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

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)

World Health Organization – 2008
 M onitor tobacco use and tobacco control policy
 P rotect people from tobacco smoke

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

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

 Pharmacologic nicotine dependence
DOPAMINE

 Pharmacologic nicotine dependence
→ Craving (nicotine “hunger”)
→ Nicotine withdrawal symptoms
 Irritability, anger, impatience
 Restlessness
 Difficulty concentrating
 Insomnia
 Anxiety
 Depressed mood
 Increased appetite


Pharmacologic nicotine dependence
 Psychological factors
•
Cues (meals, alcohol, other smokers)
•
Coping with stress, emotions (anger)


Pharmacologic nicotine dependence
 Psychological factors
 Psychiatric co-morbidity
•
Depression
•
Schizophrenia
•
Substance abuse

 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
 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

 The evidence about treatment comes mostly from studies done in high-income countries
 Few trials have been done in middle- or lowincome countries
 Less awareness of health risks
 Fewer have tried to quit and failed
 Biology is relatively constant
 Cultural context varies by country

SMOKING CESSATION METHODS
2008 US Public Health Service Guidelines
 Effective treatments
 Counseling
 Pharmacotherapy
 Combination better than either one alone
 More is better but brief intervention works
 Treating tobacco is highly cost-effective

 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

 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

 Definition
Proactive multi-session counseling by phone
 Advantages
Convenience
Privacy
 Effective
(pooled OR 1.4, 95% CI 1.3-1.6)*
 Quitlines can also provide medication
Facilitate access to medications
Strategy for promoting calls to a quitline
*Stead LF et al. Tobacco Control 2007;16(suppl 1):i3

PHARMACOTHERAPY
1 st Line 2008 US Public Health Service Guidelines
 Nicotine replacement



Skin patch
Gum
Oral inhaler
OR
1.9
1.5
2.1
 Nasal spray
2.3
 Lozenge
2.0
 Bupropion SR
(Zyban,Wellbutrin SR) 2.0
 Varenicline
(Chantix/Champix) 3.1

Cigarettes vs. Nicotine Replacement Products
12
10
8
6
4
2
0
18
16
14
0 10 20 30 40 50 60 70 80 90 100 110 120
Time post administration (min)
Cigarette (1-2 mg)
Nasal spray (1 mg)
Gum (4 mg)
Patch (21 mg)

NICOTINE REPLACEMENT
Long-acting, slow onset → skin patch



Constant nicotine level to avoid withdrawal
Simplest to use, best compliance
User has no control of dose
Short-acting
Intermediate onset → oral (gum, lozenge, inhaler)
More rapid onset → nasal (spray)


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

(Zyban, Wellbutrin SR)

Doubles cessation rate independent of its antidepressant effect

Quit rates higher if add counseling

Reduces post-cessation weight gain

Reduces seizure threshold
(risk: 1/1000)

NH
N
N

Binds selectively to the α4β2 nicotinic receptor, which mediates nicotine dependence

Dual mechanism of action
 Partial agonist
Stimulates receptor to treat craving, withdrawal

Antagonist
Prevents nicotine from binding to the receptor →
Blocks reward, reinforcement of smoking

Varenicline efficacy across studies
Continuous Abstinence Rates (Weeks 9 –52)
25
OR: 3.14
(95% CI: 1.93 – 5.11) p < 0.0001
OR 4.04
(95% CI, 2.13, 7.67) p < 0.001
20 19.2
18.6
OR 2.86
(95% CI,1.72, 4.11) p < 0.001
22.4
Varenicline
Placebo
15
9.3
10
7.2
5.6
5
0 n = 355 n = 359
Stable CVD 1 n = 248 n = 251
COPD 2 n = 344 n = 341
Healthy smokers 3
1 Rigotti et al, Circulation 2010; 2 Tashkin D et al. Chest 2010 .
3 Gonzales et al ., JAMA 2006; Jorenby et al ., JAMA 2006.

July 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 …”

The 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.

Cohort 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

My 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

Meta-analysis for 2008 USPHS Guideline
Drug
Nicotine patch
Other nicotine products or bupropion
Varenicline
Combinations
Long-term patch + gum or nasal spray
Patch + bupropion SR
Estimated OR (95% CI)
1.0 (reference)
Not significantly different from nicotine patch
1.6 (1.3-2.0)
1.9 (1.3-2.7)
1.3 (1.0-1.8)

CO-Confirmed 4-Wk Continuous Quit Rates - Wks 9 – 12
100
60
OR=3.91
*
(95% CI 2.74, 5.59
)
OR=1.96
*
(95% CI 1.42, 2.72)
44.4
OR=3.85
*
(95% CI 2.69, 5.50)
OR=1.89
*
(95% CI 1.37, 2.61)
44.0
40
29.5
30.0
20
17.7
17.7
0
N=349 N=329 N=344 N=343 N=340
Study I
Varenicline Zyban Placebo
Study II
* p<0.0001 Jorenby et al, Gonzales et al, JAMA, July 5, 2006
N=340

Open label randomized controlled trial
(5 countries, n= 746)
Varenicline NRT
60
50
40
30
20
56
43
10
0
Weeks 9-12
End of treatment
OR 1.70 (1.26-2.28)
Aubin HJ. Thorax 2008
26
20
Weeks 9-52
Continuous abstinence
OR 1.40 (0.99-1.99)

Piper, 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

(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 MODEL
2000 U.S. Public Health Service Guidelines
 ASK all patients about smoking


ADVISE
ASSESS all smokers to quit smoker’s readiness to quit
 ASSIST smokers to quit
 ARRANGE follow-up care

5A BRIEF COUNSELING MODEL
2000 U.S. Public Health Service Guidelines
 ASK
 ADVISE
 ASSESS
 ASSIST
 ARRANGE
Core physician role

5A BRIEF COUNSELING MODEL
2000 U.S. Public Health Service Guidelines
 ASK
 ADVISE
 ASSESS
 ASSIST
 ARRANGE
Done by office staff (‘vital sign’)
Core physician role

5A BRIEF COUNSELING MODEL
2000 U.S. Public Health Service Guidelines
 ASK
 ADVISE
 ASSESS
Done by office staff
Core physician role
 ASSIST Connect to office or community
 ARRANGE supports (clinics, quit lines,…)

 A problem in many countries
 Health professionals act as role models
 Clinicians who smoke are less likely to counsel patients who smoke
 Treatment strategies must include cessation programs for health care professionals and students

SMOKING CESSATION METHODS
2008 US Public Health Service Guidelines
 Effective treatments
 Counseling
 Pharmacotherapy
 Combination better than either one alone
 More is better but brief intervention works
 Treating tobacco is highly cost-effective

World 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