Buprenorphine's Dose Response Curve

Evaluation of Opioid Antagonist Activity in Humans

This is a residential study that looks at the effects of buprenorphine in persons who abuse but are not dependent on opioids. Animal studies show that very high doses of buprenorphine produce less effects than mid-range doses. This suggests that buprenorphine can be a very safe medication. However, no studies in humans have tested higher doses in a similar way. The goal of this study is to show the effects of single doses of buprenorphine, across a range of doses, in persons who are not physically dependent on opioids (but do abuse opioids).

Study Overview

• Status: Completed
• Conditions: Opioid-related Disorders
• Intervention / Treatment: Drug: Placebo; Drug: Morphine; Drug: Buprenorphine

Detailed Description

Preclinical studies have demonstrated for a variety of measures that buprenorphine has a bell-shaped dose response curve. However, human studies with buprenorphine have not shown such an effect, although controlled studies have generally not tested higher acute doses of buprenorphine. Current clinical recommendations generally place an upper limit of daily buprenorphine dosing at 32 mg of sublingual tablets, although considerably higher acute doses have been administered to humans (primarily in clinical studies of less than daily dosing). Determining the relationship between higher doses of buprenorphine in humans and effects produced would be valuable; it would be scientifically interesting to demonstrate a bell-shaped curve in humans, and it would help guide clinical practice (for example, with respect to dosing, safety, and side effect considerations. The purpose of this study is to characterize the dose response curve for buprenorphine in humans, utilizing acute single doses of parenteral buprenorphine.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University (BPRU) Bayview Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. current opioid abuse but not physically dependent on opioids

Exclusion Criteria:

1. evidence of significant medical (e.g., insulin dependent diabetes) or psychiatric (e.g., schizophrenia) illness
2. anemia defined as a hematocrit less than 30%
3. females are required to provide a negative pregnancy test prior to study participation
4. baseline electrocardiogram (ECG) showing prolongation of the corrected QT interval (QTc)
5. current significant alcohol or sedative/hypnotic drug use
6. Forced expiratory volume at one second (FEV1) of less than 50% at the time of screening
7. applicants seeking treatment for their substance abuse will not be admitted to the study, and should be provided information about treatment services available

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Placebo; Intramuscular; double blind; once per week
Experimental: Morphine 15; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Morphine; Intramuscular; up to 1-2 times per week; doses (15, 30 mg) double blind
Experimental: Morphine 30; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Morphine; Intramuscular; up to 1-2 times per week; doses (15, 30 mg) double blind
Experimental: Buprenorphine 8; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Buprenorphine; Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.
Experimental: Buprenorphine 16; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Buprenorphine; Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.
Experimental: Buprenorphine 32; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Buprenorphine; Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.
Experimental: Buprenorphine 48; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Buprenorphine; Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.
Experimental: Buprenorphine 60; All participants are randomly assigned to receive an order of the 8 study drugs/doses (placebo, 2 doses of morphine, 5 doses of buprenorphine).	Drug: Buprenorphine; Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Change From Baseline in Drug Effect Assessed by Visual Analog Scale (VAS)	Opioid agonist effects measured by peak change from baseline drug effect visual analog scale. Scores range from 0 (not all all) to 100 (extremely); higher scores indicate a stronger drug effect.	Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Psychomotor/Cognitive Performance Effects Assessed by Digit Symbol Substitution Test (DSST)	Digit Symbol Substitution Test (DSST) is a sub-test within the Wechsler Adult Intelligence Scale and is frequently used to assess psychomotor performance changes associated with drug effects. The higher the percent correct on this measure the better the performance.	Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Psychomotor/Cognitive Performance Effects Assessed by Trails B	The Trails B task specifically measures set shifting and executive functioning within the Trail-Making Test. Part B consists of 25 circles distributed over a sheet of paper. Participants are asked to connect the circles in an ascending pattern, alternating between numbers and letters (i.e., 1-A-2-B-3-C, etc.). Results are reported as the number of seconds required to complete the task; therefore, higher scores reveal greater impairment.	Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Physiologic Effects as Assessed by Blood Pressure		Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Physiologic Effects as Assessed by Heart Rate		Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Physiologic Effects as Assessed by Body Temperature		Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Physiologic Effects as Assessed by Oxygen Saturation		Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)
Physiologic Effects as Assessed by Pupil Diameter		Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Eric C Strain, M.D., Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: April 11, 2007
• First Submitted That Met QC Criteria: April 11, 2007
• First Posted (Estimate): April 13, 2007

Study Record Updates

• Last Update Posted (Actual): March 3, 2017
• Last Update Submitted That Met QC Criteria: January 11, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Buprenorphine; Opioid addiction; Opioid dependence
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Buprenorphine; Morphine
• Other Study ID Numbers: NIDA-08045-8; DPMCDA (Other Identifier: NIDA); 5R01DA008045-08 (U.S. NIH Grant/Contract); R01DA008045 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No