Narcotic Abuse
Conditions
Keywords
opioid, oxycodone, NK1 antagonist, aprepitant, intranasal, abuse
Brief summary
Addressing the issue of opioid dependence and tolerance has public health implications for the treatment of opioid abuse (both heroin as well as pharmaceutical opioids) and for the treatment of pain. Recent preclinical data suggest a role for Substance P (NK-1) receptors in modulating both the acute and chronic response to opioids. The objective of this study is to determine whether pretreatment with aprepitant, a selective neurokinin-1 (NK-1) antagonist can reduce the direct response to an opioid agonist (oxycodone) on measures related to abuse liability and reinforcing effects.
Detailed description
Healthy adult volunteers with histories of illicit opioid use by the intranasal and oral routes will be admitted to this 6-week inpatient, crossover study. They will participate in 15 experimental test sessions, each lasting approximately 6.5 hours, during which they will receive a range of acute doses of aprepitant, including placebo, followed by challenge with oxycodone or placebo (given intranasally or orally). Multi-dimensional outcomes, including physiological (blood pressure, oxygen saturation, pupil diameter), subjective (questionnaires related to mood, abuse liability) and observer ratings will be collected repeatedly throughout each session. Data will be analyzed using parametric approaches to within-subject designs.
Interventions
DRUGAprepitant 0mg
Aprepitant 0mg, p.o. pretreatment
DRUGAprepitant 40mg
Aprepitant 40mg, p.o. pretreatment
DRUGAprepitant 200mg
Aprepitant 200mg, p.o. pretreatment
DRUGOxycodone 0mg, p.o.
Oxycodone 0mg, p.o.
DRUGOxycodone 20mg, p.o.
Oxycodone 20mg, p.o.
DRUGOxycodone 40mg, p.o.
Oxycodone 40mg, p.o.
DRUGOxycodone 0mg, IN
Oxycodone 0mg, IN
DRUGOxycodone 15mg, IN
Oxycodone 15mg, IN
DRUGOxycodone 30mg, IN
Oxycodone 30mg, IN
Sponsors
National Institute on Drug Abuse (NIDA)
Merck Sharp & Dohme LLC
Sharon Walsh
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Within subject crossover designed that examined 15 experimental conditions within a single group of participants
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Recreational user of opioids * Healthy * Ages 18-55 years old * Able to provide informed consent
Exclusion criteria
* Ongoing medical or psychiatric condition that would be contraindicated for participation * Past 30 day use of and P4503A4 inhibitor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Abuse Liability Proxy | 42 days | Visual analog scale ratings (from 0-100) on the subject-rated measure of How much do you like the drug? with higher scores indicating greater abuse liability (and 100 anchored with extremely and zero indicating none anchored with none at all. Data were collected across multiple time points but the peak maximum score was used for the primary outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Respiration Depression | 42 days | Respiration rate measured over 60 seconds. Data were collected across multiple time points, but the peak minimum score was used for this outcome measure. |
Countries
United States
Participant flow
Recruitment details
All recruitment was conducted through a research clinic at a public university.
Pre-assignment details
Subjects were initially screened for inclusion/exclusion criteria. Fifteen subjects signed the screening consent but only nine were qualified to participate and signed the study consent. One subject left the study before receiving any interventions.
Participants by arm
| Arm | Count |
|---|---|
| Crossover Within Subject All subjects were exposed to every condition. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Crossover Within Subject |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 32.3 years STANDARD_DEVIATION 3 |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Abuse Liability Proxy
Visual analog scale ratings (from 0-100) on the subject-rated measure of How much do you like the drug? with higher scores indicating greater abuse liability (and 100 anchored with extremely and zero indicating none anchored with none at all. Data were collected across multiple time points but the peak maximum score was used for the primary outcome measure.
Time frame: 42 days
Population: Prior laboratory-based within subject studies of the pharmacodynamic response to opioid challenges. The within subject data analysis does not lend itself to reporting data in the format provided below.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Placebo (in and po) | Abuse Liability Proxy | 0.197 units on a scale (points 0-100) | Standard Deviation 0.197 |
| Aprepitant 40 mg - Placebo | Abuse Liability Proxy | 0.483 units on a scale (points 0-100) | Standard Deviation 0.397 |
| Aprepitant 200 mg- Placebo | Abuse Liability Proxy | 0.159 units on a scale (points 0-100) | Standard Deviation 0.159 |
| Placebo- 15 mg Oxycodone Intranasal | Abuse Liability Proxy | 7.678 units on a scale (points 0-100) | Standard Deviation 2.656 |
| Placebo- 30 mg Oxycodone Intranasal | Abuse Liability Proxy | 17.450 units on a scale (points 0-100) | Standard Deviation 4.275 |
| Placebo- 20 mg Oxycodone Oral | Abuse Liability Proxy | 9.850 units on a scale (points 0-100) | Standard Deviation 5.09 |
| Placebo - 40 mg Oxycodone Oral | Abuse Liability Proxy | 16.646 units on a scale (points 0-100) | Standard Deviation 4.203 |
| Aprepitant 40 mg- 15 mg Oxycodone Intranasal | Abuse Liability Proxy | 8.543 units on a scale (points 0-100) | Standard Deviation 2.892 |
| Aprepitant 40 mg - 30 mg Oxycodone Intranasal | Abuse Liability Proxy | 15.092 units on a scale (points 0-100) | Standard Deviation 4.706 |
| Aprepitant 40 mg- 20 mg Oxycodone Oral | Abuse Liability Proxy | 13.281 units on a scale (points 0-100) | Standard Deviation 4.009 |
| Aprepitant 40 mg - 40 mg Oxycodone Oral | Abuse Liability Proxy | 17.244 units on a scale (points 0-100) | Standard Deviation 4.788 |
| Aprepitant 200 mg - 15 mg Oxycodone Intranasal | Abuse Liability Proxy | 17.195 units on a scale (points 0-100) | Standard Deviation 4.897 |
| Aprepitant 200 mg - 30 mg Oxycodone Intranasal | Abuse Liability Proxy | 28.211 units on a scale (points 0-100) | Standard Deviation 4.365 |
| Aprepitant 200 mg- 20 Oxycodone Oral | Abuse Liability Proxy | 8.196 units on a scale (points 0-100) | Standard Deviation 2.667 |
| Aprepitant 200 mg- 40 Oxycodone Oral | Abuse Liability Proxy | 26.322 units on a scale (points 0-100) | Standard Deviation 3.702 |
Comparison: Area-under-the-curve (AUC) scores were derived from time course data and analyzed using two-factor ANOVA \[aprepitant dose (3 levels)x oxycodone dose (3 levels)\].~All analyses were conducted using SAS 9.1 for Windows (SAS Institute Inc., Cary, NC, USA) and were considered significant when P 0.05.p-value: <0.05ANOVA
Secondary
Respiration Depression
Respiration rate measured over 60 seconds. Data were collected across multiple time points, but the peak minimum score was used for this outcome measure.
Time frame: 42 days
Population: Prior laboratory-based within subject studies of the pharmacodynamic response to opioid challenges.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Placebo (in and po) | Respiration Depression | 13.75 number of breaths per minute | Standard Deviation 3.15 |
| Aprepitant 40 mg - Placebo | Respiration Depression | 11.63 number of breaths per minute | Standard Deviation 1.6 |
| Aprepitant 200 mg- Placebo | Respiration Depression | 11.25 number of breaths per minute | Standard Deviation 1.75 |
| Placebo- 15 mg Oxycodone Intranasal | Respiration Depression | 12.13 number of breaths per minute | Standard Deviation 2.3 |
| Placebo- 30 mg Oxycodone Intranasal | Respiration Depression | 10.25 number of breaths per minute | Standard Deviation 1.98 |
| Placebo- 20 mg Oxycodone Oral | Respiration Depression | 12.25 number of breaths per minute | Standard Deviation 2.19 |
| Placebo - 40 mg Oxycodone Oral | Respiration Depression | 12.25 number of breaths per minute | Standard Deviation 2.12 |
| Aprepitant 40 mg- 15 mg Oxycodone Intranasal | Respiration Depression | 11.00 number of breaths per minute | Standard Deviation 2.33 |
| Aprepitant 40 mg - 30 mg Oxycodone Intranasal | Respiration Depression | 12.38 number of breaths per minute | Standard Deviation 1.92 |
| Aprepitant 40 mg- 20 mg Oxycodone Oral | Respiration Depression | 11.63 number of breaths per minute | Standard Deviation 2.56 |
| Aprepitant 40 mg - 40 mg Oxycodone Oral | Respiration Depression | 14.00 number of breaths per minute | Standard Deviation 2.33 |
| Aprepitant 200 mg - 15 mg Oxycodone Intranasal | Respiration Depression | 14.00 number of breaths per minute | Standard Deviation 2.33 |
| Aprepitant 200 mg - 30 mg Oxycodone Intranasal | Respiration Depression | 12.13 number of breaths per minute | Standard Deviation 2.17 |
| Aprepitant 200 mg- 20 Oxycodone Oral | Respiration Depression | 12.00 number of breaths per minute | Standard Deviation 1.93 |
| Aprepitant 200 mg- 40 Oxycodone Oral | Respiration Depression | 11.38 number of breaths per minute | Standard Deviation 3.02 |