Effects of Nicotine on Brain Opioid Receptors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01040338
Recruitment Status : Terminated (Issues & unreliability with [11C]Carfentanil production)
First Posted : December 29, 2009
Last Update Posted : July 19, 2013
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
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 or disease Intervention/treatment
Nicotine Dependence Drug: 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.

Study Type : Observational
Actual Enrollment : 15 participants
Observational Model: Case-Crossover
Time Perspective: Prospective
Official Title: Functional Characterization of OPRM1 A118G in Nicotine Dependence: IV Nicotine Study
Study Start Date : February 2010
Actual Primary Completion Date : March 2011
Actual Study Completion Date : March 2011

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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.

Primary Outcome Measures :
  1. MOR binding potential [ Time Frame: 5/31/2011 ]

Secondary Outcome Measures :
  1. Subjective reward/liking and cravings to smoke [ Time Frame: 5/31/2011 ]

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.

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01040338

United States, Pennsylvania
Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
National Institute on Drug Abuse (NIDA)
Principal Investigator: Caryn Lerman, PhD University of Pennsylvania

Additional Information:
Responsible Party: University of Pennsylvania Identifier: NCT01040338     History of Changes
Other Study ID Numbers: 809187
R21DA027066 ( U.S. NIH Grant/Contract )
First Posted: December 29, 2009    Key Record Dates
Last Update Posted: July 19, 2013
Last Verified: July 2013

Keywords provided by University of Pennsylvania:

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