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

• ClinicalTrials.gov Identifier: NCT03015246
• Recruitment Status: Recruiting
• First Posted: January 10, 2017
• Last Update Posted: January 18, 2020
• Sponsor: Wayne State University
• Information provided by (Responsible Party): Mark Greenwald, PhD, Wayne State University

Study Description

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: Buprenorphine-Naloxone; Drug: Extended-release Morphine; Drug: Yohimbine; Drug: Hydrocortisone; Drug: Matching Placebo for Yohimbine; Drug: Matching Placebo for Hydrocortisone	Phase 1

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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Estimated Primary Completion Date: June 2020
• Estimated Study Completion Date: August 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Buprenorphine-Naloxone; Participants will be maintained on Buprenorphine-Naloxone (Zubsolv™) sublingual tablets. Every participant will be maintained two weeks at each dosage level, in randomized order, on Buprenorphine-Naloxone (Zubsolv™) doses of 1.4/0.36 mg/day, 4.2/1.08 mg/day, and 12.8/3.16 mg/day.	Drug: Buprenorphine-Naloxone; To blind the varying maintenance doses, on each protocol day the participant will always take a total of 4 tablets at the same time, with a mixture of active and placebo tablets. Total daily doses will differ, depending on the periods/weeks within each study phase.; Other Name: Zubsolv™; Drug: Extended-release Morphine; During each participant's first experimental week, morphine doses (tailored to each individual) will be administered orally prior to each of the first 2 inpatient experimental sessions.; Other Name: Morphine; Drug: Yohimbine; Yohimbine (or matching placebo)will be administered at 12:00pm on each of the experimental sessions.; Other Name: Yohimbine hydrochloride powder; Drug: Hydrocortisone; Hydrocortisone or matching placebo will be administered 45 min after Yohimbine.; Other Name: Cortef™; Drug: Matching Placebo for Yohimbine; Yohimbine (or matching placebo) will be administered at 12:00pm on each of the experimental sessions.; Other Name: placebo yohimbine (lactose); Drug: Matching Placebo for Hydrocortisone; Hydrocortisone or matching placebo will be administered 45 min after Yohimbine.; Other Name: placebo hydrocortisone (lactose)
Buprenorphine-Naloxone Stabilization; After completing the three Buprenorphine-Naloxone maintenance-dose conditions, each participant will be stabilized on a daily dose of Buprenorphine-Naloxone 4.2/1.08 mg for one week, then the daily dose will be tapered over 3 weeks to 2.8/0.72 mg (week 1), 1.4/0.36 mg (week 2) and 0/0 mg (week 3).	Drug: Buprenorphine-Naloxone; To blind the varying maintenance doses, on each protocol day the participant will always take a total of 4 tablets at the same time, with a mixture of active and placebo tablets. Total daily doses will differ, depending on the periods/weeks within each study phase.; Other Name: Zubsolv™

Outcome Measures

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

• 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

Contacts

Contact: Debra Kelsh, M.D.; (913) 696-1601 ext 6160; DKelsh@altasciences.com

Locations

United States, Kansas

Vince and Associates; Recruiting

Overland Park, Kansas, United States, 66212

Contact: Debra Kelsh, M.D. 913-696-1601 ext 6160 dkelsh@altasciences.com

Principal Investigator: Mark Greenwald, PhD

Principal Investigator: Debra Kelsh, M.D.

Sponsors and Collaborators

Wayne State University

Investigators

• Principal Investigator: Mark Greenwald, PhD; Wayne State University

More Information

• 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
• Last Update Posted: January 18, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Heroin Dependence; Opioid-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Morphine; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Naloxone; Yohimbine; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Narcotic Antagonists; Anti-Inflammatory Agents; Mydriatics; Autonomic Agents; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents