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.

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

• “Urges” FDA to foster innovation in tobacco dependence treatment & to consider “initiation”, “dependence”, “cessation” & “population effects” in tobacco regulation

2

TWO psychiatric disorders TWO psychiatric disorders are related to tobacco useare related to tobacco use

DependenceDependence:: addictive use resulting from tobacco/nicotine exposure

WithdrawalWithdrawal: Symptoms are causedby untreated cessation

How can I deal with giving up smokingwhen its impairing my ability to work,my performance, my reputation?I thought giving up smoking was supposedto make my life better. It’s worse!

Cessation precipitates withdrawal –a disorder in its own right

Nicotine Withdrawal is Associated WithNicotine Withdrawal is Associated With Brain DysfunctionBrain Dysfunction

1.1. InsomniaInsomnia2.2. Depressed moodDepressed mood3.3. Irritability, angerIrritability, anger4.4. AnxietyAnxiety5.5. Difficulty concentratingDifficulty concentrating

a.k.a. mental acuity & cognitiona.k.a. mental acuity & cognition6.6. RestlessnessRestlessness7.7. Decreased heart rateDecreased heart rate8.8. Appetite & weight gainAppetite & weight gain

•Taste•Smell•Sight

Additives (sensory)

Additives (sensory)

•Acetaldehyde•Chocolate•Levulinic acid•DAP•Menthol? •Dose modulators

•Speed of delivery•Ammonia•pH•Ventilation

Sensory StimuliSensory Stimuli

NicotineNicotine

•Lung Exposure•Direct effect of compounds•Particle size•Freebase fraction 6

Tobacco Delivered Nicotine: More than Just Nicotine

MOA inhibition in cigarette smokers (Fowler et al., 1996)

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Treatment

Tobacco Use Trajectory: How Treatment Fits

Treatment

NIDA CTN StudiesReid 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 StudiesSmoking 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 SupportedResearch 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

•Saul Shiffman, U of Pittsburg/Pinney Assoc

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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 NicotineMetabolism

15.617.6

22.5

27.0

0

10

20

30

Nic

oti

ne

Cle

ara

nc

e

(ml/

min

/kg

)

Men Women(no OCP)

Women(+ OCP)

PregnantWomen

All Groups Significantly Different from One Another

JPET 2002; 301:594CPT 2006; 79:480

Pretreatment Biomarker of Nicotine Metabolism Rate Predicts Therapeutic Response to Nicotine Patch

% Quit

slow Fast metabolism

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

Patterson et al., Clinical Pharmacology & Therapeutics, 2008

% Quit

Pretreatment Biomarker of Nicotine Metabolism Rate Predicts Therapeutic Response to Nicotine Patch

Slow Fast metabolism

•Decreased quit rates also observed with placebo

•Increased liability to relapse in fast metabolizers is reversed by bupropion

•Fast metabolizers are candidates for bupropion

OR=4.59 (1.5-13.6), p=.006

Extended Transdermal Nicotine Therapy Reduces Relapse

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)

Schnoll et al., Annals of Internal Med, 2010

Varenicline Increases Working Memory-related 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.

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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.

•  

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Diving in Uncharted Waters: Smoking Cessation in Chronic

Disease PopulationsCancer 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

22

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

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 tobacco industry actions to undermine abstinence

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CTN Studies Should Build on A Strong Science Foundation, e.g., Animal Models provide the building blocks to understand

addiction and develop treatment

25

0

25

50

75

100

125

150

175

200

225

Re

spo

nse

s

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Day

Males

Females

FR2FR1 FR5

26

Nicotine self-administration in rats Potential sex differences

(Donny et al., 2000)

0

25

50

75

100

125

150

175

200

225

Act

ive

Re

spo

nse

s

0 5 10 15 20 25

Day

Saline + No Cues

Saline + Cues

Nicotine + No Cues

Nicotine + Cues

FR1 FR2 FR5

27

Acquisition: Effects of environmental stimuli

(Donny et al., 2002)

Nicotine + Cues

Tobacco Dependence Treatment:One Size Does NOT Fit All!

Further and Faster with Treatments that Meet Diverse Needs

OR ---Stick withone sizefits all

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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, MPHSenior Medical Advisor, Center for Tobacco Products

FDAApril 8, 2010

33 33

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

34 34

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.”

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

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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.

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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.

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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

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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

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40 40

NIDA CTN could help FDA develop new use(s) and label within 3 years

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

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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 CTN42