Effects of Nicotine on Brain Opioid Receptors

This study has been terminated.
(Issues & unreliability with [11C]Carfentanil production)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01040338
First received: December 24, 2009
Last updated: July 18, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention
Nicotine Dependence
Drug: Nicotine

Study Type: Observational
Study Design: Observational Model: Case-Crossover
Time Perspective: Prospective
Official Title: Functional Characterization of OPRM1 A118G in Nicotine Dependence: IV Nicotine Study

Resource links provided by NLM:


Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • MOR binding potential [ Time Frame: 5/31/2011 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Subjective reward/liking and cravings to smoke [ Time Frame: 5/31/2011 ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

The samples that shall be collected for this study are as follows:

  1. A 2ml saliva sample will be collected for DNA extraction using the Oragene™ kit at the Medical screening session for genetic analyses.
  2. An additional saliva sample (~ 5ml) will be also be collected at Medical screening and will be used to analyze baseline nicotine metabolites (i.e., cotinine and 3-hydroxycotinine).
  3. All participants will provide two tubes of blood (10 ml each) to measure plasma estradiol & cortisol levels before each PET scanning session. They will also provide two tubes of blood (10 ml each) at the end of the scan to measure plasma nicotine and cortisol levels.

Enrollment: 15
Study Start Date: February 2010
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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.
Other Name: Nicotine
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.
Other Name: Nicotine

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.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.

Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01040338

Locations
United States, Pennsylvania
Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Investigators
Principal Investigator: Caryn Lerman, PhD University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01040338     History of Changes
Other Study ID Numbers: 809187, R21DA027066
Study First Received: December 24, 2009
Last Updated: July 18, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pennsylvania:
Smoking
Tobacco
Nicotine
Dependence
Genetics

Additional relevant MeSH terms:
Tobacco Use Disorder
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Nicotine
Autonomic Agents
Cholinergic Agents
Cholinergic Agonists
Ganglionic Stimulants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nicotinic Agonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014