A Study Using fMRI Imaging to Evaluate the Effect of NKTR-181 on Brain Activity in Healthy, Non-physically Dependent Recreational Opioid Users.

The main purpose of this study is to evaluate the effect of NKTR-181 on brain activity in healthy, non-physically dependent recreational opioid users. This study will last about 88 days for each participant.

This study is a single-center study in which approximately 24 subjects will be randomized to one of two treatment groups. Subjects will enter a screening period between Day -28 and Day -2. Upon meeting all criteria for enrollment, on Day -1 subjects will enter the clinical research study unit (CRSU) for an overnight confinement. On Day 1, subjects will undergo a baseline MRI and will then be randomized to NKTR-181 or oxycodone immediate release (IR). Once randomized, subjects will receive a single dose of study drug (NKTR-181 or oxycodone IR) and matched alternate-treatment placebo. Subjects will undergo a series of three fMRIs (functional magnetic resonance imaging) post dose (at hours 1, 2, and 4). At post-dose hours 0.5, 1, 2, 3, 4, 5, 6, and 8, pupillometry will be performed and PK blood samples will be drawn. Following a 14- to 17-day safety follow-up period, subjects will return to the research facility clinic for the End of Study (EOS) visit (Day 16-19).

Eligibility Criteria:
Key Inclusion Criteria:

* Healthy male and female recreational opioid users, 18-65 years of age inclusive.
* Body Mass Index (BMI) between 19.0 to 45.0kg/m2
* Have at least one urine drug screen positive for opioids during Screening to confirm recreational opioid use. Subjects testing positive for methadone or buprenorphine prescribed for treatment will be excluded.
* Subjects must agree to practice adequate contraception as outlined in the protocol.

Key Exclusion Criteria:

* Any metal fragments or other bodily metal that would pose a risk to subjects during MRI scanning as determined by the MRI technologist and/or MRI physicist
* Any clinically significant disease or condition that might compromise the cardiovascular, hematological, renal, hepatic, pulmonary, endocrine, central nervous, or gastrointestinal systems or other conditions that may interfere with the absorption, distribution, metabolism, or excretion of the study drug or would place the subject at increased risk
* History of clinically significant acute asthma or other obstructive airway disease requiring daily controller medication or any condition that may increase the risk for respiratory depression
* Current neurologic conditions such as convulsive disorders, or history of severe head injury.
* Any current DSM-5 axis I psychiatric disorder or neurological disorder requiring ongoing treatment
* Current substance use disorder (moderate to severe), other than Opioid, Nicotine, THC (tetrahydrocannabinol), cocaine, or caffeine as defined by DSM-5
* Physical dependence of opioids
* History of claustrophobia or any other psychiatric disorder that would preclude subject tolerance of MRI procedures.
* Current use of any medication that could affect central nervous system blood flow (e.g. certain cardiovascular medications, triptan migraine medications)
* Clinical Opiate Withdrawal Scale (COWS) score of greater than 5 during screening or prior to first scan.
* Positive urine drug screen for buprenorphine or methadone immediately prior to the first scan.