nancy rigotti, md

Nancy Rigotti, MD

Treatment Review:Overview of the Evidence Base

for Tobacco Dependence Treatment

10/09/2011

OVERVIEW

Why is tobacco treatment necessary for global tobacco control?

Why do smokers keep smoking?

What smoking cessation treatments are effective?

Behavioral

Pharmacological

Role of health care providers

WHY TREATMENT MATTERS

Tobacco use is the #1 preventable cause of death

Stopping tobacco use reduces health risks

Tobacco prevention works slowly

CESSATON vs. PREVENTION

WHY TREATMENT MATTERS

Tobacco use is the #1 preventable cause of death

Stopping tobacco use reduces health risks

Tobacco prevention works slowly

Tobacco use is an addictive disorder

Tobacco treatment aids tobacco control policies overall (and vice versa)

MPOWER ReportWorld Health Organization – 2008

M onitor tobacco use and tobacco control policy

P rotect people from tobacco smoke

O ffer help to quit tobacco use

W arn about the dangers of tobacco

E nforce bans on tobacco advertising, promotion

R aise taxes on tobacco

http://www.who.int/entity/tobacco/mpower/package/en/index.html

OVERVIEW




Behavioral

Pharmacological


WHY DO SMOKERS KEEP SMOKING?

Pharmacologic nicotine dependence

DOPAMINE


Irritability, anger, impatience Restlessness Difficulty concentrating Insomnia Anxiety Depressed mood Increased appetite

Pharmacologic nicotine dependence → Craving (nicotine “hunger”)

→ Nicotine withdrawal symptoms



Psychological factors

• Cues (meals, alcohol, other smokers)

• Coping with stress, emotions (anger)



Psychological factors

Psychiatric co-morbidity

• Depression

• Schizophrenia

• Substance abuse

THE CHALLENGE FOR TREATMENT

We have effective treatments, but…

We need better treatments

We need to deliver the treatments we have to more of the smokers who need them

OVERVIEW




Behavioral

Pharmacological


LIMITATION OF OUR EVIDENCE

The evidence about treatment comes mostly from studies done in high-income countries

Few trials have been done in middle- or low-income countries

Less awareness of health risks Fewer have tried to quit and failed

Biology is relatively constant

Cultural context varies by country

SMOKING CESSATION METHODS2008 US Public Health Service Guidelines

Effective treatments

More is better but brief intervention works

Treating tobacco is highly cost-effective

Counseling

Pharmacotherapy

Combination - better than either one alone

COUNSELING – Content

Smokers who want to quit Cognitive-behavioral counseling

Social support

Encourage medication use and adherence

Smokers who are unwilling to quit Motivational interviewing

Effective in meta-analysis, quit rates low

COUNSELING – Method of Delivery

In-person * - one-on-one or group

By telephone * - proactive quitlines

Self-help materials – little efficacy

Newer technologies Web- based – evidence is growing but not definitive

Text-messaging – 1 randomized trial (Lancet 2011)

Social media – little evidence

* Endorsed as effective by 2008 USPHS Guideline Update

TELEPHONE QUITLINES

Definition

Proactive multi-session counseling by phone

AdvantagesConveniencePrivacy

Effective (pooled OR 1.4, 95% CI 1.3-1.6)*

Quitlines can also provide medicationFacilitate access to medicationsStrategy for promoting calls to a

quitline

*Stead LF et al. Tobacco Control 2007;16(suppl 1):i3

PHARMACOTHERAPY1st Line - 2008 US Public Health Service Guidelines

Nicotine replacement OR Skin patch 1.9

Gum 1.5

Oral inhaler 2.1

Nasal spray 2.3

Lozenge 2.0

Bupropion SR (Zyban,Wellbutrin SR) 2.0

Varenicline (Chantix/Champix) 3.1

0

2

4

6

8

10

12

14

16

18

0 10 20 30 40 50 60 70 80 90 100 110 120

Time post administration (min)

Pla

sma

nico

tine

leve

l (ng

/mL)

Cigarette (1-2 mg)

Nasal spray (1 mg)

Gum (4 mg)

Patch (21 mg)

PLASMA NICOTINE LEVELSCigarettes vs. Nicotine Replacement Products

NICOTINE REPLACEMENT

Long-acting, slow onset → skin patch

Short-acting Intermediate onset → oral (gum, lozenge, inhaler)

More rapid onset → nasal (spray)

Constant nicotine level to avoid withdrawal Simplest to use, best compliance User has no control of dose

User controls dose Nicotine blood levels fluctuate more Requires more training to use properly

New Ways to Use

NICOTINE REPLACEMENT(Supported by evidence and USPHS*)

* Combine short- and long-acting forms“Patch plus” regimen

* Extend treatment to prevent relapse

Start NRT 2 weeks before quit date

Reduce to quit strategy

BUPROPION SR (Zyban, Wellbutrin SR)

Doubles cessation rate independent of its antidepressant effect

Reduces post-cessation weight gain

Quit rates higher if add counseling

Reduces seizure threshold (risk: 1/1000)

VARENICLINE

Binds selectively to the α4β2 nicotinic receptor, which mediates nicotine dependence

Dual mechanism of action

Partial agonist Stimulates receptor to treat craving, withdrawal

AntagonistPrevents nicotine from binding to the receptor →Blocks reward, reinforcement of smoking

NH

N

N

OR 2.86(95% CI,1.72, 4.11)

p < 0.001

25

20

15

10

0

Con

tinuo

us A

bstin

ence

(%

)

n = 355 n = 359

19.2

7.2

OR: 3.14(95% CI: 1.93 – 5.11)

p < 0.0001

18.6

5.6

OR 4.04(95% CI, 2.13, 7.67)

p < 0.00122.4

9.3

Stable CVD 1

n = 344 n = 341

Healthy smokers 3

n = 248 n = 251

COPD 2

Varenicline

Placebo

5

Varenicline efficacy across studiesContinuous Abstinence Rates (Weeks 9–52)

1 Rigotti et al, Circulation 2010; 2 Tashkin D et al. Chest 2010. 3 Gonzales et al., JAMA 2006; Jorenby et al., JAMA 2006.

FDA Public Health AdvisoryJuly 2009

“Chantix (varenicline) or Zyban (bupropion) has been associated with reports of changes in behavior such as hostility, agitation, depressed mood, and suicidal thoughts or actions.”

“FDA is requiring the manufacturers of both products to add a new Boxed Warning:

People who are taking Chantix or Zyban and experience any serious and unusual changes in mood or behavior or who feel like hurting themselves or someone else should stop taking the medicine and call their healthcare professional right away.

Friends or family members …”

VARENICLINE SAFETYThe dilemma

Smokers have an increased risk of suicide.

Stopping smoking produces nicotine withdrawal symptoms (depressed mood, anxiety, and irritability)

When these symptoms occur in a smoker who is stopping smoking on varenicline, did the drug or did quitting smoking cause the symptom?

Case reports cannot answer this question.

Clinical trials of varenicline detected no excess of depression or suicidal thoughts, but these studies did not include patients with mental illness.

VARENICLINE SAFETYCohort study (Gunnell et al, BMJ 2009)

UK General Practice Research Database Population based data: 3.6 million patients in 500 practices Data from electronic medical records

Patients starting smoking medication (9/06 – 5/08) NRT (n=63,265) Bupropion (n=6422) Varenicline (n=10,973)

Outcome: rates of suicide, suicide attempt, suicidal thoughts, and new antidepressant therapy

Results: No evidence of increased risk of suicidal outcomes for varenicline vs NRT, bupropion vs NRT

VARENICLINE SAFETYMy Bottom Line

Varenicline may increase risk of psychiatric symptoms in some patients. The potential risk is not yet well defined.

Prescribing varenicline, like prescribing any drug, requires balancing risks and benefits.

- Varenicline is one of the most effective drugs available to treat tobacco dependence

- Continuing to smoke is clearly hazardous

In most cases, the benefits of varenicline outweigh the risks

Which drug is most effective?Which drug is most effective?Meta-analysis for 2008 USPHS GuidelineMeta-analysis for 2008 USPHS Guideline

DrugDrug Estimated OR Estimated OR (95% CI)(95% CI)

Nicotine patchNicotine patch 1.0 (reference)1.0 (reference)Other nicotine products or Other nicotine products or bupropionbupropion

Not significantly different from Not significantly different from nicotine patchnicotine patch

VareniclineVarenicline 1.6 (1.3-2.0)1.6 (1.3-2.0)

CombinationsCombinations

Long-term patch + Long-term patch +

gum or nasal spraygum or nasal spray1.9 (1.3-2.7)1.9 (1.3-2.7)

Patch + bupropionPatch + bupropion SRSR 1.3 (1.0-1.8)1.3 (1.0-1.8)

Varenicline vs bupropion vs placeboCO-Confirmed 4-Wk Continuous Quit Rates - Wks 9–12

OR=3.91OR=3.91**

(95% CI 2.74, 5.59)

OR=1.96OR=1.96**

(95% CI 1.42, 2.72)

OR=3.85OR=3.85**

(95% CI 2.69, 5.50)

OR=1.89OR=1.89**

(95% CI 1.37, 2.61)

100

44.4 44.0

30.029.5

17.717.7

0

20

40

60

Study I Study II

Res

po

nse

Rat

e (%

)

Varenicline Zyban Placebo

N=349 N=329 N=344 N=343 N=340 N=340

*p<0.0001 Jorenby et al, Gonzales et al, JAMA, July 5, 2006

VARENICLINE vs. NICOTINE PATCHOpen label randomized controlled trial

(5 countries, n= 746)

0

10

20

30

40

50

60

Weeks 9-12 Weeks 9-52

Varenicline NRT

Aubin HJ. Thorax 2008

End of treatmentOR 1.70 (1.26-2.28)

Continuous abstinenceOR 1.40 (0.99-1.99)

2620

56

43

2 head-to-head randomized trialsPiper, Arch Gen Psychiat 2009; Smith, Arch Int Med 2010

Tested 5 drug treatments (vs placebo) Monotherapy: Patch, lozenge, bupropion Combos: Patch + lozenge, bupropion + lozenge

Tested drugs in 2 settings Clinical trial (on-site counseling) Primary care clinics (using state quitline)

Results Each drug was better than placebo Combinations > monotherapy No 1 combination was better than the other in

both trials

CYTISINE (Tabex)

Used for many years in Eastern Europe, Russia

Pharmacology is similar to varenicline Binds selectively to the α4β2 nicotinic receptor

Cheaper than varenicline ($6 in Russia, $15 in Poland)*

Missing data: Is it effective (and safe)?

New large placebo controlled trial * 740 adult smokers in Poland 25 days of treatment (6 pills/day → 2 pills/day)

Validated abstinence at 1 yr : 8.4% vs 2.4% (p<.001)

7-day abstinence at 1 yr: 13.2% vs 7.3% (p<.01)

* West et al, NEJM 2011;365:1193

PHYSICIAN INTERVENTION

Routine advice to quit is effective Odds of quitting by 66% (vs no advice) *

Brief counseling is more effective Odds of quitting by 37% (vs brief advice) *

Brief intervention by other clinicians is effective

*

Cochrane reviews

5A BRIEF COUNSELING MODEL2000 U.S. Public Health Service Guidelines

ASK all patients about smoking

ADVISE all smokers to quit

ASSESS smoker’s readiness to

quit

ASSIST smokers to quit

ARRANGE follow-up care


ASK

ADVISE Core physician role

ASSESS

ASSIST

ARRANGE


ASK Done by office staff (‘vital sign’)


ASSESS

ASSIST

ARRANGE


ASK Done by office staff


ASSESS

ASSIST Connect to office or

community

ARRANGE supports (clinics, quit lines,

…)

TOBACCO USE TOBACCO USE BY HEALTH PROFESSIONALSBY HEALTH PROFESSIONALS

A problem in many countriesA problem in many countries

Health professionals act as role modelsHealth professionals act as role models

Clinicians who smoke are less likely to counsel Clinicians who smoke are less likely to counsel patients who smokepatients who smoke

Treatment strategies must include cessation Treatment strategies must include cessation programs for health care professionals and programs for health care professionals and studentsstudents

SMOKING CESSATION METHODS2008 US Public Health Service Guidelines

Effective treatments

More is better but brief intervention works

Treating tobacco is highly cost-effective

Counseling

Pharmacotherapy

Combination - better than either one alone

FCTC Article 14 - ImplementationWorld Health Organization

Countries should offer 3 types of treatment

Advice to quit in primary health care

Telephone quit lines – free and accessible

Pharmacotherapies – low-cost and accessible

Thank You

nancy rigotti, md

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