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| ID | Type | Description | Link |
|---|---|---|---|
| P20GM130414 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of General Medical Sciences (NIGMS) | NIH |
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Although stress has long been linked to substance use, craving and relapse, there are no available medications that target stress-induced substance use disorder (SUD). In particular, with the rise in opioid use, there is still a crucial need for developing effective pharmacological treatments that target and integrate the complexity of this disease. The long term goal of this project is to identify the key neuroendocrine pathways that are responsible for stress-induced craving in individuals with opioid use disorder (OUD) in order to better understand how they can be effectively treated.
The goal of this research is to evaluate whether oxytocin, a hormone with anti-stress properties, dampens the effects of stress and opioid-associated cues on opioid craving and thus may be an effective adjunctive treatment for OUD.
The central hypothesis of this research is that oxytocin will reduce stress-induced opioid craving in patients with OUD treated with buprenorphine/naloxone as opioid replacement therapy (ORT). This hypothesis is based on the model of addiction (Koob, Neuron 2008) in which chronic substance use and stress lead to neurobehavioral counter-adaptations that dysregulate biobehavioral response.
In this double-blind, cross-over, placebo controlled, randomized trial, individuals with OUD (N=20 who are currently receiving treatment with buprenorphine/naloxone or methadone will be randomized to intranasal oxytocin (40 international units, IU) and oxytocin-matched placebo, administered twice/day for 7 days with a minimum of two days between the opposite condition (oxytocin or placebo). On days 5 and 7, and on days 14 and 16, participants will complete two counter-balanced sessions in which they receive yohimbine (32.4 mg) or yohimbine-matched placebo.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Oxytocin first, then placebo | Experimental | Oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days. After a 2 day washout period, Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days. |
|
| Matching placebo, then oxytocin | Placebo Comparator | Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days. After a 2 day washout period, oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| intranasal oxytocin, 40 IU, twice a day for 7 days | Drug | Adjunct therapy |
|
| Measure | Description | Time Frame |
|---|---|---|
| Opioid Craving | The primary outcome will test the effect of oxytocin, compared to placebo, on opioid craving during two laboratory stress induction, paired to a cue reactivity paradigm. The dependent measure for the primary aim is the Desire for Drug Questionnaire (DDQ). The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the DDQ will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. Minimum score=0 no craving at all, maximum score= 91 severe craving (13 questions on a 7-step Likert-scale) | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Opiate Withdrawal Syndrome | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: opiate withdrawal syndrome by Clinical Opiate Withdrawal Scale (COWS) pre and post the laboratory procedures. The COWS is an 11-item scale designed to be administered by a clinician. Minimum=0 (no withdrawal); Maximum=36 (sever withdrawal). The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. High score worse outcome. At each visit the COWS will be administered 2 times: before starting any procedure, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. |
| Measure | Description | Time Frame |
|---|---|---|
| Stress-related Response in OUD Individuals Receiving Opioid Agonist Therapy: Salivary Cortisol | Cortisol (biomarker for stress level) will be measured at the same 3 time points as other measures. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the cortisol will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brown University | Providence | Rhode Island | 02291 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39534517 | Result | Gully BJ, Brown ZE, Hornbacher R, Brown JC, Back SE, McCance-Katz EF, Swift RM, Haass-Koffler CL. Oxytocin Reduces Noradrenergic-Induced Opioid-Like Withdrawal Symptoms in Individuals on Opioid Agonist Therapy. Biol Psychiatry Glob Open Sci. 2024 Sep 18;5(1):100395. doi: 10.1016/j.bpsgos.2024.100395. eCollection 2025 Jan. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Oxytocin First, Then Placebo | Oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days: Adjunct therapy |
| FG001 | Matching Placebo First, Then Oxytocin | Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days: Adjunct therapy |
| Title | Milestones | Reasons Not Completed | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1st Allocation, 7 Days |
| ||||||||||||||||
| 2nd Allocation (Cross Over) |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Outcome measures are grouped into a single arm: all study participants. This is because the crossover design led participants to receive both oxytocin and the matched placebo during the study. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Opioid Craving | The primary outcome will test the effect of oxytocin, compared to placebo, on opioid craving during two laboratory stress induction, paired to a cue reactivity paradigm. The dependent measure for the primary aim is the Desire for Drug Questionnaire (DDQ). The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the DDQ will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. Minimum score=0 no craving at all, maximum score= 91 severe craving (13 questions on a 7-step Likert-scale) | Posted | Mean | Standard Deviation | score on a scale | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
|
Safety and tolerability were measured retrospectively during the one-week outpatient setting
We did not enroll any participant who was at risk of mortality, suicide or serious adverse event
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Oxytocin | Oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days: Adjunct therapy |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | Systematic Assessment |
Attempting to probe and measure opioid craving in this setting. This study utilized a guided opioid visualization technique, the presence of drug paraphernalia, and an opioid-related video cue. These cues were broad, and different aspects of them may have proved significant to participants at different times. While this is a laboratory procedure limitation, it may also further support the use of OAT for craving management. The study's small sample size and balance between males/females.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Carolina Haass-Koffler, PharmD, PhD (PI) | Brown University | 4155191385 | carolina_haass-koffler@brown.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 5, 2022 | Jan 4, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 5, 2022 | Jan 4, 2025 | SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 5, 2022 | Jan 4, 2025 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D009293 | Opioid-Related Disorders |
| ID | Term |
|---|---|
| D000079524 | Narcotic-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D010121 | Oxytocin |
| ID | Term |
|---|---|
| D010909 | Pituitary Hormones, Posterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
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| Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
| Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Anxiety | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor anxiety (HAMA) during lab sessions. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of Minimum=0 (not present), Maximum=56 (sever), where <17 mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. High score worse outcome. At each visit the HAMA will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
| Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Systolic Blood Pressure (SBP) | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor systolic blood pressure (SBP) during lab sessions. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the SBP will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
| Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Heart Rate (HR) | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor Heart rate (HR) during lab sessions. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the HR will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
| Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
|
| COMPLETED |
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| NOT COMPLETED |
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|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Clinical Opiate Withdrawal Scale (COWS) | Mean | Standard Deviation | score on an 11-item scale |
|
Oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days: Adjunct therapy
| OG001 | Matching Placebo | Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days. |
|
|
| Secondary | Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Opiate Withdrawal Syndrome | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: opiate withdrawal syndrome by Clinical Opiate Withdrawal Scale (COWS) pre and post the laboratory procedures. The COWS is an 11-item scale designed to be administered by a clinician. Minimum=0 (no withdrawal); Maximum=36 (sever withdrawal). The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. High score worse outcome. At each visit the COWS will be administered 2 times: before starting any procedure, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Posted | Mean | Standard Deviation | score on a scale | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
|
|
|
| Secondary | Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Anxiety | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor anxiety (HAMA) during lab sessions. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of Minimum=0 (not present), Maximum=56 (sever), where <17 mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. High score worse outcome. At each visit the HAMA will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Posted | Mean | Standard Deviation | score on a scale | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
|
|
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| Secondary | Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Systolic Blood Pressure (SBP) | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor systolic blood pressure (SBP) during lab sessions. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the SBP will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Posted | Mean | Standard Deviation | mmHg | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
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| Secondary | Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Heart Rate (HR) | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor Heart rate (HR) during lab sessions. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the HR will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Posted | Mean | Standard Deviation | beat/min | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
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| Other Pre-specified | Stress-related Response in OUD Individuals Receiving Opioid Agonist Therapy: Salivary Cortisol | Cortisol (biomarker for stress level) will be measured at the same 3 time points as other measures. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the cortisol will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. | Posted | Mean | Standard Deviation | ug/dL | Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16. |
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|
| 0 |
| 16 |
| 0 |
| 16 |
| 8 |
| 16 |
| EG001 | Matching Placebo | Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days: Adjunct therapy | 0 | 17 | 0 | 17 | 8 | 17 |
| Decrease in appetite | Gastrointestinal disorders | Systematic Assessment |
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| Difficulty sleeping | Nervous system disorders | Systematic Assessment |
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| Slowness, sleepiness, or fatigue | Nervous system disorders | Systematic Assessment |
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| Difficulty with concentration or attention | Nervous system disorders | Systematic Assessment |
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| Tingling in fingers or toes | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Tremor | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Nervousness or anxiety | Psychiatric disorders | Systematic Assessment |
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| Irritability | Nervous system disorders | Systematic Assessment |
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| Depression or other mood disturbance | Psychiatric disorders | Systematic Assessment |
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| Muscle aches | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| D006730 |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| Baseline (Yohimbine-placebo Condition) |
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| Post (Yohimbine-placebo Condition) |
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| after cue exposure (Yohimbine condition) |
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| Baseline (Yohimbine-placebo condition) |
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| after stress (Yohimbine-placebo condition) |
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| after cue exposure (Yohimbine-placebo condition) |
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| after cue exposure (yohimbine condition) |
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| baseline (yohimbine-placebo condition) |
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| after stress (yohimbine-placebo condition) |
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| after cue exposure (yohimbine-placebo condition) |
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| after cue exposure (yohimbine condition) |
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| baseline (yohimbine-placebo condition) |
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| after stress (yohimbine-placebo condition) |
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| after cue exposure (yohimbine-placebo condition) |
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| after cue exposure (yohimbine condition) |
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| baseline (yohimbine-placebo condition) |
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| after stress (yohimbine-placebo condition) |
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| after cue exposure (yohimbine-placebo condition) |
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