Heroin Dependence
Conditions
Keywords
opioid dependence
Brief summary
The study is designed to compare the abuse liabilities of intranasal buprenorphine and buprenorphine/naloxone in individuals who are physically dependent on sublingual buprenorphine. The investigators hypothesize that the abuse liability of buprenorphine/naloxone is lower than that of buprenorphine alone.
Detailed description
Although sublingual buprenorphine is an effective treatment for opioid addiction, the medication itself has abuse liability and, in some countries, has largely replaced heroin as the opioid drug of choice. In response to the reports of diversion and abuse of sublingual (SL) buprenorphine, a potentially less abusable formulation of buprenorphine that contains naloxone is being marketed in several countries. However, the relative abuse liability of buprenorphine alone and the buprenorphine/naloxone combination in buprenorphine-dependent individuals is unclear. Preliminary data from a study funded by Schering-Plough Corporation suggest that the buprenorphine/naloxone combination, when given intravenously (IV), does indeed have less abuse liability than IV buprenorphine in buprenorphine-dependent individuals. In addition to IV abuse of buprenorphine, epidemiological data suggest that buprenorphine is widely abused by the intranasal (IN) route. However, no data exist on the abuse liability of either IN buprenorphine alone or the buprenorphine/naloxone combination. Several studies have shown that naloxone is an effective antagonist of opioid agonist effects when given intravenously, but it is not clear whether naloxone given intranasally is as effective as when it is given by other routes of administration. Some studies have suggested that they are equally effective (Loimer et al., 1994), but others have shown that naloxone given intranasally is less effective (i.e., has a slower onset of effects) than when given by other routes of administration (Kelly et al., 2005). How this may impact on the ability of naloxone to reduce the reinforcing effects of IN buprenorphine is unclear. The primary aim of the current study proposal is to compare the reinforcing effects of IN buprenorphine and buprenorphine/naloxone in IN opioid abusers who are maintained on SL buprenorphine using a study design parallel to that used in our recent studies of the abuse liability of IV buprenorphine and buprenorphine/naloxone. Placebo, heroin, and naloxone will be used as neutral, positive, and negative controls, respectively. Secondary aims are to compare the subjective, performance, and physiological effects of IN buprenorphine and buprenorphine/naloxone. Overall, this study will complement our investigations of IV buprenorphine products by allowing for a complete overview within the same laboratory self-administration model of both the intravenous and intranasal abuse liability of buprenorphine versus buprenorphine/naloxone in individuals maintained on buprenorphine. The primary aim of the study is to compare the reinforcing effects of IN buprenorphine and IN buprenorphine/naloxone in opioid abusers maintained on different doses of sublingual buprenorphine. Secondary aims of the study are to compare the subjective, performance and physiological effects of IN buprenorphine and IN buprenorphine/naloxone. IN-administered placebo (lactose powder), 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 (5-South) during a 7 to 8-week study. This research will provide useful information to 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
DRUGIntranasal challenge drug
Each of the experimental challenge drugs were administered intranasally to all participants in random order.
Sponsors
Indivior Inc.
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
In this study's design, all participants received each of the 9 intranasal test drugs under investigation. This study employed a Latin-square randomization procedure, therefore, the sequence of testing for the 9 intranasal drugs was unique for each participant.
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* 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 opioids in amounts and/or frequencies that meet or exceed those used in the proposed study (e.g., 1-2 bags of heroin per occasion at least twice per day) * Self-administer IN buprenorphine above placebo levels during the qualification phase (see below)
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 * AST or 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 Self-administration | Throughout the testing sessions (approximately 9 weeks). | The maximum number of responses (clicks on a computer mouse) the participant was willing to perform in order to receive a dose of the intranasal challenge drug under investigation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SOWS | Throughout the testing sessions (approximately 9 weeks). | Subjective opioid withdrawal scale (SOWS) measure (0-64). Greater score indicates more severe withdrawal. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intranasal Challege Drug Each of the 9 experimental challenge drugs were administered intranasally to all participants in random order. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Intranasal Challege Drug |
|---|---|
| Age, Continuous | 39.3 years STANDARD_DEVIATION 7.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 27 |
| serious Total, serious adverse events | 0 / 27 |
Outcome results
Primary
Drug Self-administration
The maximum number of responses (clicks on a computer mouse) the participant was willing to perform in order to receive a dose of the intranasal challenge drug under investigation.
Time frame: Throughout the testing sessions (approximately 9 weeks).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bup 8 | Drug Self-administration | 350 Clicks on a computer mouse | Standard Error 135 |
| Bup 16 | Drug Self-administration | 255 Clicks on a computer mouse | Standard Error 121 |
| Bup/Nal 8/2 | Drug Self-administration | 223 Clicks on a computer mouse | Standard Error 113 |
| Bup/Nal 8/8 | Drug Self-administration | 113 Clicks on a computer mouse | Standard Error 83 |
| Bup/Nal 8/16 | Drug Self-administration | 2.7 Clicks on a computer mouse | Standard Error 2.7 |
| Bup/Nal 16/4 | Drug Self-administration | 191 Clicks on a computer mouse | Standard Error 112 |
| Heroin | Drug Self-administration | 755 Clicks on a computer mouse | Standard Error 156 |
| Placebo | Drug Self-administration | 38 Clicks on a computer mouse | Standard Error 23 |
| Naloxone 4 mg | Drug Self-administration | 45 Clicks on a computer mouse | Standard Error 30 |
Secondary
SOWS
Subjective opioid withdrawal scale (SOWS) measure (0-64). Greater score indicates more severe withdrawal.
Time frame: Throughout the testing sessions (approximately 9 weeks).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bup 8 | SOWS | 3 units on a scale | Standard Error 0.5 |
| Bup 16 | SOWS | 3 units on a scale | Standard Error 0.7 |
| Bup/Nal 8/2 | SOWS | 3 units on a scale | Standard Error 0.9 |
| Bup/Nal 8/8 | SOWS | 3 units on a scale | Standard Error 0.8 |
| Bup/Nal 8/16 | SOWS | 5 units on a scale | Standard Error 1 |
| Bup/Nal 16/4 | SOWS | 3 units on a scale | Standard Error 0.5 |
| Heroin | SOWS | 2 units on a scale | Standard Error 0.3 |
| Placebo | SOWS | 2 units on a scale | Standard Error 0.53 |
| Naloxone 4 mg | SOWS | 7 units on a scale | Standard Error 1 |