Mu Opioid Receptor Genes, Remifentanil, and Pain Sensitivity

This study is currently recruiting participants.
Verified November 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
ClinicalTrials.gov Identifier:
NCT01878006
First received: June 12, 2013
Last updated: March 14, 2014
Last verified: November 2013
  Purpose

Background:

- Small differences in genes may alter responses to drugs. One gene that has different forms is the mu opioid receptor gene. People with one form of this gene are more sensitive to alcohol. People with a different form are sometimes more sensitive to pain. Morphine and other prescription pain pills produce pain relief by acting at the mu opioid receptor. Researchers want to see how well a drug called remifentanil can help determine sensitivity to pain. Remifentanil is a strong but short-acting pain medication that is sometimes used for anesthesia during surgery. The study will test how much the drug causes the pupils to constrict.

Objectives:

- To see if remifentanil can help determine pain sensitivity.

Eligibility:

- Individuals between 21 and 55 years of age who are taking pain pills that were prescribed to treat pain from a medical or dental procedure.

Design:

  • This study has a screening phase and a study phase. The screening phase involves one or two visits of 5 to 6 hours. The study phase is one outpatient visit that will take about 3 hours.
  • Participants will be screened with a medical and psychiatric history and physical exam. They will be asked about drinking and drug-taking history, and any family history of alcoholism or drug abuse. Blood, urine, and breath samples will be collected.
  • During the study session, participants will test their sensitivity by placing one hand in cold water. Pupil diameter will be measured before and after the sensitivity test.
  • After a blood sample is taken, participants will receive the remifentanil. The sensitivity test will be repeated. Final blood samples will be collected. A brief physical exam will also be performed.
  • Participants will stay in the clinic until the effects of the drug have worn off.
  • About 1 week after the study session, participants will have a follow-up phone call.

Condition Intervention Phase
Polymorphism-Genetic
Alcohol Drinking
Alcohol-Related Disorders
Alcoholism
Allelic Frequencies of Genetic Markers
Genetic: OPRM1 AA118
Drug: Morphine
Drug: Placebo
Genetic: OPRM1 GX118
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Official Title: OPRM1 A118G SNP Effect on Striatal Dopamine Response to an IV Opiate

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Differences 11C raclopride displacement in ventral striatum based on genotype for OPRM1 [ Time Frame: immediate ] [ Designated as safety issue: No ]
  • Differences in subjective perceptions of morphine intoxication and opiate effects based on genotype for OPRM1 [ Time Frame: immediate ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Differences in pupillary constriction, respiratory rate, pain response based on genotype for OPRM1 [ Time Frame: immediate ] [ Designated as safety issue: No ]
  • Differences in neuroendocrine measures (ACTH, cortisol) based on genotype for OPRM1 [ Time Frame: Once Analyzed ] [ Designated as safety issue: No ]

Estimated Enrollment: 120
Study Start Date: April 2013
Estimated Study Completion Date: September 2020
Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)
Intervention Details:
    Genetic: OPRM1 AA118
    N/A
    Drug: Morphine
    N/A
    Drug: Placebo
    N/A
    Genetic: OPRM1 GX118
    N/A
Detailed Description:

Objectives

Mesolimbic dopamine (DA) release is a key signal for drug reward, and endogenous opioids are thought to exert their effects in part by modulating the activity of this system. A functional (Micro)-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) has been associated with increased risk for heroin addiction in some studies. This polymorphism has been shown to confer differential pain sensitivity and to alter the release of DA following an alcohol challenge. The objective of this study is to examine the role of the A118G OPRM1 polymorphism for responses to a challenge of an opiate (remifentanil) with regard to psycho-physiological variables measured in the laboratory and for brain dopamine release measured by [11C]raclopride PET.

Study Population

Healthy male participants who have had experience with oral prescription analgesics (e.g., Oxycontin, Vicodin, Percocet, oxycodone) will be recruited for the study. These volunteers will be screened to obtain samples of two groups of subjects: 1) persons homozygous for the major 118A allele (118AA genotype); 2) persons carrying one or two copies of the variant 118G allele (118AG or 118GG genotype, hereafter called 118GX). We will recruit up to 120 participants to obtain 40 completers per genotype for the study.

Design

We will compare the response of these groups to a challenge with morphine given intravenously. Participants will receive a standardized IV challenge of morphine (10.0 mg/70 kg over 1 minute; morphine concentration 2 mg/ml). Pre and post injection measures will be made in two areas: 1) subjective response as measured by standardized questionnaires, and 2) measures of physiological response, including pupil response to light, respiratory rate, oxygen saturation and a pain rating from putting a hand in cold water and blood chemistries. In addition, during this visit, participants will wear the AutoSense mobile physiological monitor; parameters measured by AutoSense include respiration rate, heart rate, heart-rate variability, skin conductance, and activity level. The injection will be repeated in all participants in the PET scanner, once with morphine and once with normal saline. Dopamine release will be assessed by determining the difference between the binding potential for [11C]raclopride, a positron emitter labeled ligand which binds preferentially to D2 receptors during saline administration and its binding potential during morphine administration.

Outcome measures

We hypothesize that 118GX subjects will have significantly different subjective response to the challenge than 118AA subjects as observed in participants receiving alcohol in a similar study (Ramchandani et al. 2011). However, the genotype effect on the response may be opposite from the effect of genotype on the alcohol response. We also hypothesize that the PET studies with [11C]raclopride will show that 118GX subjects have less dopamine release during morphine administration than 118 AA subjects.

  Eligibility

Ages Eligible for Study:   21 Years to 55 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

    1. Male participants between 21-55 years of age.
    2. Good health as determined by medical history, physical exam, EKG and lab tests.
    3. Current non-smokers or light smokers (< 20 cig/week) who can easily abstain from smoking for 1-2 days/week.
    4. Current non-drinkers or social drinkers (< 15 drinks/week, < 5 drinks on any occasion within the last 6 months).
    5. An equal number of final participants will be of OPRM1 118 A/A vs. 118A/G or 118G/G genotype. This means that after the first group (n40) is complete then only participants with the required genotype for the other group will be included.
    6. Prior opiate use, at least one experience with one of the opiates.
    7. Comprehension/fluency with English Language.
    8. Right-handed

EXCLUSION CRITERIA:< TAB>

  1. Current or prior history of any significant disease, including cardiovascular, respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders, or a positive hepatitis or HIV test at screening, disorders that could make administration of an opiate more risky (e.g., asthma, COPD, sleep apnea, or other breathing disorders; liver or kidney disease; thyroid disorder; trouble swallowing, or a blockage in the digestive tract (stomach or intestines); neurologic disorders (e.g., a history of head injury or brain tumor, epilepsy or other seizure disorder, CVA, migraine in treatment, etc.); low blood pressure; hypertension; neuromuscular disorder; gallbladder disease; Addison's disease or other adrenal gland disorders, enlarged prostate, urination problems)
  2. Current Axis-I psychiatric illness.
  3. Current or prior history of any alcohol or drug dependence.
  4. Positive result on urine screen for illicit drugs.
  5. Current chronic prescription or over the counter medications or use of prescription or OTC medications known to interact with dopamine receptors within 2 weeks of the study. Drugs known to inhibit or induce enzymes that metabolize opiates should not be used for 4 weeks prior to the study. These include chlorzoxazone, isoniazid, metronidazole and disulfiram. Cough-and-cold preparations that contain anti-histamines, pain medicines and anti-inflammatory drugs such as aspirin, ibuprofen, acetaminophen, celecoxib and naproxen, will be withheld for at least 72 hours prior to each study session.
  6. Morbid obesity (BMI > 40 kg/m(2))
  7. Previous negative effects of opioid administration
  8. Presence of certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia. Justification: Implanted devices may increase the risk of MRI scanning and/or adversely affect the quality of the data; body morphology may prevent optimal positioning in the scanner and thus affect the quality of the data; participants with claustrophobia may find the MRI scan too unpleasant and may exhibit excess movement that will adversely affect the quality of the data. Assessment tool(s): Prospective participants will fill out an MRI screening questionnaire and undergo an interview with an MR technologist. Questions concerning suitability for scanning will be referred to the Medical Advisory Investigator. Prospective participants will be questioned about symptoms of claustrophobia and placed in the mock scanner during their first visit to assess for possible difficulty tolerating the confinement of the scanner and for ability to fit into the scanner.
  9. Conditions restricting participant s ability to lie flat for up to two hours (such as coagulopathies, superficial or deep vein thrombosis, or musculoskeletal abnormalities). Justification: PET scanning sessions require participants to lie flat on their backs and remain perfectly still for approximately two hours. Therefore, conditions that would make that difficult (e.g. chronic back pain, significant scoliosis) or dangerous (e.g. familial hypercoagulability syndrome, history of thrombosis) will be exclusionary. Assessment tool(s): History and physical examination by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner to assess comfort.
  10. Head injury resulting in unconsciousness for > 5 minutes
  11. Exposure to ionizing radiation from research studies that, in combination with the study tracer, would result in cumulative exposure of > 5 rem within the previous 12 month period.
  12. Self-reported and/or observed signs, symptoms, or diagnosis of Raynaud s or Buerger s disease (e.g., pain in hands or feet at times of rest, during/following cold exposure or stress, any significant color changes in hands or toes). Additionally, medical staff will be present to watch for these symptoms during the actual cold pressor test.
  13. Currently taking medications for heart burn, muscle relaxants orand seizures or currently using respiratory, cardiovascular or anticonvulsant medications that may interfere with the BOLD MRI signal.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01878006

Contacts
Contact: Alane Kimes, Ph.D. (800) 535-8254 akimes@mail.nih.gov
Contact: Markus A Heilig, M.D. (301) 435-9386 mheilig@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
National Institute on Alcohol Abuse and Alcoholism (NIAAA), 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information contact Mathew's Media Group Recruiting    800-535-8254    researchstudies@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Markus A Heilig, M.D. National Institute on Alcohol Abuse and Alcoholism (NIAAA)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
ClinicalTrials.gov Identifier: NCT01878006     History of Changes
Other Study ID Numbers: 130061, 13-AA-0061
Study First Received: June 12, 2013
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Narcotics
Positron Emission Tomograhy
PET Study
Dopamine
Opioid Receptor
Genetic Polymorphisms
Opioid Dependence
OPRM1
Dopamine D2 Receptors
Analgesic

Additional relevant MeSH terms:
Narcotics
Alcohol Drinking
Alcoholism
Alcohol-Related Disorders
Drinking Behavior
Substance-Related Disorders
Mental Disorders
Dopamine
Morphine
Analgesics, Opioid
Cardiotonic Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Analgesics
Sensory System Agents
Central Nervous System Agents
Central Nervous System Depressants

ClinicalTrials.gov processed this record on April 14, 2014