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

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ClinicalTrials.gov Identifier: NCT03015246
Recruitment Status : Completed
First Posted : January 10, 2017
Last Update Posted : November 10, 2020
Sponsor:
Information provided by (Responsible Party):
Mark Greenwald, PhD, Wayne State University

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Heroin Dependence Opioid Use Disorder 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 Phase 1 Phase 2

Detailed Description:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Outcomes Assessor)
Masking Description: Medication conditions blinded using different-sized buprenorphine/naloxone sublingual tablets including placebo. Stress conditions blinded using encapsulation of yohimbine/placebo and hydrocortisone/placebo. Only pharmacy aware of drug codes.
Primary Purpose: Basic Science
Official Title: Biobehavioral Studies of Opioid Seeking: Effects of Buprenorphine/Naloxone Dose on Experimental Stress Reactivity and Opioid Abstinence
Actual Study Start Date : December 2016
Actual Primary Completion Date : June 2020
Actual Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Extended-Release Morphine + placebo stressor
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
Dose (tailored to each participant based on his/her pre-experimental opioid use amount) is administered in 3 divided daily doses.

Drug: Placebo stressor
Lactose
Experimental: Buprenorphine/Naloxone low dose + placebo stressor
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
Buprenorphine/Naloxone dose of 1.4/0.36 mg/day
Other Name: Zubsolv™ sublingual tablet

Drug: Placebo stressor
Lactose
Experimental: Buprenorphine/Naloxone moderate dose + placebo stressor
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
Buprenorphine/Naloxone dose of 4.2/1.08 mg/day
Other Name: Zubsolv™ sublingual tablet

Drug: Placebo stressor
Lactose
Experimental: Buprenorphine/Naloxone high dose + placebo stressor
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
Buprenorphine/Naloxone dose of 12.8/3.16 mg/day
Other Name: Zubsolv™ sublingual tablet

Drug: Placebo stressor
Lactose
Experimental: Extended-Release Morphine + active stressor
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
Dose (tailored to each participant based on his/her pre-experimental opioid use amount) is administered in 3 divided daily doses.

Drug: Active stressor
Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet
Experimental: Buprenorphine/Naloxone low dose + active stressor
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
Buprenorphine/Naloxone dose of 1.4/0.36 mg/day
Other Name: Zubsolv™ sublingual tablet

Drug: Active stressor
Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet
Experimental: Buprenorphine/Naloxone moderate dose + active stressor
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
Buprenorphine/Naloxone dose of 4.2/1.08 mg/day
Other Name: Zubsolv™ sublingual tablet

Drug: Active stressor
Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet
Experimental: Buprenorphine/Naloxone high dose + active stressor
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
Buprenorphine/Naloxone dose of 12.8/3.16 mg/day
Other Name: Zubsolv™ sublingual tablet

Drug: Active stressor
Yohimbine hydrochloride 60mg + Hydrocortisone 20mg tablet


Outcome Measures
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Primary Outcome Measures :
  1. Opioid price-inelasticity (economic demand) [ Time Frame: measured once (end of session) in each of the 8 experimental sessions over 7 weeks ]
    demand intensity (L) and demand elasticity (a) on hypothetical drug purchasing task


Secondary Outcome Measures :
  1. Opioid Symptom Questionnaire: Agonist symptoms [ Time Frame: 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. ]
    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)

  2. Opioid Symptom Questionnaire: Withdrawal symptoms [ Time Frame: 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. ]
    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)

  3. Visual Analog Scale (VAS) ratings [ Time Frame: 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. ]
    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).

  4. Profile of Mood States (POMS) [ Time Frame: 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. ]
    72-item POMS questionnaire, which has several subscale scores

  5. Blood pressure [ Time Frame: 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. ]
    Systolic/diastolic blood pressure (mm Hg)

  6. Heart rate [ Time Frame: 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 (beats/min)

  7. Pupil diameter [ Time Frame: 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 (mm) measured with digital pupillometer

  8. Plasma noradrenaline level [ Time Frame: Measured once per session at 2-hours post Yohimbine in each of the 8 experimental sessions ]
    Plasma noradrenaline level (µg/ml)

  9. Plasma BDNF level (µg/ml) [ Time Frame: Measured once per session at 2-hours post Yohimbine in each of the 8 experimental sessions ]
    Plasma brain derived neurotrophic factor level (pg/ml)

  10. Plasma IL-1Ra level (µg/ml) [ Time Frame: Measured once per session at 2-hours post Yohimbine in each of the 8 experimental sessions ]
    Plasma interleukin 1Ra level (pg/ml)

  11. Saliva cortisol level [ Time Frame: 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 cortisol level (µg/dL)

  12. Saliva alpha-amylase level [ Time Frame: 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 (U/dL)


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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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): NCT03015246


Locations
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United States, Kansas
Vince and Associates
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
Wayne State University
Investigators
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Principal Investigator: Mark Greenwald, PhD Wayne State University
More Information
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Responsible Party: Mark Greenwald, PhD, Professor of Psychiatry and Behavioral Neurosciences; and Director, Substance Abuse Research Division, Wayne State University
ClinicalTrials.gov Identifier: NCT03015246    
Other Study ID Numbers: BOS-1
First Posted: January 10, 2017    Key Record Dates
Last Update Posted: November 10, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Opioid-Related Disorders
Heroin Dependence
Narcotic-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Morphine
Buprenorphine
Buprenorphine, Naloxone Drug Combination
 Naloxone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists