tobacco smoking as an addiction karl fagerstrom ph.d. smokers information centre
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Tobacco Smoking as an Addiction Karl Fagerstrom Ph.D. Smokers Information Centre Helsingborg, Sweden karl,[email protected]. Addiction to Nicotine or Tobacco ? WHO-ICD prefers Tobacco, APA Nicotine. Tobacco contains many more pharmacologically active substances than nicotine. - PowerPoint PPT PresentationTRANSCRIPT
Tobacco Smoking as an Addiction
Karl Fagerstrom Ph.D.Smokers Information CentreHelsingborg, Swedenkarl,[email protected]
Addiction to Nicotine or Tobacco ?
WHO-ICD prefers Tobacco, APA Nicotine.
Tobacco contains many more pharmacologically active substances than nicotine.
No addiction in history to pure nicotine. Parallells with pure caffeine and coffee?
Nicotine is
reaching
the Brain
in a few
seconds
Nicotinic acethylcholine receptors
The most abundant form is a pentameric receptor made of 4-2 units
7 forms robust, homomeric
nAChR
7 7
7 77
Leonard & BertrandNicotine Tob Res, 2001; 3:203-223
Nicotine modulates Neurotransmitters
Nicotine
acts both
pre- and
post-
synaptically
Le HouezecAIM N°25, 1995
The Dopaminergic mesolimbic system
Nicotine acts
particularlyon
dopamine
The DA system is of key importance in animals. Also in humans?
Nicotine activates the brain
London et al 1991
Nicotine ReceptorNicotine Receptor
Normal state
= activated
= sensitive
= desensitised
Nicotine ReceptorNicotine Receptor
Initial smoking
= activated
= sensitive
= desensitised
Nicotine ReceptorNicotine Receptor
Smoking upregulation
= activated
= sensitive
= desensitised
Smoker Non SmokerC-11
Nikotine
Nordgerg Pers comm
Nicotine ReceptorNicotine Receptor
Under withdrawal
= activated
= sensitive
= desensitised
TOLERANCE
Short term:Related to the status of the receptor
Long term:Related to number of receptors
Fiore MC et al. JAMA 1992; 268: 2687–2694.
Withdrawal SymptomsIrritation, angerWeight gainInsomniaConcentration difficultiesAnxietyRestlessnessDysphoriaDecreased heart rate
Performance deficitsCravingHeadache
Time Course of Withdrawal Symptoms
Can occur after a few hours
Usually peaks within 2 weeks
Energy expenditure and mood effectsnot true withdrawal symptoms
WHO ICD-10 Criteria for Tobacco Dependence
A Strong desire to smoke
B. Difficulties to control the amount
C. Continued use despite harmful concequences
D. Influencing priorities of other activities
E. Increased tolerance
F. Physical withdrawal Three need to be present for a diagnosis
Very Difficult to Give Up
2-3% succeeds long term
Hughes 1999
75% of addicts to other drugs find it at least as difficult to give up smoking
Kozlowski et al 1983
The The FagerströmFagerström Test for Test for Nicotine DependenceNicotine Dependence
1. How soon after you wake up do you Within 5 min 3
smoke your first cigarette? 6-30 min 2
31-60 min 1
After 60 min 0
2. Do you find it difficult to refrain from Yes 1
smoking in places where it is forbidden? No 0
3. Which cigarette would you hate The first one in the morning 1
most to give up? Any other 0
4. How many cigarettes per day do 10 0
you smoke? 11-20 1
21-30 2
>31 3
5. Do you smoke more frequently during the first Yes 1
hours after waking than during the rest of the day? No 0
6. Do you smoke if you are so ill Yes 1
that you are in bed most of the day? No 0
Points
Comments to different degrees of dependence
Points % smokers Comments0-1 20 Very low dependence
Few and light withdrawal symptomsSeldomly need help to give up
2-3 30 A big group of smokersA certain degree of dependenceDifficult withdrawal symptoms can occurOften manages to give up by themselvesMedicines can be of help
4-5 30 A big group os smokersOver average dependenceWithdrawal symptoms commonMedicines often very helpfulRisk for smoking related disorders is real
6-7 15 Strong dependence and withdrawalLikelihood to give up smoking poorHigh risk for smoking related disordersMedicines important, possibly combinationsHigher dose, longer duration may be neededSupport treatment importantDepression and high alcohol intake common
8-10 5 Smal group with extreme dependenceChances to give up are very smalHandicapping withdrawal symptomsSupport Tx and medicines essential, preferably over long time and in high doseMost will have smoking related disordersAnxiety, depression, pain and alcohol dependence common
0
5
10
15
20
25
30
Percen
tag
e o
f sm
okers
DISTRIBUTION OF TIME TO FIRST CIGARETTEIN SMOKERS IN PRIMARY CARE
"How soon after waking do you smokeyour first cigarette of the day?"
Less than
5 minutes
5-15
minutes
15-30
minutes
30 min
to 1 hr
1 to 2
hours
More than
2 hours
50
100
150
200
250
300
350
400
450
Sa
liv
a c
otin
ine
(n
g/m
l)
Mean + 95% CI-
TIME TO FIRST CIGARETTE OF THE DAY
Less than
5 minutes
5-15
minutes
15-30
minutes
30 min
to 1 hr
1 to 2
hours
More than
2 hours
n=307n=182n=214n=205n=322n=260
Jarvis et al 2000
Dependence
Pro
bab
ilit
y to
qu
it
Without Tx
With treatment
SMOKERS
COPD N=153 HEALTHY N=870
DEPENDENCE 4.8 3.1 p<.001(FTND)
CARB. MONOX. 19.7 ppm 15.4 ppm p<.000
Jimenéz-Ruiz et al. 2001
Is the role of nicotine over empahzised
• No epidemic use of pure nicotine• No misuse of nicotine replacement• Nicotine not a strong reinforcer in animals (McDonald et al 1997).
• Human i.v. self-administration studies not very convincing (Henningfield & Goldberg 1983, Henningfield et al 1983).
• Human self-administration of NR not very convincing (Patch, e.g. Benowitz et al. 1998, Gum, e.g. Hughes et al 2000, Spray,e.g. Perkins et al 2001).
• Other pharmacoligically active sustances in tobacco, CO, MAO-inhibitors (Fowler et al 2003), Acetaldehyde (Castagnoli 2001).
Available drugs tested for smoking cessation• Naltrexone Opioid anatgonist• Selegeline MAO-B inhibitor• Nortriptyline Anti-depressant• (Glucose)
Under investigation• Benoxatone MAO inhibitor• Rimonabont CB-1 blocker• Varenicline Part nic rec agon• Dianicline ”• Nicotine vaccines
Under pre-clinical testingGlutamate receptor 5 antagonist, GABA enhancers
• The Endocannabinoid System (EC System)– A natural physiological system believed to play a role in maintaining
energy balance through the regulation of food intake and energy expenditure.
– The EC system also plays a role in tobacco dependence.
– Over-activity of the EC System is associated with obesity and tobacco
dependence
• Rimonabant– First selective CB1 Blocker.– Selectively blocks CB1 receptors and helps to normalize the disrupted
EC System.
Rimonabant and The Endocannabinoid System
Treatment Procedure
2 weeks of Rimonabont and smoking
Quitting at day 15
8 weeks on Rimonabont
Smoking cessation results, in percent,at 8 weeks from quit day. USA Europe
Placebo N=261 16 20
5 mg N=262 16 24
20 mg N=261 28 25 Antionelli et al 2004
Weight change from baseline to end of treatment (10 weeks) in non obese
Placebo 3,0 kg
5 mg 2,5 kg
20 mg 0,7 kg
Antionelli et al 2004
Most frequent side effects
• Nausea• Diarrea• Vomiting• Insomnia• Urinary tract infections
Antionelli et al 2004
Varenicline
Mode of Action
It was developed specifically as a Partial
Agonist at the 42 nicotinic
acetylcholine receptor combining agonist
and antagonist properties in one
compound.
Rationale Partial Agonist: Antagonist Effect
0%
Dose, exposure
Eff
ect
100%
50%
Partial agonist
Full agonist
Craving and withdrawal relief
Blocks reward
A partial agonist has the potential to block the reward associated with smoking and provide relief from craving
Any 4-week Continuous Quit Rate
Oncken et al 2005
CO-confirmed non-smoking
Oncken et al 2005
Studies I & II: CO-Confirmed Continuous Abstinence Rates
Wks 9-52
OR=3.13OR=3.13pp<0.0001<0.0001
OR=1.45OR=1.45pp=0.064=0.064
OR=2.66OR=2.66pp<0.0001<0.0001
OR=1.72OR=1.72 pp=0.0062=0.0062
22.1 23.0
15.016.4
10.38.4
0
20
40
Study I Study II
Res
po
nse
Rat
e (%
)
100
Varenicline Zyban Placebo
N=349 N=329 N=344 N=343 N=340 N=340
OR = odds ratio
Side effects (in percent) Placebo Varenicline Bupropion
Nausea 9 28 10 Headache 12 14 11Abnormal dreams 4 11 5Flatulence 2 5 3
Tonstad et al 2005
Scientific Rationale
The nicotine molecule itself is too small to be recognized by the immune system. Therefore it is coupled to a carrier protein to form an immunoconjugate
The immunoconjugate will elicit a humoral immune response generating nicotine selective antibodies
The antibodies will bind nicotine, thus, preventing it from reaching the brain and thereby inhibiting the occurrence of nicotine’s central nervous stimulating and addictive pharmacological effects
Carrier Protein
LinkerDrug
IMMUNOGEN
Important criteria for a nicotine vaccine
• Induction of high antibody titres against nicotine and a prolonged immune response.
• The antibodies induced should have a high specificity for nicotine and low/no specificity for metabolites from nicotine
• Possible to administer parenteral and nasal/oral
+
Blood Brain
NICOTINE DISTRIBUTION in RATS
Ni c
ot i
ne
( ug
/ g)
0
50
100
150
200
250
Serum Brain
ControlVaccine**
**
Pentel et al., Pharmacol. Biochem. Behavior 65: 191-198, 2000
Active Immunization Suppresses Nicotine-Induced DA Release in NACshell
I m m u n i z e d
C o n t r o ls
T i m e ( m in )
DA
ou
tpu
t (%
of
ba
se
lin
e)
de Villiers 2002et alImmunisations day 0 and 14. KLH-nicotine hapten and FCA, 100 or microgram /dose.
Voltametri 3-87 days after last immunisation
0
1 0
2 0
3 0
To
ta
lle
ve
rp
re
ss
es
/ho
ur
*
S a l i n e
p r i m i n g
S a l i n e
p r i m i n g
N ic o t i n e
p r i m in g
N ic o t in e
p r im in g
0
1 0
2 0
3 0
To
ta
lle
ve
rp
re
ss
es
/ho
ur
Effect of a Priming Dose of Nicotine on Nicotine-Seeking Behavior
Control animals Immunized animals
Nicotine priming dose 0.001 mg/kg i.v.
Adapted from Lindblom 2002et al.
Animal Studies: Effects of Immunotherapy
• Reduces response to nicotine – Physiological: blood pressure– Behavioral: locomotor activity
• Reduces– Nicotine relief of nicotine withdrawal– Nicotine discrimination – Acquisition of nicotine self-administration – Reinstatement
200 ug
100 ug
50 ug
Placebo
Nic
otin
e S
peci
fic A
ntib
ody
(E
LIS
A U
nits
)
Day0 50 100 150 200 250Days
20
30
10
0
Immune Response to NicVAX
Carrier Most commonside effects in %
Immuni-sations
Peakantibodies
Percent quitrate act/plac
NABI Pseudomonasaeruginosaexotoxin A
Tenderness 70 Ache 50 Induration 37 Fever 21
0, 4, 8, 26 weeks
31 weeks 33 / 9
Xenova Cholera toxin B
Tenderness 75 Induration 50 Muscle fasciculation 30 Erythema 10
0, 2, 4, 612, 32weeks
16 weeks 20 / 9 at 52w
Cytos Cholera toxin B
Not reported 0, 4, 8, 12, 16 weeks
40 / 31*
* Quit rate among actively vaccinated was related to antibody response.
Vaccines: Summary of early development
Vaccines against nicotine a promising new tool that can be used for
a) achieving abstinence
b) prevent relapse
Summary
In a few years we will have moreand probably also more efficacioustreatments to offer the smokers.
Thank you for the attentıon
”Cancers of the respiratory tract are responsible for one death in 20 in the EU. These cancers are mainly due to Nicotine poisoning”.
EUROSTAT. Mortality in the EU 2004.
Nicotine addiction: Anatomy of Reinforcing Behavior
• Nicotine activates DA neurons in
the Ventral Tegmental Area (VTA)• Systemic nicotine stimulates DA
release in the nucleus accumbens
Nicotine’s reinforcing effects are likely due to its effects on the mesolimbic dopamine (DA)
systemPrefrontal
cortex
Nucleusaccumbens
Ventral Tegmental
Area(VTA)
DA
DADA
Locomotor effects produced by systemic nicotine, or local nicotine injection into VTA, are blocked by lesions of the VTA
Nicotinic antagonists infused into the VTA block self-administration
X