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Brain Dopaminergic Signaling in Opioid Use Disorders

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ClinicalTrials.gov Identifier: NCT03190954
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Brief Summary:

Background:

The chemical messenger dopamine carries signals between brain cells. It may affect addiction. Heavy use of pain medicines called opioids may decrease the amount of dopamine available to the brain. Researchers want to study if decreased dopamine decreases self-control and increases impulsiveness.

Objective:

To learn more about how opiate use disorder affects dopamine in the brain.

Eligibility:

Adults 18-65 years old who are moderate or severe opiate users

Healthy volunteers the same age

Design:

Participants will first be screened under another protocol. They will:

  • Have a physical exam
  • Answer questions about their medical, psychiatric, and alcohol and drug use history
  • Take an MRI screening questionnaire
  • Give blood and urine samples
  • Have their breath tested for alcohol

Participants will have up to 3 study visits.

They will have 2-3 positron emission tomography (PET) scans. A radioactive chemical will be injected for the scans. Participants will lie on a bed that slides in and out of the donut-shaped scanner. A cap or plastic mask may be placed on the head.

Vital signs will be taken before and after the PET scans.

Participants will get capsules of placebo or the study drug. They will rate how they feel before, during and after.

Participants will have their breath and urine tested each day.

Participants will have magnetic resonance imaging (MRI) scans. They will lie on a table that slides into a cylinder in a strong magnetic field. They may do tasks on a computer screen while inside the scanner.

Participants will have tests of memory, attention, and thinking.

Participants will wear an activity monitor for one week....


Condition or disease Intervention/treatment Phase
Normal Physiology Opioid-Related Disorders Other: Placebo Drug: Methylphenidate Early Phase 1

Detailed Description:

Objectives: Primary objective is to assess whether the balance between dopamine D1 (D1R) and D2 receptors (D2R) signaling in striatum is disrupted in participants with an opioid use disorder (OUD) who are on opioid agonist medication (MAT+: methadone or buprenorphine) relative to OUD participants treated with the opioid antagonist medication (naltrexonel) and OUD participants not being treated with medications (MAT). Secondary objectives are to assess how striatal D1R to D2R availability (assessed with PET) influences: (1) striatal dopamine (DA) release; (2) the function of brain reward and self-control networks (assessed with task fMRI activation and with resting functional connectivity, RFC) and (3) behavior (locomotor activity and neuropsychological tests) and (4) to assess if DA increases, as induced by oral methylphenidate (MP), improve the function of brain reward and control networks in OUD; and (5) to assess if there is recovery after protracted treatment (comparing treated and non-treated) by repeating fMRI at 6 month follow-up.

Study population: We will complete studies in 120 (n=120) subjects: N=30 healthy control adults and N=90 90 OUD participants (30 MAT+, 30 naltrexone-treated and 30 MAT-) aged 18-65 (male/female) will be included.

Design: Single-blind. Participants will undergo three scans with positron emission tomography (PET): one with [11C]NNC-112 to assess baseline D1R, another with [11C]raclopride after placebo to assess baseline D2R and a third one with [11C]raclopride after MP administration (60mg oral) to assess striatal DA release (assessed as the difference in specific binding of [11C]raclopride between baseline and MP). In addition, participants will undergo two imaging sessions with MRI to assess functional reactivity to drug-cues and to a measure of self-control (delayed discounting task), to assess RFC and to obtain structural brain measures (including diffusion tensor imaging, DTI). One of the sessions will be done under baseline conditions (no drug administered) and the other after MP (about one hour after the [11C]raclopride MP scan is completed). Neuropsychological tests (NP) and accelerometers will be used to assess cognitive performance and locomotor activity respectively

Outcome Measures: Main outcome: (1) Differences in D1R to D2R striatal ratio between participants with an OUD and controls and between MAT+, natrexone, and MAT- groups. Secondary outcomes: Correlations between striatal D1R to D2R and (1) striatal DA release; (2) fMRI activation in reward and controls networks (assessed with cuereactivity and delay discounting tasks, and with RFC) and (3) NP performance and locomotor activity. (4) Differences in fMRI activation and RFC after MP when compared with baseline measures.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Brain Dopaminergic Signaling in Opioid Use Disorders (OUD)
Actual Study Start Date : August 17, 2017
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1
Single-blind. Participants will undergo three scans with positron emission tomography (PET): one with [11C]NNC-112 to assess baseline D1R, another with [11C]raclopride after placebo to assess baseline D2R and a third one with [11C]raclopride after MP administration (60mg oral) to assess striatal DA release (assessed as the difference in specific binding of [11C]raclopride between baseline and MP). In addition, participants will undergo two imaging sessions with MRI to assess functional reactivity to drug-cues and to a measure of self-control (delayed discounting task), to assess RFC and to obtain structural brain measures (including diffusion tensor imaging, DTI). One of the sessions will be done under baseline conditions (no drug administered) and the other after MP (about one hour after the [11C]raclopride MP scan is completed). Neuropsychological tests (NP) and accelerometers will be used to assess cognitive performance and locomotor activity respectively
Other: Placebo
Placebo (po) will be given 60 minutes prior to [11C]raclopride scan. MRI scan to follow end of PET scan.

Drug: Methylphenidate
Methylphenidate 60 mg. po will be given 60 minutes prior to [11C]raclopride scan. MRI scan to follow end of PET scan.




Primary Outcome Measures :
  1. To assess whether the balance between D1R and D2R in striatum is disrupted in participants with an opioid use disorder (OUD) who are being treated with an opioid medication (MAT+) and does who are not (MAT-). [ Time Frame: Study Completion ]

Secondary Outcome Measures :
  1. To assess the impact of disruptions on striatal D1R to D2R availability on: DA release; Function of brain reward and control networks; Behavior. [ Time Frame: Study Completion ]
  2. To assess if DA increases as achieved with oral MP influence the brain functional measures. [ Time Frame: Study Completion ]


Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

Healthy Volunteer Participants

  1. Males or females between 18 and 65 years of age.
  2. Ability to provide written informed consent.

MAT- Opiate Use Disorder (OUD) Participants

  1. Males or females between 18 and 65 years of age.
  2. Ability to provide written informed consent.
  3. DSM-5 diagnosis of a moderate or severe OUD (established through history and clinical exam).
  4. Active abuse of opiates (last use within one week of study as assessed by self-reports).
  5. Minimum 5 year history of opiate abuse - self-report.
  6. Must consume opiates at least 5 days per week as per self-report.
  7. Currently not receiving medications for OUD (methadone, buprenorphine or naltrexone).

MAT+ OUD Participants

  1. Males or females between 18 and 65 years of age.
  2. Ability to provide written informed consent.
  3. DSM-5 diagnosis of a moderate or severe OUD (established through history and clinical exam).
  4. Active or non-active abuse of opiates.
  5. Minimum 5 year history of opiate abuse as per self-report.
  6. Must have consumed at least 5 days per week (prior opiate use) as per self-report.
  7. Receiving opioid agonist therapy for OUD (e.g., methadone or buprenorphine) and must have taken for at least week before imaging study.

Naltrexone OUD Participants

  1. Males or females between 18 and 65 years of age.
  2. Ability to provide written informed consent.
  3. DSM-5 diagnosis of a moderate or severe OUD (established through history and clinical exam).
  4. Active or non-active abuse of opiates.
  5. Minimum 5 year history of opiate abuse as per self-report.
  6. Must have consumed at least 5 days per week (prior opiate use) as per self-report.
  7. Receiving naltrexone treatment for their OUD and must have taken at least one week before imaging study.

EXCLUSION CRITERIA:

All Subjects

-Unwilling or unable to refrain from use within 24 hours of scheduled study procedures: psychoactive medications or medication that may affect study results (e.g., antibiotics (must finish course at least 24 hours prior to a scheduled procedure), analgesics (non-narcotic and narcotic for healthy volunteers only); antidiarrheal preparations, anti-inflammatory drugs [systemic corticosteroids are exclusionary], anti-nausea, cough/cold preparations) (self-report, medical history). The following medications are allowable for entry on this study: analgesics (non-narcotic and narcotic for OUD participants only); antacids; antiasthma agents that are not systemic corticosteroids; antifungal agents for topical use; antihistamines (nonsedating); antihypertensives (except beta blockers); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of H2-Blockers/PPI (proton pump inhibitors), antihypertensives (other than beta-blockers), antihyperlipidemics and/or diuretics are permitted if they have been taken for at least 1 month before procedure visits and dose has been stabilized. The episodic use of benzodiazepines such as alprazolam ( Xanax), diazepam ( Valium) and lorazepam ( Ativan), will not exclude participants from this study unless they have been taken within the last 24 hours prior to the study.

  • Current DSM-5 diagnosis of a psychiatric disorder (other than OUD or mild/moderate alcohol/substance use disorders in OUD participants and nicotine/caffeine use in all participants) that requires/required daily medications in the past three months and that could impact brain function at the time of the study as determined by history and clinical exam. Healthy Volunteers with current co-morbid psychiatric disorders, which may confound the data, will not be enrolled.
  • Current DSM-5 diagnosis of a psychiatric disorder (other than OUD or mild/moderate alcohol/substance use disorders in OUD participants) that required hospitalization in the past year and that could impact brain function at the time of the study as determined by history and clinical exam.
  • The following current chronically used medications are exclusionary from the study: stimulant or stimulant-like medications (amphetamine, methylphenidate, modafinil); analgesics containing narcotics (for controls only); anorexics (orlistat); antianginal agents; antiarrhythmics; antiasthma agents that are systemic corticosteroids; antibiotics; anticholinergics; anticoagulants; anticonvulsants; antidepressants; antidiarrheal preparations; antifungal agents (systemic); antihistamines (sedating); beta-blocker antihypertensives; anti-inflammatory drugs (systemic); antineoplastics; antiobesity; antipsychotics; antivirals (except for treatment of HSV with agents without CNS activity, e.g. acyclovir, ganciclovir, famciclovir, valacyclovir); anxiolytics (benzodiazepine or barbiturates); hormones (exceptions: thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy); insulin; lithium; muscle relaxants; psychotropic drugs not otherwise specified (nos) including herbal products (no drugs with psychomotor effects or with anxiolytics, stimulant, antipsychotic, or sedative properties); sedatives/hypnotics. OUD subjects are excluded if use of listed medications were taken chronically in the past 3 months. Note that nicotine and/or caffeine use will not exclude participants and that the use of opiate drugs will not exclude participants with OUD. Also note that subjects on stable hypertensive medications (except for beta blockers) may be included on the study provided they are on stable dose for at least one month [BP less than or eual to 90].
  • Current or past month continuous treatment (> 3 weeks) with methadone, buprenorphine or naltrexone for controls or MAT- OUD participants; or naltrexone for MAT+ OUD participants; or agonist treatment (methadone or buprenorphine) for OUD participants treated with Naltrexone.
  • Major medical problems that can permanently impact brain function (e.g., CNS including seizures and psychosis; cardiovascular including uncontrolled hypertension [BP > 140/90] and clinically significant arrhythmias except bradycardia; metabolic, autoimmune, endocrine; +HIV) as determined by history. OUD subjects with Hepatitis (HCV) who have normal liver synthetic functions (normal alb, PT, PLT, bili, no clinical evidence of active liver disease) and no more than minimally elevated ALT (<1.5 UNL) may be included.
  • Any clinically significant laboratory finding as determined during the screening procedures that could impact brain function or study procedures as evidenced from clinical laboratory results. Only abnormal laboratory findings associated with altered brain function (e.g., arrhythmias or renal failure) will be exclusionary.
  • Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that, with the exposure from this study, would exceed NIH annual research limits as determined by medical history and physical exam.
  • Head trauma with loss of consciousness for more than 30 minutes as determined by medical history and physical exam.
  • Pregnant or breast-feeding: Females of childbearing potential, or with tubal ligation, or are post-menopausal and are age 60 or less will undergo a urine pregnancy test and it must be negative to continue participation. Urine pregnancy tests will be repeated on subsequent days of study. Females must not be currently breastfeeding.
  • Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments) or fear of enclosed spaces - self-report checklist.
  • Personal or family history for cerebral aneurysm.
  • Past or present history of chest pain and trouble breathing with activity.
  • Glaucoma as assessed by medical history.
  • Diabetes as assessed by medical history.
  • Cannot lie comfortably flat on their backs for up to 2 hours in the PET and MRI scanners self-report.
  • Weight > 400 pounds, which is the maximum weight the PET scanner can hold.
  • Study investigators and staff, as well as their superiors, subordinates and immediate family members (adult children, spouses, parents, siblings).

Additional exclusion criteria for MAT+ / MAT- / Naltrexone OUD participants:

  • Participation in a court ordered treatment program.
  • Scores on MADRS 20 or higher.

Additional exclusion criteria for MAT- OUD participants only:

-Currently seeking treatment for OUD, for the MAT- group.

--Note that subjects will not be excluded from enrollment onto this study if their urine test is positive for drugs on initial screening. The following guidelines will be followed for positive drug screens on study procedure days:

--- If a Healthy Volunteer subject s urine drug screen test is positive on days involving imaging (MRI and/or PET) and NP testing, the procedures will be postponed and rescheduled. We will allow for up to 3 rescheduled study days resulting from positive urine drug screens. If the urine drug screen is positive for THC-COOH, a saliva drug screen will be performed and subject may proceed with

MRI/PET/NP testing procedures if saliva results for THC are negative. If the urine/saliva drug test is positive on the third rescheduled visit, the participant will be withdrawn from the study.

--- If an OUD subject s urine drug screen test is positive for drugs (except opiates), the procedures will be postponed and rescheduled to another day. If the urine drug screen is positive for THC-COOH, a saliva drug screen will be performed and subject may proceed with MRI/PET/NP testing procedures if saliva results for THC are negative. We will not place a limit on rescheduling study days in this group.

Also, note that at any time during participation in this study any subject expresses that he/she wants to get treatment for their OUD, we will immediately refer him/her to a treatment program. The subject will be withdrawn from the study at that time. No medications will be stopped or held for participation in this protocol.


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 ClinicalTrials.gov identifier (NCT number): NCT03190954


Contacts
Contact: Gene-Jack Wang, M.D. (301) 496-5012 gene-jack.wang@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
Principal Investigator: Gene-Jack Wang, M.D. National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Additional Information:
Publications:
Responsible Party: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ClinicalTrials.gov Identifier: NCT03190954     History of Changes
Other Study ID Numbers: 170114
17-AA-0114
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 11, 2019

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) ):
C-11 Raclopride
[11C] NNC-112
Functional Magnetic Resonance Imaging (fMRI)
Dopamine D1 Receptor
D2 Receptors

Additional relevant MeSH terms:
Disease
Opioid-Related Disorders
Pathologic Processes
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Methylphenidate
Dopamine
Raclopride
Dopamine Agonists
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Protective Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists