Oxytocin, Stress, Craving, Opioid Use Disorder

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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=50 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.

Official Title
-----------------
Oxytocin to Reduce Stress-induced Craving in Individuals With Opioid Use Disorder

Conditions
-----------------
Opioid Use Disorder

Intervention / Treatment
-----------------
* Drug: intranasal oxytocin, 40 IU, twice a day for 7 days


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female (50%), 18 to 65 (inclusive) years of age; Currently meets DSM-5 criteria for OUD; Currently on a stable dose of buprenorphine/naloxone for at least 3 months; In good health as confirmed by medical history, physical examination and blood work (Liver function within 5x the Upper normal limits (AST/ALT) and renal function within 2x the Lower Normal Limit (bilirubin, creatine clearance). Willing to take medication and adhere to the study procedures;- Understand informed consent and questionnaires in English at an 8th grade level; Clinical Opiate Withdrawal Scale (COWS) = 0 at study screening and prior laboratory sessions. Exclusion Criteria: Women who are breastfeeding, test positive for pregnancy or are unwilling to use medically-approved birth control; Suicide attempts in the last three months; Current substance disorder other than marijuana, nicotine and caffeine as assessed by self-report and urine toxicology screen at baseline; Current use of medications that may interact with study medications; History of hypersensitivity to study medications; Clinically significant electrolyte abnormalities, current rhinitis or use of vasoconstricting medications or prostaglandins.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: oxytocin<br>The oxytocin will be formulated at 5mg/0.1mL (5mg/spray) and dispensed as 10-mL nasal spray, twice a day (2 sprays per nostril) for 7 days (total daily dose: 40 international units, IU). | Drug: intranasal oxytocin, 40 IU, twice a day for 7 days<br>* Adjunct therapy<br>* Other names: Pitocin;|
| Placebo Comparator: matching placebo<br>The oxytocin-matched placebo will be formulated at 5mg/0.1mL (5mg/spray) and dispensed as 10-mL nasal spray, twice a day (2 sprays per nostril) for 7 days (total daily dose: 40 international units, IU). | Drug: intranasal oxytocin, 40 IU, twice a day for 7 days<br>* Adjunct therapy<br>* Other names: Pitocin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 Opioid Craving Questionnaire (OCQ) the stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the OCQ will be administered 4 times: before starting any procedure, during the yohimbine challenge, at the cue-reactivity and end of experiment. The primary outcome will be the area under the curve (AUC) formed by the OCQ score. This outcome will be compared between oxytocin and matching-placebo during the stress induction produced by yohimbine or matching-placebo. | one week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of oxytocin and yohimbine in OUD individuals receiving buprenorphine/naloxone: side effects | Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. To monitor safety and tolerability during the entire course of the study, we will examine between-group differences (oxytocin, placebo) and during yohimbine administration in reports of side effects (headache, vertigo, edema, nausea, somnolence, anxiety, abdominal pain, palpitations) at the laboratory sessions and at the follow up visit. Reporting of the study results will be of a descriptive nature and presented using summary statistics: number of subjects (n), mean (M), standard deviation (SD) or standard error of the mean (SEM), co-efficient of variation (CV), median, minimum, maximum or frequency distributions (n, %) | one week | 
| Safety and tolerability of oxytocin and yohimbine in OUD individuals receiving buprenorphine/naloxone: opiate withdrawal syndrome | Safety measures include: opiate withdrawal syndrome by Clinical Opiate Withdrawal Scale (COWS) that will be monitored during the entire study timeline. | one week | 
| Safety and tolerability of oxytocin and yohimbine in OUD individuals receiving buprenorphine/naloxone: anxiety | To monitor safety and tolerability during the entire course of the study, we will examine between-group differences (oxytocin, placebo) and during yohimbine administration in assessing anxiety using the Hamilton scale. Reporting of the study results will be of a descriptive nature and presented using summary statistics: number of subjects (n), mean (M), standard deviation (SD) or standard error of the mean (SEM), co-efficient of variation (CV), median, minimum, maximum or frequency distributions (n, %) | one week | 
| Safety and tolerability of oxytocin and yohimbine in OUD individuals receiving buprenorphine/naloxone: blood pressure (BP) | To monitor safety and tolerability during the entire course of the study, we will examine between-group differences (oxytocin, placebo) and during yohimbine administration in reports of blood pressure. Reporting of the study results will be of a descriptive nature and presented using summary statistics: number of subjects (n), mean (M), standard deviation (SD) or standard error of the mean (SEM), co-efficient of variation (CV), median, minimum, maximum or frequency distributions (n, %) | one week | 
| Safety and tolerability of oxytocin and yohimbine in OUD individuals receiving buprenorphine/naloxone: heart rate (HR) | To monitor safety and tolerability during the entire course of the study, we will examine between-group differences (oxytocin, placebo) and during yohimbine administration in reports of heat rate (HR). Reporting of the study results will be of a descriptive nature and presented using summary statistics: number of subjects (n), mean (M), standard deviation (SD) or standard error of the mean (SEM), co-efficient of variation (CV), median, minimum, maximum or frequency distributions (n, %) | one week |