Buprenorphine's Dose Response Curve

Evaluation of Opioid Antagonist Activity in Humans

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00460239

Enrollment

Registered

2007-04-13

Start date

2007-01-31

Completion date

2009-07-31

Last updated

2017-03-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Opioid-related Disorders

Keywords

Opioid addiction, Opioid dependence, Buprenorphine

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.

Interventions

DRUGBuprenorphine

Intramuscular, doses (8, 16, 32, 48, 60 mg) are blind; administered up to 1-2 times per week.

DRUGMorphine

Intramuscular; up to 1-2 times per week; doses (15, 30 mg) double blind

DRUGPlacebo

Intramuscular; double blind; once per week

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

21 Years to 55 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Peak Change From Baseline in Drug Effect Assessed by Visual Analog Scale (VAS)	Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)	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.
Psychomotor/Cognitive Performance Effects Assessed by Digit Symbol Substitution Test (DSST)	Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)	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.
Psychomotor/Cognitive Performance Effects Assessed by Trails B	Each experimental test session (8 experimental test sessions assessed for up to 6-7 weeks)	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.
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)	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
All Study Participants All Study Participants	12
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008
Overall Study	Physician Decision	0	1	0	0	0	2	0	0	0
Overall Study	Withdrawal by Subject	0	0	0	0	0	1	0	0	0

Baseline characteristics

Characteristic	All Study Participants
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	12 Participants
Age, Continuous	39.2 years STANDARD_DEVIATION 6.48
Gender Female	0 Participants
Gender Male	12 Participants
Region of Enrollment United States	12 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	0 / 12	0 / 12	0 / 12
serious Total, serious adverse events	0 / 12	0 / 12	0 / 12

Outcome results

Primary

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.