Effects of Nicotine on Brain Opioid Receptors

April 9, 2019 updated by: University of Pennsylvania

Functional Characterization of OPRM1 A118G in Nicotine Dependence: IV Nicotine Study

A substantial body of evidence implicates the endogenous opioid system, and the mu opioid receptor (MOR) in particular, in the reinforcing effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the mu opioid receptor gene (OPRM1 Asp40) is associated with the ability to quit smoking, as well as nicotine reward and withdrawal symptoms. However, the precise mechanism through which this SNP influences nicotine dependence remains unresolved. This positron emission tomography (PET) study will examine whether this OPRM1 SNP alters MOR binding in response to nicotine in human smokers. Specifically, we will use [11 C]carfentanil PET imaging to assess the effects of intravenous (IV) nicotine versus saline (within-subject) on MOR binding potential in 24 chronic smokers genotyped prospectively and stratified by OPRM1 genotype.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

The study uses a mixed factorial design with one between subject factor (OPRM1 genotype_: Asn40/Asn40 vs. Asn40/Asp40 or Asp40/Asp40) and one within-subject factor (IV nicotine vs. IV saline) to examine genotype by nicotine interactions on MOR binding potential (BP_ND ) assessed via PET imaging with [11 C]carfentanil. Twenty-four smokers (12 male, 12 female; 12 from each genotype group) will participate in two 90 minute PET sessions following overnight (14-hours) abstinence from nicotine. Genotype groups will be matched for age and sex . One week prior to the first PET session, there will be an adaptation session during which participants will receive IV saline followed 30 minutes later by IV nicotine (1 mg/70 kg) to ensure that they tolerate the procedure. In the PET sessions, participants will receive either IV nicotine (1 mg/70 kg) or saline (within-subject, double blind, counterbalanced). The primary outcomes will be BP_ND in ventral striatum and anterior cingulate cortex (ACC). Normally menstruating women will be scheduled for their sessions during the early follicular phase. Sessions will be separated by 1 month for all participants to reduce variability in MOR binding due to hormonal changes during females menstrual cycles. Participants will complete subjective measures of nicotine reward and craving at each session.

Study Type

Observational

Enrollment (Actual)

15

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

24 adult, non-treatment seeking smokers of European ancestry, reporting consumption of ≥10 cigarettes per day for at least the past 6 months.

Description

Inclusion Criteria:

  • Non-treatment seeking smokers of European ancestry
  • Between 18 and 50 years old
  • Smoking at least 10 cigarettes per day for at least the past 6 months
  • Able to provide informed consent
  • Fluent, English-speaking
  • Weight ≤ 300 lbs.

Exclusion Criteria:

  • Current enrollment or plans to enroll in a smoking cessation program, or use other smoking cessation medications in the next 2 months
  • Provide a Carbon Monoxide reading of ≤10 ppm at Medical screening.
  • History of substance abuse and/or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants)
  • Current alcohol consumption that exceeds 25 standard drinks/week
  • Providing a breath alcohol concentration (BAC) reading of > 0.01 at any session.
  • Women who are pregnant, planning a pregnancy, or lactating; all female subjects shall undergo a urine pregnancy test at each session
  • Women of child-bearing age must agree in writing to use an approved method of contraception
  • History or current diagnosis of psychosis, major current depression or bipolar disorder, ADHD, schizophrenia, or any Axis 1 disorder as identified by the MINI
  • Serious or unstable disease within the past 6 months (e.g., cancer [except melanoma], heart disease, HIV)
  • History of epilepsy or a seizure disorder
  • History or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia (>100 beats/minute); history or current diagnosis of COPD, cardiovascular disease (stroke, angina, coronary heart disease), heart attack in the last 6 months, uncontrolled hypertension (SBP>150 or DBP>90)
  • Any medical or neurological condition that might interfere with the distribution of the radiotracer as determined by the study MD
  • Current or past use (within past 12 months) of any medications containing naltrexone or other MOR antagonists (e.g., Revia, Trexan)
  • Current use or recent discontinuation (within last 14-days) of the following medications
  • Any form of smoking cessation medication (Zyban, Wellbutrin, Wellbutrin SR, Chantix, NRT)
  • Recent (within last 2 weeks) or planned use of psychotropic medications (anti-psychotics, anti-depressants (tricyclic, SSRI, MAOI), anti-anxiety or panic medications, and stimulants (e.g., Provigil, Ritalin), and opiate-containing medications for chronic pain
  • Allergic response to any form of opioids or naloxone
  • Participants shall be instructed to refrain from using any study prohibited drugs (note - participants are allowed to take prescription medicines not in the exclusion list) throughout their participation in the study.
  • Self-reported history of head trauma or prior seizure, brain (or CNS) tumor
  • Self-reported history of claustrophobia (contraindicated for PET)
  • Inability to complete the baseline study procedures within four hours and/or correctly, as determined by the principal investigator.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
OPRM1 A118G AA genotype
Individuals with the AA genotype at the OPRM1 A118G polymorphism.
Drug: Nicotine
Participants shall receive an intravenous injection of nicotine during their practice session and one of their PET scans (double-blind). The dose of IV nicotine will be 1mg/70kg and the maximum dose that shall be injected is 1.2mg.
OPRM1 A118G AG or GG genotype
Individuals with the */G allele at the OPRM1 A118G polymorphism
Drug: Nicotine
Participants shall receive an intravenous injection of nicotine during their practice session and one of their PET scans (double-blind). The dose of IV nicotine will be 1mg/70kg and the maximum dose that shall be injected is 1.2mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
MOR binding potential
Time Frame: 5/31/2011
5/31/2011

Secondary Outcome Measures

Outcome Measure
Time Frame
Subjective reward/liking and cravings to smoke
Time Frame: 5/31/2011
5/31/2011

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pennsylvania

Collaborators

National Institute on Drug Abuse (NIDA)

Investigators

  • Principal Investigator: Caryn Lerman, PhD, University of Pennsylvania

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2010

Primary Completion (Actual)

March 1, 2011

Study Completion (Actual)

March 1, 2011

Study Registration Dates

First Submitted

December 24, 2009

First Submitted That Met QC Criteria

December 28, 2009

First Posted (Estimate)

December 29, 2009

Study Record Updates

Last Update Posted (Actual)

April 11, 2019

Last Update Submitted That Met QC Criteria

April 9, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 809187
  • R21DA027066 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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