Buprenorphine's Dose Response Curve

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

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.

Official Title
-----------------
Evaluation of Opioid Antagonist Activity in Humans

Conditions
-----------------
Opioid-related Disorders

Intervention / Treatment
-----------------
* Drug: Buprenorphine
* Drug: Morphine
* Drug: Placebo


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

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 55 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>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<br>* Intramuscular; double blind; once per week<br>|
| Experimental: Morphine 15<br>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<br>* Intramuscular; up to 1-2 times per week; doses (15, 30 mg) double blind<br>|
| Experimental: Morphine 30<br>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<br>* Intramuscular; up to 1-2 times per week; doses (15, 30 mg) double blind<br>|
| Experimental: Buprenorphine 8<br>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<br>* Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.<br>|
| Experimental: Buprenorphine 16<br>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<br>* Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.<br>|
| Experimental: Buprenorphine 32<br>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<br>* Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.<br>|
| Experimental: Buprenorphine 48<br>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<br>* Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.<br>|
| Experimental: Buprenorphine 60<br>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<br>* Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.<br>|

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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Opioid addiction, Opioid dependence, Buprenorphine