Opioid-related Disorders
Conditions
Brief summary
The study is designed to compare the abuse liabilities of intravenous buprenorphine and buprenorphine/naloxone in individuals who are physically dependent on sublingual buprenorphine. We hypothesize that the abuse liability of buprenorphine/naloxone is lower than that of buprenorphine alone.
Detailed description
Drug dependence is a major international public health problem of which opioid dependence, notably involving heroin, is a major component. Opioid dependence affects an estimated 13 million injection drug users (IDUs) worldwide. The high health service costs for the treatment of diseases related to non-medical drug use and the high cost to society of drug-related behavior have prompted researchers to seek new medications and treatment strategies for opioid dependence. Buprenorphine, a mu-opiate receptor partial agonist and kappa-opiate receptor antagonist, is one such new medication that has had a significant role in expanding access to effective opioid dependence treatment. It is available as Subutex (buprenorphine alone) or Suboxone (a combination of buprenorphine and naloxone). Although it is commonly believed that the abuse potential of buprenorphine is low, numerous countries have reported illicit diversion of buprenorphine and a growing population of buprenorphine abusers. Theoretically, Suboxone would have lower abuse potential. When used sublingually, as prescribed, the amount of naloxone absorbed is negligible. However, if a patient crushes the tablet and attempts to inject or sniff the medication, the naloxone will become effective as an opioid antagonist and may precipitate withdrawal signs and symptoms in individuals dependent on full opioid agonists and/or attenuate the euphoric effects of the buprenorphine that is also contained in the medication. To date, few laboratory studies have evaluated the abuse liability of buprenorphine in humans using a drug self-administration protocol. We are proposing to evaluate the abuse potential of intravenous (IV) buprenorphine compared to IV buprenorphine/naloxone in buprenorphine-maintained injection drug users (IDUs), incorporating self-administration procedures with other measures of opioid effects. The proposed study will investigate the conditions that affect the self-administration of IV buprenorphine by buprenorphine abusers. The primary aim of the study is to compare the reinforcing effects of IV buprenorphine and IV buprenorphine/naloxone in IDUs maintained on different doses of sublingual buprenorphine (2, 8, and 24 mg/day). Secondary aims of the study are to compare the subjective, performance and physiological effects of IV buprenorphine and IV buprenorphine/naloxone. IV-administered placebo (saline), naloxone alone, and heroin alone will be tested as neutral, negative, and positive control conditions, respectively. Participants (N=12 completers) will reside on an inpatient unit (the General Clinical Research Unit, GCRU) during a 7 to 8-week study. This research will provide useful information for clinicians treating opioid dependent individuals with buprenorphine, and importantly, will provide information about the abuse potential and effects of buprenorphine on multiple measures of human functioning.
Interventions
DRUGHeroin
Heroin (25 mg)
DRUGNaloxone
.4 mg
DRUGLow Bup Dose
4 and 8 mg
DRUGHigh Bup Dose
8mg and 16 mg
DRUGLow Bup/Nal Dose
Buprenorphine/Naloxone 4/1 mg, 8/2 mg
DRUGHigh Bup/Nal Dose
Buprenorphine/Naloxone 8/2 mg, 16/4 mg
DRUGPlacebo (PCB)
Placebo control administration
Sponsors
Schering-Plough
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Diagnostic and Statistical Manual (DSM) IV criteria for heroin dependence * No major mood, psychotic, or anxiety disorder * Physically healthy * Able to perform study procedures * 21-45 years of age * Normal body weight * Current use of i.v. opioids in amounts and/or frequencies that meet or exceed those used in the proposed study (1-2 bags of heroin per occasion at least twice per day) * Self-administer at least 4 mg i.v. buprenorphine above placebo levels during the dose run up phase
Exclusion criteria
* DSM IV criteria for dependence on drugs other than opioids, nicotine or caffeine * Participants requesting treatment * Participants on parole or probation * Pregnancy or lactation * Birth, miscarriage or abortion within 6 months * Current or recent history of significant violent behavior * Current major Axis I psychopathology, other than opioid dependence (e.g., mood disorder with functional impairment or suicide risk, schizophrenia), that might interfere with ability to participate in the study * aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 times the upper limit of normal * Significant suicide risk * Current chronic pain * Sensitivity, allergy, or contraindication to opioids * Current or recent (past 30 days) physical dependence on or treatment with methadone, buprenorphine, or the buprenorphine/naloxone combination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug's Breakpoint | Single measurement taken following each of the 7 IV experimental doses | Measure of a drug's reinforcing effects. The Breakpoint is the point at which the participant stop performing an operant task (clicks on a mouse) in order to received the drug. Therefore, the reported breakpoint is the total amount of work the participant was willing to perform to receive the dose being tested |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Drug Liking | Peak (highest) rating obtained following drug administration throughout the entire 3 hr session | Participant's subjective ratings of how much they Like the dose they just received on a scale of 0 -100. |
Countries
United States
Participant flow
Recruitment details
Enrollment dates: September 10, 2007 - August 13, 2008 Location: Medical clinic
Participants by arm
| Arm | Count |
|---|---|
| Challenge Doses This study employs a within-subjects design, all participant experience all challenge doses. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not qualify | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Undisclosed back pain | 1 |
| Overall Study | Undisclosed excessive methadone use | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Challenge Doses |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 36.2 years STANDARD_DEVIATION 6.2 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 17 |
| serious Total, serious adverse events | 0 / 17 |
Outcome results
Primary
Drug's Breakpoint
Measure of a drug's reinforcing effects. The Breakpoint is the point at which the participant stop performing an operant task (clicks on a mouse) in order to received the drug. Therefore, the reported breakpoint is the total amount of work the participant was willing to perform to receive the dose being tested
Time frame: Single measurement taken following each of the 7 IV experimental doses
Population: Heroin users, not seeking treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heroin | Drug's Breakpoint | 1200 number of clicks on a mouse | Standard Deviation 200 |
| Naloxone | Drug's Breakpoint | 10 number of clicks on a mouse | Standard Deviation 10 |
| Low Bup Dose | Drug's Breakpoint | 1100 number of clicks on a mouse | Standard Deviation 180 |
| High Bup Dose | Drug's Breakpoint | 1200 number of clicks on a mouse | Standard Deviation 190 |
| Lower Bup/Nal Dose | Drug's Breakpoint | 300 number of clicks on a mouse | Standard Deviation 100 |
| High Bup/Nal Dose | Drug's Breakpoint | 750 number of clicks on a mouse | Standard Deviation 175 |
| Placebo | Drug's Breakpoint | 0 number of clicks on a mouse | Standard Deviation 0 |
Secondary
Drug Liking
Participant's subjective ratings of how much they Like the dose they just received on a scale of 0 -100.
Time frame: Peak (highest) rating obtained following drug administration throughout the entire 3 hr session
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heroin | Drug Liking | 41.5 units on a scale | Standard Error 5 |
| Naloxone | Drug Liking | 3 units on a scale | Standard Error 2.7 |
| Low Bup Dose | Drug Liking | 29.8 units on a scale | Standard Error 4 |
| High Bup Dose | Drug Liking | 42.5 units on a scale | Standard Error 5 |
| Lower Bup/Nal Dose | Drug Liking | 10.5 units on a scale | Standard Error 2.4 |
| High Bup/Nal Dose | Drug Liking | 27 units on a scale | Standard Error 4 |
| Placebo | Drug Liking | 1 units on a scale | Standard Error 0.6 |