand, Philippines.
8.1.3. Bupropion SR
Bupropion hydrochloride is an antidepressive drug (an
aminoketone) which has been shown to be an effective
aid to cessation in smokers who smoke more than 10
cigarettes/day and who are motivated to stop.
Bupropion inhibits neuronal reuptake of noradrenaline
and dopamine, with minimal effect on the re-uptake of
serotonin and no inhibitory effect on monoamine
oxidase.
Part I of V
It has been shown to reduce the activity of these dopaminereleasing neurones and thereby may deactivate the reward
circuit and reduce craving.
Sustained-release (SR) bupropion is considered a useful
option for smokers attempting to stop smoking for the first
time, especially those who cannot tolerate NRT, who prefer
non-nicotine treatment or who have failed to quit with NRT
[2-6,16-19].
For smoking cessation the recommended dose of bupropion
SR is 150 mg/day for the first week, thereafter increasing to
300 mg/day (150 mg twice daily).
Part II of V
Smokers using bupropion SR are advised to continue to
smoke until the target quit day which usually is set after
1 week of treatment.
A reduced maintenance dose—that is, 150 mg daily—is
recommended in elderly smokers, or those with liver or
renal impairment or below 45 kg in body-weight.
The recommended duration of treatment for smoking
cessation is 7–12 weeks.
Part III of V
Bupropion SR is a prescription-only medicine.
The most common side effects are sleep disturbances
and dry mouth.
A serious but rare side effect is seizures
(<1:1000).[140]. The drug is contraindicated in
patients with current or past epilepsy, and should be
used with extreme caution in smokers with conditions
predisposing to a low threshold for seizure, such as
history of head trauma, or alcohol abuse.
Part IV of V
Caution is needed regarding the dose in patients with
diabetes treated with hypoglycaemic agents or insulin, and
in patients taking drugs that lower the seizure threshold (e.g,
antipsychotics, antidepressants, theophylline and systemic
corticosteroids).
Bupropion is also contraindicated in patients with a history
of anorexia nervosa and bulimia, severe hepatic necrosis, or
bipolar disorder.
Bupropion should not be used with a monoamine oxidase
inhibitor, and at least 14 days should elapse between
stopping such treatment and starting bupropion [9,139, 167170].
Part V of V
8.1.4. Efficacy of bupropion in patients with COPD who
smoke
Very few studies have used bupropion SR for smoking
cessation in patients with chronic diseases such as
COPD.
These abstinence rates are much lower than those
observed in similar studies with bupropion SR in healthy
subjects, suggesting that COPD patients may be
relatively “hard core.”
8.2. Second-line smoking cessation treatments
Nortriptyline, a tricyclic antidepressant, is the only other
antidepressant that has demonstrated evidence of efficacy for
smoking cessation.
The dose of nortriptyline for smoking cessation is 75–150 mg
daily.
There are many contraindications with nortriptyline, including
common anticholinergic side effects and particularly cardiac
conduction disturbances and orthostatic blood pressure drop.
Part I of II
Clonidine, has been recommended as a second-line
therapy in US smoking cessation guidelines [10].
Adverse effects associated with clonidine, such as
drowsiness, fatigue and dry mouth, may limit its
use [177], and we consider it to be obsolete today.
Part II of II
SMOKING CESSATION
New Medication
Treatment
Ch Gratziou
Ass.Prof Pulmonary and Crit Care
Medical Schools,
Athens University
Nicotine Addiction
Addiction
Blood Nicotine
REWARD
Dopamine
release
Blood Brain Barrier
Nicotine Achetylocholine
Brain receptors
Medication Treatment
Addiction
Nicotine in Blood
Reward
X
Dopamine
release
X
Blood brain Barrier
X
Nicotine Ach Receptors
New Medications
for Smoking Cessation
Cannabinoid Receptor
Antagonists
Cannabinoid Receptors CB1
Rewarding stimulies (including palatable food ) and other
abuse substances produce dopamine release
in the nucleus accumbens
CB1
CB1
Glu
GABA DA
CB1 plays an important role in Nac dopamine release
by inhibition of GABA release
Cannabinoid Receptors
THE NECTAR OF DELIGHT
• The primary psychoactive
constituent of marijuana, is
related to the action on two
cannabinoid receptors :
CB(1) and CB(2)
Cannabinoids Receptors
CB1-receptor
CB2-receptor
Appetite
Pain
Brain
Lung
+++
+
++
++
• CB1 are associated with the intake of food and smoking
addiction
• Blocking the CB1 may reduce food craving .
• Blocking the CB1 may reduce tobacco depedence by less
motivation to take nicotine possibly due to impairment of
dopamine release by the nucleus accumbens
Rimonabant :
a CB1- cannabinoid receptor
antagonist
Pharmacological Characteristics
• T ½ : 8-15 days
• Metabolised by oxidation in the liver
Why Rimonabant has a
place for Smoking Cessation
Animal Studies
• Endocannabinoids are released by chronic
nicotine administration (Gonzalez et al, 2002)
• Rimonabant blocks nicotine –induced
reinforcement and nicotine self administration(Cohen et al, 2002)
• Rimonabant produces loss of weight
Weight and Smoking !!
Rimonabant
Clinical trials phase ΙΙΙ ( 7 studies)
Dose 20mg /day for 10 w
Weight Control
Diabetics, Hyper cholesterolemia
Multicentre International study
(RIO Europe)
Rimonabant 5 or 20 mg/day
Prolonged Abstinence (10 weeks)
Placebo
Rimonabant 5 mg
Rimonabant 20 mg
40
Abstinent (%)
35
OR=2.0 - 95% CI=[1.296; 3.046]
P=.004
27.6
30
25
20
16.1
15.6
n=261
n=262
15
10
5
0
USA study
ITT
n=261
American College of
Cardiology 2004
Rimonabant 5 or 20 mg/day
Prolonged Abstinence (10 weeks)
Placebo
Rimonabant 5 mg
Rimonabant 20 mg
40
P= NS
Abstinent (%)
35
30
25
24
25
20
20
15
10
5
0
European study
1.Lancet 2005; 365: 1389-1364.
ITT
Side effects with Rimonabant
Placebo
2.3 %
3.8 %
5-mg rimonbant
1.5 %
20-mg rimonabant
2.7 %
Dropouts due to Adverse Events
5.7 %
6.9 %
Cardiovascular Safety Profile
No safety issue has been detected through laboratory, vital
signs, or ECG data
The most frequent side effects reported with rimonabant were
nausea, diarrhoea, vomiting, urinary tract infections, anxiety and
upper respiratory tract infections.
Rimonabant
Not APPROVED for Smoking Cessation
Treatment
Drug for a specific target group ?
• Hypertension , cardiovascular diseases
• Diabetes,
• Hypercholesterolemia,
• Overweight
Rimonabant
• Relative low abstinence rate
• Long term results?
• Prevention of weight gain .
Modification to the molecule might give
better efficacy
New Medications
for Smoking Cessation
Nicotine Acetylcholine
Receptors
n-ACh antagonists
Nicotine Addiction and n ACh
Receptors Endogenous nACh Rs
are found throughout
the central and
peripheral nervous
system.
Cholinergic
action
nACh –
Receptor
Meta-synapsic
membrane
Pre-synaptic
Synapsis
Cellular Body of
Dopaminergic neuron
The most abundant
form of nACh
receptors is a
pentameric made of
a4b2 units
Leonard & Bertrand
Nicotine Tob Res 2001;3
The a4b2 receptor is critical for self administration of
nicotine
Picciotto et al 1998, Tanner et al 2004
Varenicline: New Molecule
• Developed specifically for targeting the main
nicotinic receptor responsible for nicotine
addiction : a4b2 n ACh receptors
H
N
NH
Varenicline
N
S-(-)-Nicotine
N
N
• Not a substitute for nicotine
• Not an antidepressant
Varenicline
New mechanism of Action
Varenicline was developed as Partial
agonist of 42 nicotinic acetylcholine
recptors combining agonist and
antagonist properties in one compound
Varenicline : New Mechanism of
Action
A selective nicotinic receptor partial agonist evokes a reduced
level of response, while antagonizing the response of a full agonist
100
Response
level
50
(%)


The nicotinic AcHR is a
ligand-gated pentameric
ion channel; downstream
effects include DATO
0
Full
agonist
(nicotine)
Antagonist
(mecamylamine)
Full
agonist
+
antagonist
Partial
agonist
Partial
agonist
+
nicotine
Dopamine
turnover
(DATO)
Varenicline: A Partial Agonist
Maximum effect
Full agonist
100%
Blocks reward
Effect
Partial agonist
50%
Craving;
withdrawal relief
0%
Dose, exposure
Varenicline
a Partial Agonist
How Varenicline helps to overcome
nicotine addiction
As Partial agonist
 minimises the withdrawal symptoms
( agonist effect)
 blocks the pathway that is associated
with reward system after nicotine intake
( antagonist effect )
Varenicline
Pharmacological Characteristics
Absorption
Highly absorbed 99 %
Half life 17h
Distribution
Low Protein binding
Metabolism
Excretion
Non metabolised
No drug interaction with c Ρ450
Excreted as unchanged in the urine
Renally cleared >90 %
No interaction with Food
No interaction with other Medications
Varenicline: Clinical
Studies
JAMA July 2006 : 3 randomised trials
1. Gonzales D, Rennard SI, Nides M, et al. Varenicline, an a4b2
nicotinic acetylcholine receptor partial agonist, vs sustainedrelease bupropion and placebo for smoking cessation: a
randomized controlled trial.
JAMA. 2006;296:47-55.
2. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an
a4b2 nicotinic acetylcholine receptor partial agonist, vs
placebo or sustained-release bupropion for smoking
cessation: a randomized controlled trial.
JAMA. 2006;296:56-63.3.
Varenicline Clinical Studies: Design
Treatment Phase
Nontreatment Phase
Varenicline 1mg bid
Bupropion 150 mg bid
Placebo
Wk
Screening
Visit Baseline
Randomization
Target
Quit Date
1
9
12
52
Primary Endpoint:
CO- confirmed 4-wk continuous
quit rate wks 9-12
Secondary Endpoint:
CO-confirmed continuous abstinence
rate wks 9-52
Continuous abstinence rates
(confirmed by CO )
44%
P.001
Randomised
double blind
29.5%
(P=.007),
29.5%
(P=.057),
19 centres
in USA
21.9%
20.7%
17.7%
P.001
1025 smokers
10.5%
16.1%
(P=.001)
8.4%
Treatment 12w
Follow-up 40 w
Gonzales et al. JAMA. 2006;296:47-55.
Continuous abstinence rates
(confirmed by CO )
P.001
43.9%
29.8%
29.7%
23%
Randomised
double blind
17.6%
14 centres
20.2%
13.2%
14.6%
10.3%
1413 smokers
Treatment 12w
Follow-up to 52 w
Jorenby et al. JAMA. 2006;296:56-63.
Side effects
Jorenby et al. JAMA. 2006;296:56-63.
Maintenance treatment with
varenicline
Tonstad S, Tønnesen P, Hajek P, et al. Effect of
maintenance therapy with varenicline on smoking cessation:
a randomized controlled trial.
JAMA. 2006;296:64-71.
To determine whether smokers who quit after 12 weeks of
treatment with varenicline, maintain greater continuous
abstinence rates than placebo controls during an additional
12 weeks of treatment and until 52 weeks after treatment
initiation.
Maintenance of Abstinence:
Study Design
OPEN-LABEL
Varenicline 1mg bid
DOUBLE-BLIND
NONTREATMENT
FOLLOW-UP
Varenicline 1mg bid
12 weeks
Quitters randomized
Placebo
Wk12
24
52
Primary Endpoint:
CO-confirmed continuous abstinence rate wk 13–24
Secondary Endpoint:
CO-confirmed continuous
abstinence rate wk 13–52
Maintenance treatment :
7 day point prevalence abstinence
1st phase Open study 12w
2nd phase Randomised double blind additional 12w
14 centres 1927smokers
63 % participate in 2nd phase
Tonstad et al . JAMA. 2006;296:64-71
Maintenance of Abstinence Study:
CO-confirmed Continuous Abstinence Rates
Wks 13–24
Response Rate (%)
100
OR=2.47
(95% CI 1.95, 3.15) p<0.0001
80
60
OR=1.35
70,6
(95% CI 1.07, 1.70) p=0.0126
49,8
40
44,0
37,1
20
0
OR = odds ratio
Wks
Wks 13–52
24-52
N=602
Varenicline
N=604
Placebo
N=602
Varenicline
N=604
Placebo
Side effects
Tonstad et al . JAMA. 2006;296:64-71
Varenicline: Published Studies
Varenicline is an efficacious, safe, and well-tolerated
smoking cessation pharmacotherapy.
Varenicline’s short-term and long-term efficacy exceeded
that of both placebo and bupropion SR.
Gonzales et al. JAMA. 2006;296:47-55.
Jorenby et al. JAMA. 2006;296:56-63.
Extended use of varenicline helps recent ex-smokers to
maintain their abstinence and prevent relapse
Tonstad et al . JAMA. 2006;296:64-71
Cahill et al, Cochrane Database of SR, 2007
Cahill et al, Cochrane Database of SR, 2007
New Medications
for Smoking Cessation
Modifiers of
nicotine metabolism
Modifiers of nicotine
metabolism
• Inhibitors of CYP2A6
Nicotine
CYP2A6
Cotinine
CYP2A6
3-hydroxycotinine
Cytochrome CYP2A6
• CYP2A6 Polymorfism (26 alleles)
is Related with
• Nicotine metabolism
• Lower smoking initiation rate and lower
smoking dependence
• Lower smoking habit
• Reduced risk for lung cancer
CYP2A6 Inhibitors
• Enhance the action and effectiveness of
NRTs.
• Reduce the number of cigarettes
consumption
• Control the desire for smoking
• Reduce the activation of precarcinogens to carcinogens
• Reduce the risk for Lung Cancer
CYP2A6 Inhibitors
• Μethoxsalen 10mg , 30 mg
• Tranylcypromine (MAO inhibitor)
– 2.5mg, 10mg
Increase plasma level of nicotine
Reduce smoking desire and cigarette
Sellers et al.Research focus2003
consumption
Zhang et al. Drug Metab. Dispos.2001
Other New Approaches
for
Smoking Cessation
Vaccination ????
Vaccine : Mechanism of Action
Addiction
Nicotine in Blood
Reward
Dopamine
release
X
Blood brain Barrier
Nicotine Ach Receptors
Vaccine : Mechanism of Action
Addiction
Nicotine in Blood
Reward
X
Dopamine
release
X
Blood brain Barrier
Nicotine Ach Receptors
Possible place for Vaccine
•
•
•
Relapse prevention
Advantages
No daily use
No action in CNS
Combination with other therapies
Preparation of heavy smokers for smoking
abstinence
Early prevention of Smoking Dependence
??
Vaccines against Smoking
• ΤΑ-ΝΙC (Xenova research Ltd, UK)
• NicVAX ( Nabi , USA)
• Nicotine –Qbeta ( Cytos, Switzerland)
Successful clinical trials phase Ι and II
Few Side Effects
More ongoing studies
1: Curr Opin Investig Drugs. 2007 Jan;8(1):71-7.
Drug evaluation: CYT-002-NicQb, a therapeutic vaccine for the
treatment of nicotine addiction.
Heading CE.
The Open University in the North, Faculty of Science, Eldon House,
Regent Centre, Gosforth, Newcastle
upon Tyne NE3 3PW, UK. [email protected]
Cytos Biotechnology AG is developing an intramuscular therapeutic
vaccine, CYT-002-NicQb (also known as nicotine-Qbeta), based on its
Immunodrug (formerly known as alpha vaccine) nicotine-specific
antibody-generating technology, for the potential treatment of nicotine
addiction. A phase II trial was initiated in Switzerland in January 2005 and
in February 2006, Cytos Biotechnology announced that it planned to
begin a phase IIb/III trial in 2007.
Vaccines against Smoking
Questions !!
•
•
•
•
•
•
More clinical studies in smokers
Safety ( long term use)
Cost of Therapy
Duration of action and effectiveness
Use Frequency
Ethical issues
– Prevention of tobacco use in adolescents ,
– Use in pregnancy ??
Further Questions on
New Treatments
More clinical trials and real phase studies
to assess :
• Effectiveness
• Long term use
– Relapse Prevention
– Weight gain
• Combined use
8.3. New medications
8.3.1. Varenicline
Varenicline is a partial agonist at the subtype of
neuronal nicotinic receptors composed of α4 and β2
subunits.
Varenicline initially stimulates the α4β2 receptors
that mediate the effects of the nicotinic agonist on
dopamine release in the nucleus accumbens (the
agonist function).
If nicotine is added to varenicline treatment no
increase in dopamine response is seen (the antagonist
function).
Part I of II
As varenicline combines both agonist and
antagonist function it can reduce nicotine
dependence and can also attenuate the effects of
nicotine withdrawal [179,180].
Smokers are asked to up-titrate their dose to
varenicline 1 mg twice daily during the first 7
days of treatment, the stop smoking on day 8, and
continue treatment for 12 weeks.
We expect that with more documentation and
experience varenicline will be a first-line drug in
smoking cessation.
Part II of II
Table 7. Continuous quit rates, in percent, from week 9 to 52 in two phase III
trials of varenicline for smoking cessation
Study
Placebo
Varenicline
2 mg/day
Bupropion SR
300 mg/day
P value
Gonzalez
[179]
Study 1
8.4
22.1
16.4
varenicline vs placebo
p<0.001
varenicline vs bupropion
p<0.07
bupropion vs varenicline
p<0.001
Jorenby
[180]
Study 2
10.3
23.0
15.0
varenicline vs bupropion
p<0.001
bupropion vs placebo
p<0.001
varenicline vs placebo
p<0.001
8.3.2. Rimonabant
The stimulation of CB1 receptors by endocannabinoids
within the brain plays an integral role in the development
and maintenance of nicotine and tobacco dependence, and
rimonabant exerts its effects in addicted individuals by
inhibiting this role of the endocannabinoid system [182].
The most frequent side effects reported with rimonabant
were nausea, diarrhoea, vomiting, urinary tract infections,
anxiety and upper respiratory tract infections.
Part I of II
Rimonabant’s effects do not seem to be
significantly better than currently available
cessation treatments.
With its better-documented efficacy on obesity
treatment [184], one might speculate that
rimonabant could be useful in overweight smokers
for whom weight gain is a major barrier to quitting.
Part II of II
8.4. Key points: Pharmacotherapy and smoking
cessation
NRT and bupropion SR are first-line treatments
for smoking cessation (Evidence A)
Smokers attempting to quit should be
encouraged to use these drugs to aid cessation,
except in the presence of contra-indications
(Evidence A).
NRT (gum, patch, inhaler, nasal spray, lozenge
and sublingual tablets) are equally effective as
smoking cessation treatments (Evidence A). Part I of II
Combining the nicotine patch with a selfadministered form of NRT can be more effective
than a single form of NRT (Evidence B).
NRT should be used to aid cessation in all
smokers with COPD, regardless of disease
severity and number of cigarettes smoked
(Evidence B).
Combined treatment with bupropion SR and
NRT might be more effective in heavy smokers
(Evidence C)
Part II of IV
Both NRT and bupropion SR are effective and
well tolerated in smokers with stable cardiovascular
disease and in COPD patients.(Evidence A)
-
Nortriptyline may be used as second-line
medication to treat tobacco dependence (Evidence
B).
There is no evidence that selective serotonin
reuptake inhibitors (SSRIs) have any effect in
smoking cessation.
Part II of IV
Varenicline might have additional therapeutic
effect as smoking cessation treatment and are
considered a second-line agent until more
documentation and experience occur (Evidence B)
-
Regular follow-up visits are important and are
linked with longer-term successful outcome
(Evidence B).
Part IV of IV
Figure 2. An illustration of the recommended smoking cessation steps and approved
first-line interventions
Yes
No
No
Yes
Part I of II
Successful quitter
Relapse
NRT= nicotine replacement therapy
Part II of II
9. Other interventions
9.1. Acupuncture and laser therapy
9.2. Hypnotherapy
There is no evidence that hypnosis, acupuncture or
laser therapy has any effect in smoking cessation
11. Organisational anchorage and education
Smoking cessation services should be an integral part of a chest
unit, offering advice and help to all smokers with respiratory
diseases independently of the smoker’s motivation, but focusing
primarily on those who want to try to quit.
As a minimum, chest departments should offer smoking cessation
support, NRT and/or bupropion SR and at least four follow-up
visits to all smokers.
The precise details of each service are likely to depend on local
factors and national differences, taking into account the fact that
individual clinicians fail to intervene with more than one-third of
smokers [9].
11.1. Systematic identification of smokers
Focusing on hospitals - either inpatients or outpatients
– there should be an organisational plan for
identifying smokers, documenting smoking data in
patients’ records, and delivering brief advice with an
offer of referral to the smoking cessation service
[9,198].
11.2. Equipment and staffing
Certain requirement and expertise should be available in
each clinic unit to perform the assessments described
previously. It should be possible to assess CO level,
nicotine dependence and motivation to quit [80,199,200].
If the clinic cannot offer smoking cessation there should be
written flow-charts stating where to refer the patients.
It is also important to engage GPs in smoking cessation, as
many COPD patients consult their GP frequently.
11.3. Education
The following tools have been shown to alter
physicians’ behaviour [202]:
-
Education by physician “opinion leaders”
Computerised concurrent feedback on clinical
decisions,
Academic detailing i.e. one-on-one education,
often by a pharmacist,
Physician incentives, but also patient education
or information and patient incentives.
Part I of III
Guidelines should be simple, pragmatic, usable and
flexible with an increasing focus on
implementation [201,203].
Smoking cessation should be part of the core
curriculum of the undergraduate and postgraduate
education and training of physicians.
Part II of III
As smoking plays so large an aetiological role for a majority
of pulmonary disorders, the pulmonary clinician must know
about smoking cessation at a level similar to the knowledge
about other respiratory therapies e.g. bronchodilators and
inhaled steroids.
Formal training courses are needed to educate smoking
cessation counsellors, and courses must be repeated to take
account of turn-over among staff members. It would be
optimal if all pulmonary clinicians participated in the above
education.
There should also be postgraduate smoking cessation courses
at the annual ERS conference.
Part III of III
11.4. Smoke-free health care
Smoking should be banned in hospitals, both for
hospitalised and ambulatory patients and for staff.
The European Smoke-Free Hospital Network
consists of 16 membership countries and this
organisation has created implementation guidelines
for turning a hospital smoke-free, as well as training
guidelines and material for health care workers
[205].
12. The costs of smoking and economics of smoking cessation
13. Research prospects
1) Examine the efficacy of NRT and bupropion SR and
combinations for smoking cessation in patients with
respiratory diseases, particularly COPD and asthma.
Smoking cessation studies are also needed for smokers
with several other respiratory disorders such as
tuberculosis, alpha 1 antitrypsin deficiency, histiocytosis
X, and candidates for lung transplantation.
2) Examine the efficacy of different re-treatment
interventions as well as long-term treatment for smoking
cessation in patients with respiratory diseases.
Part I of IV
3) Examine the efficacy of smokeless tobacco as a smoking
cessation tool in recalcitrant smokers.
4) Examine the efficacy of lung function screening in
asymptomatic and symptomatic smokers, combined with
different smoking cessation approaches.
5) Explore the characteristics of tobacco
dependence/nicotine addiction and barriers and
motivation to quit in patients with respiratory diseases.
Part II of IV
6) Examine whether reduced smoking in patients
not motivated to give up can increase selfconfidence and motivation to quit.
7) Examine the relationship between COPD and
depression and evaluate whether treatment for
depression can help dependent respiratory patients
to quit.
Part III of IV
8) Evaluate the efficacy of new drugs for smoking
cessation in respiratory patients.
9) Evaluate the efficacy of smoking cessation
programs in rehabilitation courses.
10) Evaluate the efficacy of web-based
programmes, quit-lines and other “mass-media”
methods for smoking cessation.
Part IV of IV
2. Key points of recommendations
1. Patients with respiratory disease have a greater and
more urgent need to stop smoking than the average
smoker. They should be encouraged to stop but
many often find it more difficult to do so (B).
2. Respiratory physicians must take a proactive and
continuing role with each smoker in motivating him
or her stop, and provide treatment to achieve
smoking cessation, however long this might take,
and deal with relapses when these occur. Smoking
cessation treatment must be considered integral to
the management of the patient’s respiratory
condition.
Part I of IV
The role includes:
• regularly assessing smoking status using
methods that can objectively detect smoking, such
as expired-air carbon monoxide (CO) tests. (C)
• pharmacological treatment for nicotine
dependence including bupropion and/or where
necessary using high-dose and/or prolonged
nicotine replacement therapy (NRT); it could also
include giving combinations of different forms of
NRT (A). Varenicline is a promising second-line
agent (B).
• behavioural support, which should be intensive
and multi-sessional, and provided by someone
who has been appropriately trained (B).
Part II of IV
3. To carry out this role effectively, respiratory
physicians must have adequate knowledge and
appropriate attitudes and skills; this requires training
and continuing medical education which should be
provided according to professional standards, and be
accredited (C).
4. The cost of this strategy will partly be offset by a
reduction in attendance for exacerbations etc., but a
budget must be established to enable implementation
of treatment protocols and provide medication and
behavioural support (A).
Part III of IV
5. It is important to check lung function regularly
in order to chart disease evolution and use this as a
motivational tool (C).
6. Smokers not motivated to stop should be offered
NRT to reduce smoking as a gateway to cessation
(B).
7. Smokers who are not interested in stopping or
reducing should be advised that the physician will
return to the question at a later visit (C).
Part IV of IV
Treatments for Smoking Cessation
Smokers will never
be able to
“take just a pill”
that will make them
in a magic way
to stop smoking !!!
Smoking Cessation Treatment
Smokers must want to
stop smoking and
must be willing to
work hard to
achieve the goal of
smoking abstinence.
Brief Clinical Advice
&
Intensive Smoking cessation Programs
Thank you!
www.ersnet.org