Tobacco Smoking as an Addiction

Karl Fagerstrom Ph.D.Smokers Information CentreHelsingborg, Swedenkarl,.fagerstrom@swipnet.se

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