Genetic Effects on Dopamine Response to an Opiate

NCT01878006 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 13006113-AA-0061
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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 the effect of morphine on brain reward and subjective effects. Morphine is a strong but short-acting pain medication that is sometimes used for anesthesia during surgery. Objectives: \- To compare the effect of morphine on brain measures of dopamine release using imaging. Eligibility: \- Individuals between 21 and 55 years of age who have previously taken pain pills 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 consists of 4 study visits. Each study visit will take about 8 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 first study visit, an MRI scan may be performed, questionnaires completed, and a blood sample collected for genetic testing.
• During study visit 2, participants will test their pain sensitivity by placing one hand in cold water. Pupil diameter will be measured after the sensitivity test. After a blood sample is taken, participants will receive the morphine or a salt solution. The sensitivity test and pupil diameter test will be repeated. Final blood samples will be collected. A brief physical exam will also be performed.
• During study visits 3 and 4, participants will receive morphine or a salt solution during a PET scan. Questionnaires to assess subjective effects will be administered. 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 after study visits 2, 3, and 4.
• About 1 week after the study session, participants will have a follow-up phone call.

Conditions

Polymorphism-Genetic; Pain; Addiction

Keywords

Opiate Receptor; Genotype; PET Imaging

Outcome Measures

Primary Outcomes (4)

• 11C Raclopride Binding Potential in Caudate

  Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.

  90 minutes following injection

• 11C Raclopride Binding Potential in Nucleus Accumbens

  Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.

  90 minutes following injection

• 11C Raclopride Binding Potential in Putamen

  Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.

  90 minutes following injection

• 11C Raclopride Binding Potential in Ventral Pallidum

  Binding potential measured using regions-of-interest analysis of PET data. Parametric Binding Potential (BPND) images were obtained using the Simple Reference Tissue Model 2 (SRTM2), with cerebellum as the reference region. BPND is computed in units of mCi/ml reflecting the radioactivity (milliCuries or mCi) per unit volume (milliliters or ml) in specific brain regions. Reduction in raclopride binding is attributed to competition with endogenous dopamine, and has been shown to be proportional to the magnitude of Dopamine (DA) release.

  90 minutes following injection

Secondary Outcomes (4)

• Subjective Perception of Morphine Effect - Feel Drug

  60 minutes following injection

• Subjective Perception of Morphine Effect - Feel High

  60 minutes following injection

• Subjective Perception of Morphine Effect - Like Drug

  60 minutes following injection

• Subjective Perception of Morphine Effect - Want More

  60 minutes following injection

Study Arms (2)

Morphine

EXPERIMENTAL

Morphine injection 10 mg/70kg

Drug: Morphine

Placebo

PLACEBO COMPARATOR

Saline injection

Drug: Placebo

Interventions

Morphine DRUG

Morphine

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 21 Years - 55 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male participants between 21-55 years of age.
• Good health as determined by medical history, physical exam, EKG and lab tests.
• Current non-smokers or light smokers or e-cigarette users (\<20 cig/week) who can easily abstain from smoking or using e-cigarettes for 1-2 days/week.
• Current non-drinkers or social drinkers who do not meet past or current DSM IV criteria for alcohol abuse or alcohol dependence.
• 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.
• Prior opiate use, at least one experience with one of the opiates listed in Appendix 1 of the protocol.
• Comprehension/fluency with English Language.

You may not qualify if:

• 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)
• Current Axis-I psychiatric illness as determined by the Structured Clinical Interview for DSM IV disorders (SCID).
• Current or prior history of any alcohol or drug dependence as determined by the Structured Clinical Interview for DSM IV disorders (SCID).
• Positive result on urine screen for illicit drugs.
• Medication Use:
• 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 or opiate pain medicines will be withheld for at least 72 hours prior to each study session.
• Drugs that may interfere with the BOLD MRI signal within 2 weeks of the study. These include, but may not be limited to: muscle relaxants or respiratory, cardiovascular or anticonvulsant medications
• Morbid obesity (BMI \>40 kg/m2)
• Previous negative effects of opioid administration
• 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.
• Head trauma leading to loss of consciousness for more than 5 min or hospitalization
• 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
• 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.

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA): lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Barr CS, Schwandt M, Lindell SG, Chen SA, Goldman D, Suomi SJ, Higley JD, Heilig M. Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques. Arch Gen Psychiatry. 2007 Mar;64(3):369-76. doi: 10.1001/archpsyc.64.3.369.

  PMID: 17339526 BACKGROUND

• Bart G, Heilig M, LaForge KS, Pollak L, Leal SM, Ott J, Kreek MJ. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. Mol Psychiatry. 2004 Jun;9(6):547-9. doi: 10.1038/sj.mp.4001504. No abstract available.

  PMID: 15037869 BACKGROUND

• Callaghan RC, Cunningham JK, Verdichevski M, Sykes J, Jaffer SR, Kish SJ. All-cause mortality among individuals with disorders related to the use of methamphetamine: a comparative cohort study. Drug Alcohol Depend. 2012 Oct 1;125(3):290-4. doi: 10.1016/j.drugalcdep.2012.03.004. Epub 2012 Apr 13.

  PMID: 22503689 BACKGROUND

• Spagnolo PA, Kimes A, Schwandt ML, Shokri-Kojori E, Thada S, Phillips KA, Diazgranados N, Preston KL, Herscovitch P, Tomasi D, Ramchandani VA, Heilig M. Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men. Biol Psychiatry. 2019 Sep 1;86(5):356-364. doi: 10.1016/j.biopsych.2019.03.965. Epub 2019 Mar 15.

  PMID: 31097294 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Pain; Behavior, Addictive

Interventions

Morphine

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Compulsive Behavior; Impulsive Behavior; Behavior

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Ramchandani, Vijay
• Organization: National Institute on Alcohol Abuse and Alcoholism

vijayr@mail.nih.gov

+1 301 402 8527

Study Officials

• Vijay A Ramchandani, Ph.D.

  National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Bliniding
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: Crossover study - participants receive active and placebo treatments in randomized order.

Study Record Dates

• First Submitted: June 12, 2013
• First Posted: June 14, 2013
• Study Start: June 13, 2013
• Primary Completion: April 27, 2017
• Study Completion: April 27, 2017
• Last Updated: April 1, 2021
• Results First Posted: October 23, 2018

Record last verified: 2021-03

Locations

US (1)