Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging

The proposed research will provide significant new gender-specific information of scientific and clinical relevance on the function of the mu-opioid system in nicotine dependence and therapeutic effectiveness of nicotine replacement therapy (NRT). The studies will help to explain the differences in the prevalence of smoking in men and women, sex-specific differences in nicotine craving and withdrawal as well as the poorer therapeutic response to NRT. This work may pave the way to the design of improved pharmacotherapies that can more effectively target the endogenous opioid system in the treatment of nicotine dependence.

Study Overview

• Status: Completed
• Conditions: Nicotine Dependence
• Intervention / Treatment: Drug: placebo; Drug: Nicotine patch - transdermal

Detailed Description

While smoking prevalence has declined for both men and women over the last two decades, rates among women have shown a much shallower decrease and, in recent years, prevalence of cigarette initiation has been higher for girls than boys. Smoking among women of child-bearing age has significant negative health consequences for mother and child, increasing fetal and infant morbidity and mortality. Women are both less likely to initiate a quit attempt and more likely to relapse if these women do quit. Nicotine replacement therapy (NRT), still the most widely used smoking treatment intervention in the United States, is less effective for women compared with men, and women report less craving reduction on NRT. The endogenous opioid system is involved in smoking initiation, nicotine craving and reward as well as nicotine withdrawal symptoms. Interestingly, research suggests that sexual dimorphic features of the endogenous mu-opioid system may in part explain gender differences in nicotine effects. To better understand the role of the mu-opioid system in poorer NRT responses in women, this proposal will examine NRT effects on mu opioid receptor binding potential (MOR BP) in female compared to male smokers during active versus placebo NRT. Specifically, nicotine dependent women and men in active smoking status will undergo PET imaging for MOR BP measurement using 11C-carfentanil. Following baseline PET measurement in active smoking (scan 1), smokers will be randomized to active or placebo nicotine replacement therapy ((A-NRT or P-NRT); 72 hours later, a second scan will be obtained. As a reference group, demographically-matched women and men who have never smoked will undergo two scans as well. Behavioral measurements of nicotine reward, craving and withdrawal will be obtained repeatedly across the protocol. The proposed research will provide significant new, gender-specific information of scientific and clinical relevance on the function of the mu-opioid system in nicotine dependence and therapeutic effectiveness of nicotine replacement therapy.

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 21 - 60 years old
• must meet DSM-IV criteria for nicotine dependence and be actively smoking

Exclusion Criteria: subjects must meet study guidelines for medical and mental health status.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nicotine patch - transdermal; 21 mg nicotine patch	Drug: Nicotine patch - transdermal; 21 mg patch; Other Names: Nicotine Replacement Therapy (NRT)
Placebo Comparator: Placebo NRT; Matching placebo patch	Drug: placebo
No Intervention: Healthy non-smoker comparison; Demographically-matched women and men who have never smoked

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mu-opioid Receptor Binding Potential (BP) Between Baseline and Post-patch Scans	BP provides an estimate of the product of the density of available receptors (Bmax' or the receptor density Bmax less those occupied by endogenous transmitters) and the affinity [1/equilibrium dissociation constant (KD)]. We use reference tissue graphical analysis (RTGA) to obtain regional BP values using occipital lobe as a reference region. Negative BP change means means a decrease in the BP and positive BP change means an increase in the BP.	90 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relationship Between Change in Mu-opioid Receptor Binding Potential and Visual Analog Craving Scale Score	Regression measure (β) between change in mu-opioid receptor binding potential between baseline scan and post-treatment scan in the left amygdala and mean Craving Visual Analog Scale score on Days 2 - 4 of the Clinical Research Unit stay. Craving visual analog scale ranges from 0 (not at all) to 20 (worst ever).	72 hours
Relationship Between Change in Mu-opioid Receptor Binding Potential and Minnesota Nicotine Withdrawal Scale Score	Regression measure (β) between change in mu-opioid receptor binding potential between baseline scan and post-treatment scan and mean Minnesota Nicotine Withdrawal Scale (MNWS) score on Days 2 - 4 of the Clinical Research Unit stay. The MNWS is a self-report measure that consists of 14 nicotine withdrawal symptoms each rated on a 0 - 4 response scale for severity over the past 24 hours. Higher scores are indicative of greater nicotine withdrawal severity.	72 hours

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Mary E McCaul, Ph.D., Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: August 10, 2012
• First Submitted That Met QC Criteria: August 13, 2012
• First Posted (Estimate): August 14, 2012

Study Record Updates

• Last Update Posted (Actual): May 9, 2019
• Last Update Submitted That Met QC Criteria: April 18, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: smoking; nicotine replacement therapy; positron emission tomography; Nicotine dependence; cigarette
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: NA_00036996; R01DA026823 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO