Jack E. Henningfield*
Johns Hopkins Medical School
and Pinney Associates,
(NIDA National Drug Abuse Treatment Clinical Trials Network
10th Anniversary Meeting, Albuquerque, NM 21 April 2010)
*I consult to GlaxoSmithKline on smoking cessation medications, and to other pharmaceutical companies on
abuse liability, post marketing surveillance and risk management. I also serve as an expert witness against
the tobacco industry and share an interest in patents on a potential oral nicotine delivery system.
Overview
• Tobacco addiction perspectives
• CTN progress in tobacco treatment
• Informal survey of tobacco treatment
– Advances
– Scientific findings
– Treatment needs
• Major challenges and opportunities for CTN
– Tobacco industry works to undermine abstinence
– Tobacco Control Act & FDA Tobacco Regulation
2
• “Urges” FDA to foster innovation in tobacco dependence
treatment & to consider “initiation”, “dependence”,
“cessation” & “population effects” in tobacco regulation
TWO psychiatric disorders
are related to tobacco use
Dependence: addictive use resulting
from tobacco/nicotine exposure
Withdrawal: Symptoms are caused
by untreated cessation
Cessation precipitates withdrawal –
a disorder in its own right
How can I deal with giving up smoking
when its impairing my ability to work,
my performance, my reputation?
I thought giving up smoking was supposed
to make my life better. It’s worse!
Nicotine Withdrawal is Associated With
Brain Dysfunction
1. Insomnia
2. Depressed mood
3. Irritability, anger
4. Anxiety
5. Difficulty concentrating
a.k.a. mental acuity & cognition
6. Restlessness
7. Decreased heart rate
8. Appetite & weight gain
Tobacco Delivered Nicotine: More than Just Nicotine
Additives
(sensory)
•Acetaldehyde
•Chocolate
•Levulinic acid
•DAP
•Menthol?
•Lung Exposure
•Direct effect of
compounds
•Particle size
•Freebase
fraction
•Taste
•Smell
•Sight
•Dose modulators
•Speed of delivery
•Ammonia
•pH
•Ventilation
6
MOA inhibition in cigarette smokers
(Fowler et al., 1996)
7
Tobacco Use
Trajectory:
How Treatment
Fits
Treatment
Treatment
NIDA CTN Studies
Reid et al. JSAT 2009
• Smoking cessation treatment in community-based
rehab
– 5 Methadone clinics
– 2 Drug and alcohol clinics
• Compare TAU vs Smoking Cessation adjunct to
other Substance Abuse treatment (Counseling +
Patch)
• Significant cessation benefit + 75% reduction in
continuing smokers
• No adverse impact on Rx for other Substance
Abuse
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NIDA CTN Studies
Smoking and ADHD Treatment
• CTN-0029 -- A Pilot Study of Concerta® in Initiating
and Maintaining Abstinence in Smokers with ADHD
• Question: Would transdermal methylphenidate
(Concerta) combined with nicotine patch increase
smoking cessation in smokers with ADHD compared
to nicotine patch alone?
• The first study did not find a benefit but a second
study is underway.
• JEH NOTE: This study had to be done and the study
was important but it is unlikely that it would have
been done but for CTN
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Informal Survey of NIDA Supported
Research Leaders: NIDA Treatment
Support is having a Major Impact on
Public Health
•Neal Benowitz, U of Calif San Francisco
•Michael Fiore & Timothy Baker, U of
Wisconsin
•Ellen Gritz, MD Anderson Hospital, TX
•Caryn Lerman, U of Pennsylvania
•Raymond Niaura, Brown/Legacy-Schroeder
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•Saul Shiffman, U of Pittsburg/Pinney Assoc
Clinical Pharmacology of Nicotine:
Implications for Understanding,
Preventing and Treating Tobacco
Addiction
Neal L. Benowitz, MD
Professor of Medicine
University of California, San Francisco
Interagency Committee on Smoking and Health
December 8, 2008
Biology of Nicotine Addiction
Sex Differences in Rate of Nicotine
Metabolism
27.0
Nicotine Clearance
(ml/min/kg)
30
22.5
20
15.6
17.6
10
0
Men
Women
(no OCP)
Women
(+ OCP)
Pregnant
Women
All Groups Significantly Different from One Another
JPET 2002; 301:594
Pretreatment Biomarker of Nicotine Metabolism Rate
Predicts Therapeutic Response to Nicotine Patch
% Quit
OR=.72 (.57-.91) p=006)
•30% reduction in quit rates
with increasing metabolic
rate
•Reduction in plasma
nicotine levels from patch
•Findings replicated in
independent clinical trial
slow
Fast metabolism
., Clinical Pharmacology &
Therapeutics, 2006
Pretreatment Biomarker of Nicotine Metabolism Rate
Predicts Therapeutic Response to Nicotine Patch
% Quit
OR=4.59 (1.5-13.6), p=.006
•Decreased quit rates
also observed with
placebo
•Increased liability to
relapse in fast
metabolizers is
reversed by bupropion
•Fast metabolizers are
candidates for
bupropion
Slow
Fast metabolism
Patterson et al., Clinical Pharmacology & Therapeutics, 2008
Extended Transdermal Nicotine
Therapy Reduces Relapse
Schnoll et al., Annals of Internal Med, 2010
HR = 0.42 [0.26 - 0.67], p = 0.0003 (by week 24)
HR = 2.47 [0.52 – 11.70], p = 0.43 (week 25-28, after treatment
stopped)
Varenicline Increases Working Memoryrelated Brain Activation
(n=25 within subject analysis)
Treatment by memory load interaction (Wald(1)=10.45, p=0.005)
Loughead et al, Biological Psychiatry, in press
Michael Fiore, Timothy Baker et al. 1
•CLINICAL PRACTICE GUIDELINES
•Treatment Evaluation
•Piper, Smith, Schlam, Fiore, et al. (in press). A randomized placebo-controlled
clinical trial of five smoking cessation pharmacotherapies. Archives of General
Psychiatry.
Recruiting smokers into Primary Care Based Treatment
•Smith, McCarthy, Japuntich, Christiansen et al. effectiveness trial of 5 smoking
cessation pharmacotherapies in primary care clinics. Arch Intern Med, Dec
14/28, 2009; 169: 2148 - 2155.
Mechanisms and mediators of treatment effectiveness
Piper, Federman, McCarthy, Bolt, et al. (2008). Using mediational models to
explore the nature of tobacco motivation and tobacco treatment effects. Journal
of Abnormal Psychology, 117(1), 94-105.
1
Michael Fiore, Timothy Baker et al. 2
• Special populations
• Piper, Smith, Fleming, Bittrich, et al. (in press). Psychiatric disorders in
smokers seeking treatment for tobacco dependence: prevalence and
relations with tobacco dependence and cessation. Journal of Consulting
and Clinical Psychology.
• Smith, Jorenby, Leischow, Nides, et al. (2003). Targeting smokers at
increased risk for relapse: Treating women and those with a history of
depression. Nicotine & Tobacco Research, 5, 99-109.
• Tobacco withdrawal and relapse: treating
Withdrawal should be a key treatment target
• Piasecki, Jorenby, Fiore, & Baker, (2003). Smoking withdrawal dynamics:
I. Abstinence distress in lapsers and abstainers. Journal of Abnormal
Psychology, 112, 3-13.
•
2
Diving in Uncharted Waters:
Smoking Cessation in Chronic
Disease Populations
Cancer and HIV/AIDS
Ellen R. Gritz, Ph.D.
Olla S. Stribling Distinguished Chair
for Cancer Research
Professor and Chair
Department of Behavioral Science
SRNT Annual Meeting
Epidemiology and Public Health Lecture
Thursday, February 25, 2010
21
Major NIDA Rx Contribution:
CLINICAL PRACTICE GUIDELINES
Research Needs: Comorbidities
• Gather more definitive data on the adverse
effects of continued smoking on treatment and
survival related to comorbidities
• Establish a clinical trials data base to monitor
smoking from trial registration, through
treatment and follow-up to survival endpoint
• Establish optimal treatment regimens and
timing of treatment related to comorbidities
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Research Needs: HIV/AIDS &
Tobacco Use
• More data needed on adverse effects of smoking
– Monitoring of tobacco use
– Clinical trial databases
• Disparities
– Targeting high-risk populations and tailoring to
special needs
• Integrate with other HIV treatment priorities
– Medication adherence
– Decreasing CVD risk
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Henningfield, Shiffman, Ferguson & Gritz
Pharmacology & Therapeutics 2009
•Public health rationale
–Rx is cost effective and a “give-back” to society for supporting research
–Improve prognosis for co-morbid diseases (psychiatric, cancer)
•Treatment works
–Real world effectiveness demonstrated but masked in some studies in
which the most addicted are assessed for success
–“Off label” but guideline approved approaches can increase reach
•Special population needs: Ethnic, youth & gender
•New opportunities for treatment advance flow from
advances in neurobiology, understanding of product
influences on addictive process, understanding
2tobacco industry actions to undermine abstinence
CTN Studies Should Build on A Strong
Science Foundation, e.g., Animal Models
provide the building blocks to understand
addiction and develop treatment
25
Nicotine self-administration in rats
Potential sex differences
(Donny et al., 2000)
225
Females
200
Males
Responses
175
150
125
100
75
50
25
0
1 2
3 4
FR1
5 6
7
8 9 10 11 12 13 14 15 16 17 18 19 20
FR2
FR5
Day
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Acquisition: Effects of
environmental stimuli
(Donny et al., 2002)
Nicotine + Cues
27
Tobacco Dependence Treatment:
One Size Does NOT Fit All!
Further and Faster with Treatments
that Meet Diverse Needs
OR --Stick with
one size
fits all
Family Smoking Prevention and
Tobacco Control Act (P.L. 111-31)
ABUSE LIABLITY AND CONSUMER APPEAL OF TOBACCO PRODUCTS:
SCIENCE AND FUTURE DIRECTIONS
Corinne G. Husten, MD, MPH
Senior Medical Advisor, Center for Tobacco Products
FDA
April 8, 2010
32
FDA Tobacco Control Goals
• Prevent youth tobacco use
• Help adults who use tobacco to quit
• Promote public understanding of contents
and consequences of use of tobacco
products
• Develop science base and begin meaningful
product regulation to reduce the toll of
tobacco-related disease, disability, and death
33
33
Scope of FDA's Authority Under
the Tobacco Control Act
• The Act gives FDA authority to regulate
tobacco products, which are products
made or derived from tobacco intended for
human consumption.
• The Act recognized FDA as the “primary
Federal regulatory authority with respect to
the manufacture, marketing and
distribution of tobacco products.”
34
34
SEC. 918. DRUG PRODUCTS USED TO
TREAT TOBACCO DEPENDENCE
“(1) …..consider designating products for
smoking cessation …. as fast track research
and approval products …;
‘‘(2) consider approving the extended use of
nicotine replacement products ….. for the
treatment of tobacco dependence; and
‘‘(3) …consider the evidence for additional
indications for nicotine replacement products,
such as for craving relief or relapse
prevention
3
SEC. 918 – continued #2
‘‘(b) REPORT ON INNOVATIVE PRODUCTS.—
(1) IN GENERAL.—Not later than 3 years… [ from
June 22, 2009]… the Secretary… shall submit to the
Congress a report that examines how best to
regulate, promote, and encourage the development
of innovative products and treatments …. that best
protects and promotes the public health—
[Including]
(A) total abstinence from tobacco use;
(B) reductions in consumption of tobacco; and
(C) reductions in the harm associated with continued
tobacco use.
3
SEC. 918 – continued #3
‘‘(2) RECOMMENDATIONS.—
The report under paragraph (1) shall include the
recommendations of the Secretary on how the
Food and Drug Administration should
coordinate and facilitate the exchange of
information on such innovative products and
treatments among relevant offices and
centers within the Administration and within
the National Institutes of Health, the
Centers for Disease Control and Prevention,
and other relevant agencies.
3
What Can CTN Do To Further Advance
Tobacco Addiction Treatment? #1
•Recognize that many past innovations in tobacco
treatment have come from NIDA research and not
from pharmaceutical companies or other treatment
developers
–innovations in how to use NRT
–Innovations in combined behavioral and pharm Rx
–Innovations such as combination therapy
•Note that the USPHS Clinical Practice Guidelines
go beyond labeling (labeling needs to be
harmonized with the guidelines by FDA), e.g.,
combination NRT use, extended use, pretreatment
& withdrawal treatment efficacy
3
What Can CTN Do To Further Advance
Tobacco Addiction Treatment? #2
•Go where pharmaceutical companies are reluctant
–E.g., innovative claims and applications
–Special populations, including substance abusers
•Explore opportunities and needs with FDA, CDC and
other federal agencies, especially but not only in DHHS
•Investigate potential advances in effectiveness by
product and how products are used
•Investigate potential synergies with ongoing substance
abuse treatment
3
NIDA CTN could help FDA develop
new use(s) and label within 3 years
New NRT
Use &
Label
40
40
Elements of CTN to Better Move Forward
(adapted from Mitch Greenlick):
•Community participation in research
•Multi-center capacity
•Potential for comparative effectiveness research
•Ability to move policy transformation
•Trained researchers and research trained treatment
personnel
From Kathleen Carroll:
Powerful emerging science base methodologies for
development and empirical validation of behavioral
therapies
4
The NIDA CTN has emerged as
a powerful asset to advancing
the science of addiction
treatment and as an example of
research in service to society
and the advancement of public
health.
Thank you CTN
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