Effects of Buprenorphine/Naloxone Dose on Experimental Stress Reactivity and Opioid Abstinence

Study Overview
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Brief Summary
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This research deals with behaviors that are part of opioid dependence. The purpose is to study how stress and medication dose can affect opioid drug use.

Detailed Description
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If participants meet all the criteria, their involvement in the study (Phases 1 and 2 described below) will last for 10-13 weeks. Participants will be asked to stay at the research site for a minimum of 2 nights on 4 separate weeks and will have 22 office visits During that time, participants can't leave the unit unescorted or have visitors. Participants will receive a medication called Buprenorphine/Naloxone. Buprenorphine/Naloxone is approved by the Food and Drug Administration (FDA) to treat opioid addiction, and is a safe and effective alternative to methadone. Participants will receive this medication every day. When participants are not living on the inpatient unit they will come to the research clinic every day to receive the medication. On Day 1, one single 1-mL (0.2 teaspoon) blood sample will be collected to assess the effect of the Buprenorphine/Naloxone medication dose on gene expression pattern. On each day of admission (once on weeks 3, 5 and 7), a single 1-mL (0.2 teaspoon) blood sample will be collected to assess the effect of the buprenorphine/naloxone medication dose on the participant's gene expression pattern. On the 8 days while participants are an inpatient they will participate in experimental sessions that involve drug administration. On some days participants will receive morphine and on some days participants will receive oral medications called yohimbine and hydrocortisone that will be used to study stress responses. Each afternoon study staff will collect one blood sample (10 mL or 2 teaspoons) from a vein in the participant's arm; these samples will be used to measure biological signals of stress. At the end of the study participants will be detoxified from the Buprenorphine/Naloxone medication over a 3-week outpatient period. Study participants will be scheduled for one separate in-person visit at 1 month after week 11. At this follow-up visit participants will be asked to provide a urine sample and to complete questionnaires that ask about drug craving and use, withdrawal symptoms, risky situations for drug use, coping with stress, and consequences experienced from using drugs or being abstinent.

Official Title
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Biobehavioral Studies of Opioid Seeking: Effects of Buprenorphine/Naloxone Dose on Experimental Stress Reactivity and Opioid Abstinence

Conditions
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Heroin Dependence, Opioid Use Disorder

Intervention / Treatment
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* Drug: Extended release morphine
* Drug: Buprenorphine/Naloxone low dose
* Drug: Buprenorphine/Naloxone moderate dose
* Drug: Buprenorphine/Naloxone high dose
* Drug: Active stressor
* Drug: Placebo stressor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Opioid dependent, as determined by structured clinical interview for DSM-IV (SCID) and Addiction Severity Index (ASI) Positive urine test for opiates Willing to use an adequate form of contraception for the duration of the study. Reads and writes English Participants must be in generally good health to be eligible. All candidates will receive a routine medical exam (history and physical) with standard laboratory tests (including blood and urine samples, EKG, mandatory TB testing, and voluntary HIV testing). Exclusion Criteria: No candidate who has a current DSM-IV Axis I disorder other than Drug Dependence or a history of serious psychiatric problems (e.g. psychosis, bipolar or major depression) will be allowed to participate. Candidates meeting criteria for opioid or nicotine dependence will not be excluded, but those with other Substance Dependence disorders will be excluded. Those with Abuse of Alcohol, Cannabis, Cocaine, will not be excluded, but participants must provide an alcohol free breath specimen. No candidate with medical (neurological, cardiovascular, pulmonary or systemic) disorders will be allowed to participate. This will be determined with history and physical exam, standard laboratory testing (blood and urine), EKG, and TB tests (to avoid transmitting this communicable disease on the residential unit or in the laboratory). Candidates with evidence of cognitive impairment (based on reading ability and comprehension, will be excluded. Female candidates who are pregnant (urine pregnancy test), lactating, or not using adequate birth control methods (self-report) will be excluded. Candidates with injection phobia, or seeking treatment for opioid dependence will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 4x2 within-subject crossover design: 4 medication conditions (morphine first, then 3 doses of buprenorphine/naloxone), crossed with 2 stress conditions (placebo vs. stress [yohimbine + hydrocortisone], nested within medication conditions)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Extended-Release Morphine + placebo stressor<br>Participants will be maintained on extended-release morphine (dose tailored to the individual, based on pre-experimental opioid use amount), in three divided daily doses. The placebo stressor will be administered on one day. | Drug: Extended release morphine<br>* Dose (tailored to each participant based on his/her pre-experimental opioid use amount) is administered in 3 divided daily doses.<br>Drug: Placebo stressor<br>* Lactose<br>|
| Experimental: Buprenorphine/Naloxone low dose + placebo stressor<br>Participants will be maintained on Buprenorphine/Naloxone (Zubsolv™) sublingual tablet doses of 1.4/0.36 mg/day. The placebo stressor will be administered on one day. | Drug: Buprenorphine/Naloxone low dose<br>* Buprenorphine/Naloxone dose of 1.4/0.36 mg/day<br>* Other names: Zubsolv™ sublingual tablet;Drug: Placebo stressor<br>* Lactose<br>|
| Experimental: Buprenorphine/Naloxone moderate dose + placebo stressor<br>Participants will be maintained on Buprenorphine/Naloxone (Zubsolv™) sublingual tablet doses of 4.2/1.08 mg/day. The placebo stressor will be administered on one day. | Drug: Buprenorphine/Naloxone moderate dose<br>* Buprenorphine/Naloxone dose of 4.2/1.08 mg/day<br>* Other names: Zubsolv™ sublingual tablet;Drug: Placebo stressor<br>* Lactose<br>|
| Experimental: Buprenorphine/Naloxone high dose + placebo stressor<br>Participants will be maintained on Buprenorphine-Naloxone (Zubsolv™) sublingual tablet doses of 12.8/3.16 mg/day. The placebo stressor will be administered on one day. | Drug: Buprenorphine/Naloxone high dose<br>* Buprenorphine/Naloxone dose of 12.8/3.16 mg/day<br>* Other names: Zubsolv™ sublingual tablet;Drug: Placebo stressor<br>* Lactose<br>|
| Experimental: Extended-Release Morphine + active stressor<br>Participants will be maintained on extended-release morphine (dose tailored to the individual, based on pre-experimental opioid use amount), in three divided daily doses. Yohimbine 60mg powder + Hydrocortisone (Cortef™) 20mg tablet administered on one day. | Drug: Extended release morphine<br>* Dose (tailored to each participant based on his/her pre-experimental opioid use amount) is administered in 3 divided daily doses.<br>Drug: Active stressor<br>* Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet<br>|
| Experimental: Buprenorphine/Naloxone low dose + active stressor<br>Participants will be maintained on Buprenorphine/Naloxone (Zubsolv™) sublingual tablet doses of 1.4/0.36 mg/day. The placebo stressor will be administered on one day. Yohimbine 60mg powder + Hydrocortisone (Cortef™) 20mg tablet administered on one day. | Drug: Buprenorphine/Naloxone low dose<br>* Buprenorphine/Naloxone dose of 1.4/0.36 mg/day<br>* Other names: Zubsolv™ sublingual tablet;Drug: Active stressor<br>* Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet<br>|
| Experimental: Buprenorphine/Naloxone moderate dose + active stressor<br>Participants will be maintained on Buprenorphine/Naloxone (Zubsolv™) sublingual tablet doses of 4.2/1.08 mg/day. Yohimbine 60mg powder + Hydrocortisone (Cortef™) 20mg tablet administered on one day. | Drug: Buprenorphine/Naloxone moderate dose<br>* Buprenorphine/Naloxone dose of 4.2/1.08 mg/day<br>* Other names: Zubsolv™ sublingual tablet;Drug: Active stressor<br>* Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet<br>|
| Experimental: Buprenorphine/Naloxone high dose + active stressor<br>Participants will be maintained on Buprenorphine-Naloxone (Zubsolv™) sublingual tablet doses of 12.8/3.16 mg/day. Yohimbine 60mg powder + Hydrocortisone (Cortef™) 20mg tablet administered on one day. | Drug: Buprenorphine/Naloxone high dose<br>* Buprenorphine/Naloxone dose of 12.8/3.16 mg/day<br>* Other names: Zubsolv™ sublingual tablet;Drug: Active stressor<br>* Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid price-inelasticity (economic demand) | demand intensity (L) and demand elasticity (a) on hypothetical drug purchasing task | measured once (end of session) in each of the 8 experimental sessions over 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid Symptom Questionnaire: Agonist symptoms | Total opioid agonist symptom score (16 items, each scored on 0-4 scale, for a scale score range of 0-64, with higher scores indicating higher opioid agonist symptoms) | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Opioid Symptom Questionnaire: Withdrawal symptoms | Total opioid withdrawal symptom score (16 items, each scored on 0-4 scale, for a scale score range of 0-64, with higher scores indicating higher withdrawal symptoms) | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Visual Analog Scale (VAS) ratings | VAS ratings will measure liking, good drug effect, bad drug effect, stimulated, sedated, [preferred opioid] craving, and cigarette craving. Each VAS is scored from 0 (not at all) to 100 (extremely). | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Profile of Mood States (POMS) | 72-item POMS questionnaire, which has several subscale scores | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Blood pressure | Systolic/diastolic blood pressure (mm Hg) | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Heart rate | Heart rate (beats/min) | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Pupil diameter | Pupil diameter (mm) measured with digital pupillometer | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline 0930, 1030, 1145, 1230, 1300, 1330, 1400, 1430, 1500, and 1600. | 
| Plasma noradrenaline level | Plasma noradrenaline level (µg/ml) | Measured once per session at 2-hours post Yohimbine in each of the 8 experimental sessions | 
| Plasma BDNF level (µg/ml) | Plasma brain derived neurotrophic factor level (pg/ml) | Measured once per session at 2-hours post Yohimbine in each of the 8 experimental sessions | 
| Plasma IL-1Ra level (µg/ml) | Plasma interleukin 1Ra level (pg/ml) | Measured once per session at 2-hours post Yohimbine in each of the 8 experimental sessions | 
| Saliva cortisol level | Saliva cortisol level (µg/dL) | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline, 1.5, 2, 3 and 4 hours post Yohimbine in each of the 8 experimental sessions. | 
| Saliva alpha-amylase level | Saliva alpha-amylase level (U/dL) | Within-session change is being assessed, in each of 8 sessions over 7 weeks. Within-session measurements at baseline, 1.5, 2, 3 and 4 hours post Yohimbine in each of the 8 experimental sessions. |