A Study to Evaluate the Abuse Potential of Oxymorphone Compared to Other Mu Opioid Agonists.

Significant public health concerns have arisen from the misuse of oxymorphone, a potent mu
opioid pain medication approved by the Food and Drug Administration as Opana and Opana ER.
However, little is known about its abuse potential relative to other mu opioid analgesics.
The present study is designed to examine the abuse liability of intravenous oxymorphone
compared to other mu opioid agonists (oxycodone, morphine, and hydromorphone). A total of 20
participants who are physically dependent on opioids and who meet DSM 5 criteria for Opioid
Use Disorder will complete the study across 2 sites, New York State Psychiatric Institute
(NYSPI) and the University of Kentucky; a total of 6 additional participants across the 2
sites will complete a pilot phase of the study in order to establish comparable opioid
dose-response functions based on subjective ratings of Drug Liking. All participants will
reside on clinical inpatient units for the duration of the studies (both the 8- to 9- week
main and 4- to 5-week pilot studies; please note that the pilot study is identical in design
to the first 4-5 weeks of the main study). The study design is based on the 2017 FDA
Assessment of Abuse Potential of Drugs: Guidance for Industry [Center for Drug Evaluation and
Research (CDER), 2017], which suggests use of a double-blind, positive- and
placebo-controlled design that includes a qualification phase and VAS measure of Drug Liking.
The proposed study also examines the reinforcing effects of oxymorphone and other mu opioid
agonists using two different drug self-administration procedures, namely Drug versus Money
and Drug versus Drug choice procedures.

Inclusion Criteria:

1. Able to understand and provide signed and dated written consent.

2. Self-reported opioid use for nontherapeutic purposes on at least 21 days in the 30
days prior to screening, physical dependence on opioids, recent intravenous opioid
use, and meeting DSM 5 criteria for moderate-severe opioid use disorder.

3. Positive urine drug screen for opioids (those who are in a methadone or buprenorphine
treatment program are ineligible; physical dependence on street methadone or
buprenorphine are also exclusionary so participants must produce at least one
methadone- or buprenorphine-negative urine during screening).

4. ≥ 21 and ≤ 55 years of age.

5. Body mass index (BMI) ≥ 18 and ≤ 35 kg/m2 and weight ≥ 50 kg (110 pounds).

6. Otherwise healthy as determined by the investigator.

7. Demonstrate understanding how to complete the self-administration tasks and VAS
Questionnaire.

8. Women of childbearing potential must not be pregnant or breastfeeding at screening.

9. Willing and able to comply with all testing requirements defined in the protocol.

participation in the Study Treatment Phase:

1. During the Study Qualification Phase, on the bipolar 100--mm Drug Liking VAS, the
subject must provide Emax ≥ 40 mm and < 60 mm following placebo and, following
morphine 56 mg/70 kg, i.v., Emax ≥ 60 mm and ≥ 15 mm closer to "Strong Liking" than
the Emax to placebo.

2. In the judgment of the investigator, the subject is able to tolerate the i.v., opioids
administered in the study, including the ability to complete most pharmacodynamics
assessments administered post--dose.

3. In the judgment of the study staff, the subject's general behavior during the Study
Qualification Phase suggests the ability to successfully complete the Study Treatment
Phase.

Exclusion Criteria:

1. History of a medical or psychiatric disorder that would prevent successful completion
of the study.

2. Current DSM-5 diagnosis of substance use disorders requiring medical management other
than OUD.

3. Suicidal ideation or intent with or without a plan at Screening or within 6 months
prior to Screening (i.e., answering "Yes" to questions 4 and/or 5 on the Suicidal
Ideation section of the Columbia Suicide Severity Rating Scale).

4. Currently seeking or participating in treatment for substance use disorder.

5. Physically dependent on drugs of abuse (other than opioids, nicotine, or caffeine) or
alcohol.

6. Medically important deviation from normal limits on physical examination, vital signs,
screening laboratory tests, or 12--lead ECG.

7. Significant cardiovascular, hepatic, renal, respiratory, gastrointestinal, endocrine,
immunologic, dermatologic, hematologic, or neurologic disorder.

8. Any surgical, or medical condition that may interfere with the absorption,
distribution, metabolism, or excretion of the test drug.

9. Family history of long QT syndrome and/or unexpected sudden cardiac death or is known
to have QTc > 500 ms at screening.

10. Used an investigational agent within 30 days or 5 therapeutic half-lives of that
agent, whichever is longer, prior to the first dose of study drug.

11. Hypersensitivity to opioids or any drug intended for use in this study.

12. Acute gastrointestinal symptoms (e.g., nausea, vomiting, fever, or Diarrhea unrelated
to opioid withdrawal) ≤ 7 days before Day 1.

13. Any of the following values for laboratory tests at Screening:

1. A positive pregnancy test in women of childbearing potential.

2. Hemoglobin < 11 g/dL in males and < 10 gm/dL in females.

3. Neutrophil count < 1.0 × 109/L.

4. Platelet count < 75 × 109/L.

5. Creatinine clearance < 50 ml/min per modified Cockcroft—Gault equation.

6. Aspartate aminotransferase or alanine aminotransferase > 3.0x upper limit of
normal.