Brain Dopaminergic Signaling in Opioid Use Disorders

Normal Physiology Clinical Trial

Official title:

Brain Dopaminergic Signaling in Opioid Use Disorders (OUD)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03190954
• Other study ID #: 170114
• Secondary ID: 17-AA-0114
• Status: Recruiting
• Phase: Early Phase 1
• Start date: August 17, 2017
• Est. completion date: December 31, 2026

Study information

• Verified date: October 27, 2023
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Gene-Jack Wang, M.D.
• Phone: (301) 496-5012
• Email: gene-jack.wang[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 18-80 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....

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 naltrexone and OUD participants in recovery and 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); (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 180 (n=180) subjects: N=60 healthy control adults and N=120 OUD participants (60 MAT+, 30 naltrexone-treated and 30 MAT-) aged 18-80 (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+, naltrexone, 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 cue-reactivity 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

• 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. Minimum of 3 months since last regular use of opiods (no more than 1s/week in the pasat 3 months, as assessed by self report).

5. Minimum 3 year history of past opiate abuse - self-report.

6. Must have consumedd opiates at least 5 days per week (past opiod use) as per self-report.

7. Currently not receiving medications for OUD and a minimum of 3 months since last regularly taking medications for OUD (methadone, buprenorphine or naltrexone).

MAT+ OUD Participants

1. Males or females between 18 and 80 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 3 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 one 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 3 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.

For all groups of subjects regarding inclusion #1: OUD and HV subjects who are age 66-80 may be included in this study except they will not receive the methylphenidate and subsequent PET and MRI scans.

EXCLUSION CRITERIA:

Healthy Volunteer Subjects

1. Current DSM-5 diagnosis of a psychiatric disorder (other than OUD or severe alcohol/substance use disorders in OUD participants and nicotine/caffeine use in all participants) that requires/required daily psychoactive medications (antidepressant, antipsychotics, stimulants, benzodiazepines or barbiturates) in the past two months and that could impact brain function at the time of the study as determined by history and clinical exam.

2. The following current chronically used (2 months) medications are exclusionary:

stimulant or stimulant-like medications (amphetamine, methylphenidate, modafinil); opioid analgesics (for controls only); antianginal agents; antiarrhythmics; systemic corticosteroids; anticholinergics; anticoagulants; anticonvulsants; antidepressants; antihistamines (sedating); beta-blocker antihypertensives; antineoplastics; antiobesity; antipsychotics; anxiolytics (benzodiazepine or barbiturates); lithium; muscle relaxants; psychotropic drugs not otherwise specified (nos); sedatives/hypnotics, systemic steroids. Note that nicotine and/or caffeine is not exclusionary and that opiate drugs will not exclude participants with OUD. Subjects on stable antihypertensive medications (except for beta blockers) may be included provided they are on a clinically stable dose for at least a month [BP less than or equal to 140/90 if participating in MP administration scan; or BP 160/100 if not participating in MP administration scan].

3. Current continuous treatment (> 3 weeks) with methadone, buprenorphine or naltrexone.

4. Current major medical problems that can permanently impact brain function (e.g., CNS:

including seizures, psychosis, stroke, severe depression, Alzheimer s, Parkinson s disease, Traumatic brain injury; Cardiovascular: including uncontrolled hypertension [BP > 140/90] and clinically significant arrhythmias except bradycardia; and HIV+) as determined by history.

5. Clinically significant laboratory findings that could impact brain function or study procedures (e.g., active infections, arrhythmias, hepatic or renal failure) will be exclusionary.

6. 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.

7. Head trauma with loss of consciousness for more than 30 minutes as determined by medical history and physical exam.

8. Pregnant and/or currently breast-feeding. Females of childbearing potential (age 60 or less) will undergo a urine pregnancy test that must be negative to participate. Urine pregnancy tests will be repeated on subsequent days of study.

9. Presence of ferromagnetic objects in the body that are contraindicated for MRI (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.

10. Personal or family history (parents or siblings) for cerebral aneurysm.

11. Past or present history of chest pain and trouble breathing with activity.

12. Glaucoma as assessed by medical history.

13. Cannot lie comfortably flat on their backs for up to 2 hours in the PET and MRI scanners self-report.

14. Weight > 400 pounds, which is the maximum weight the PET scanner can hold.

15. Study investigators and staff, as well as their superiors, subordinates and immediate family members (adult children, spouses, parents, siblings).

16. *Non-English speakers (must also be able to read and comprehend English).

OUD Subjects

1. DSM-5 diagnosis of a psychiatric disorder that requires daily use of antipsychotic medications (schizophrenia or any other psychotic disorder) at the time of the study as determined by history and clinical exam.

2. Currently on antipsychotic medications. Subjects on stable antihypertensive medications may be included provided they are clinically stable [BP 140/90 if participating in MP administration scan; or BP 160/100 if not participating in MP administration scan]. OUD subjects who have hypertension may still be included in this study except they will not receive the methylphenidate and subsequent PET and MRI scans. OUD subjects who are taking a stimulant medication may participate in the study, except that they will be asked to not take their prescribed stimulant medication on the days of the [11C]raclopride scans.

3. Current continuous treatment (> 3 weeks) with methadone, or buprenorphine for MAT- OUD participants or naltrexone for MAT+ OUD participants; or agonist treatment (methadone or buprenorphine) for OUD participants treated with Naltrexone.

4. Current major medical problems that can permanently impact brain function (e.g., CNS:

including seizures, psychosis, stroke, severe depression, Alzheimer s, Parkinson s disease, Traumatic brain injury; Cardiovascular: including uncontrolled hypertension [BP > 140/90 if participating in MP administration scan; or BP > 160/100 if not participating in MP administration scan] and clinically significant arrhythmias except bradycardia; and HIV+) as determined by history. However, OUD subjects who have hypertension and/or certain EKG findings results may still be included in this study except they will not receive the methylphenidate and subsequent PET and/or MRI scans.

5. Clinically significant laboratory findings that could impact brain function or study procedures (e.g., active infections, arrhythmias, hepatic or renal failure) will be exclusionary.

6. 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.

7. Head trauma with loss of consciousness for more than 30 minutes as determined by medical history and physical exam.

8. Pregnant and/or currently breast-feeding. Females of childbearing potential (age 60 or less) will undergo a urine pregnancy test that must be negative to participate. Urine pregnancy tests will be repeated on subsequent days of study.

9. Presence of ferromagnetic objects in the body that are contraindicated for MRI (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. However, OUD subjects who are contraindicated for MRI participation, or the study team cannot access prior surgical records to confirm that a subject is cleared for MRI, may still participate in all aspects of the study except MRI. If it is discovered during the clinical brain MRI or after enrollment onto the study that the subject experiences anxiety or becomes claustrophobic, we will discontinue the MRI portion of the study and he/she can continue to participate in all other aspects of the study.

10. Personal or family history (parents or siblings) for cerebral aneurysm. Participant may be included in the PL administration with PET and/or MR but is excluded from the MP administration and subsequent PET and/or MR scan if history is reported.

11. Past or present history of chest pain and trouble breathing with activity. Participant may be included in the PL administration with PET and/or MR but is excluded from MP administration and subsequent PET and/or MR scan if history is reported.

12. Glaucoma as assessed by medical history. Participant may be included in the PL administration with PET and/or MR but is excluded from MP administration and subsequent PET and/or MR scan if history of glaucoma reported.

13. Cannot lie comfortably flat on their backs for up to 2 hours in the PET and MRI scanners self-report.

14. Weight > 400 pounds, which is the maximum weight the PET scanner can hold.

15. Study investigators and staff, as well as their superiors, subordinates and immediate family members (adult children, spouses, parents, siblings).

16. *Non-English speakers (must also be able to read and comprehend English).

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

17. Participation in a court ordered residential treatment program.

Note that subjects will not be excluded from enrollment onto this study if their urine test or breath alcohol level (BAL) is positive for drugs/alcohol on initial screening. The following guidelines will be followed for positive drug/alcohol screens on study procedure days:

If a Healthy Volunteer subject s urine drug/breath alcohol (>0.08%) 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/breath alcohol screens. If urine drug screen is positive for THC-COOH, a saliva drug screen will be performed and subject may proceed with study day 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. Source - Urine drug screen (CRIS) or BAL screen (CRIS).

If an OUD subject s urine drug/breath alcohol (>0.08%) screen test is positive for drugs (other than opiates), the procedures will not be postponed. If urine drug screen is positive for THC-COOH, a saliva drug screen will be performed to verify if THC is present. Positive results for drugs other than opiates will be considered at the time of data analysis as a co-variate. Source - Urine drug screen (CRIS).

*The intent of the research has no prospect of direct benefit to the subject. Therefore, we are excluding non-English speakers in this research study since it includes the administration of questionnaires, surveys and assessments that are validated for English, although some are available in Spanish. In addition, our fMRI paradigms (particularly the Delay Discounting task) require that the subject be able to speak, read and comprehend English.

Also, note that at any time during participation in this study if 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 OUD medications will be stopped or held for participation in this protocol.

Related Conditions & MeSH terms

• Normal Physiology
• Opioid Use Disorders
• Opioid-Related Disorders
• Substance-Related Disorders

Intervention

Drug:
• [11C]raclopride plus placebo
Placebo (po) will be given 60 minutes prior to [11C]raclopride scan to measure baseline dopamine D2 receptors. MRI scan to follow end of PET scan. Subject blind as to drug administration.
• [11C]raclopride plus drug
Methylphenidate 60 mg. po will be given 60 minutes prior to [11C]raclopride scan to measure striatal dopamine release. MRI scan to follow end of PET scan. Subject blind as to drug administration.
• [11C]NNC-112
[11C]NNC-112 PET scan obtained without any drug intervention to measure dopamine D1 receptors. Blind N/A

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Differences in D1R to D2R striatal ratio and in DA release between participants with an OUD and controls and between MAT+, naltrexone, and MAT- groups.	To assess whether the balance between D1R and D2R in striatum and in DA release is disrupted in participants with an opioid use disorder (OUD) who are being treated with an opioid agonist medication (MAT+), those treated with an opioid antagonist medication (naltrexone) and OUD participants who are not being treated with medications (MAT-).	End of study
Secondary	3) To assess if there is recovery after protracted treatment (comparing treated and non-treated) by repeating fMRI at 6 month follow-up.	Determine if the brain recovers with protracted abstinence as assessed by recovery of resting brain networks and brain activation responses to stimulation.	End of study
Secondary	2) To assess if DA increases as achieved with oral MP influence the brain functional measures.	Assess the association between striatal D1R to D2R availability and striatal DA release. Assess how D1R and D2R relate to behavior (locomotor activity and NP performance).	End of study
Secondary	1) To assess the impact of disruptions on striatal D1R to D2R availability on: DA release; Function of brain reward and control networks; Behavior.2) To assess if DA increases as achieved with oral MP influence the brain functional measure...	DA release (assessed with [11C]raclopride and the MP challenge strategy). Function of brain reward and control networks (assessed with fMRI with task activation and with RFC). Behavior (assessed with NP and actigraphy).	End of study

External Links

•   NIH Clinical Center Detailed Web Page