A Study Using Functional Magnetic Resonance Imaging to Evaluate the Effect of NKTR-181 on Brain Activity in Healthy, Non-dependent Recreational Opioid Users.

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 a 2-day 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 four fMRIs
(functional magnetic resonance imaging) post dose (at hours 1, 2, 4, and 8). Pre-dose and at
post-dose hours 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24, pupillometry will be performed and PK
blood samples will be drawn. On Day 2, subjects will be discharged from the CRSU. 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).

Key Inclusion Criteria:

- Healthy male and female recreational opioid users. A recreational opioid user is
defined as one who is not currently physically dependent on opioids but has experience
in the use of opioids for non-therapeutic purposes (i.e., for psychoactive effects) on
at least 10 occasions within the last year and at least once in the 8 weeks prior to
the Screening visit.

- Have at least one urine drug screen positive for opioids other than methadone or
buprenorphine during Screening to confirm recreational opioid use.

Key Exclusion Criteria:

- Any metal fragments or other bodily metal (e.g., pacemaker, hip replacement) that
would pose a risk to subjects during MRI scanning as determined by the MRI
technologist and/or MRI physicist

- History of clinically significant acute asthma or other obstructive airway disease
(e.g., chronic obstructive pulmonary disease) requiring daily controller medication
(e.g., inhaled corticosteroids or bronchodilators) or any condition that may increase
the risk for respiratory depression (e.g., sleep apnea), judged as clinically
significant by the Investigator.

- Current neurologic conditions such as convulsive disorders, or history of severe head
injury, judged as clinically significant by the Investigator.

- Any current DSM-5 axis I psychiatric disorder, including but not limited to bipolar
disorder, major depressive disorder, attention deficit hyperactivity disorder, or
schizophrenia, or a neurological disorder requiring ongoing treatment.

- History or presence of drug or alcohol dependence (except nicotine or caffeine) as
defined by the Diagnostic and Statistical Manual of Mental Disorders 4th edition -
Text Revision (DSM-IV-TR), including subjects who have ever been in a drug
rehabilitation program (other than for treatment for smoking cessation).

- History of claustrophobia or any other psychiatric disorder that would preclude
subject tolerance of MRI procedures.

- Current suicidal or homicidal ideation or a suicide attempt within the past 6 months.

- Inability to commit to abstinence from use of any tobacco- or nicotine-containing
products during the period from admission to discharge from the CSU, despite being
administered a nicotine transdermal patch while confined in the CSU and while in the
Research Clinic for MRI scans.

- Known contraindication, sensitivity (including nausea and/or vomiting), or allergy to
any opioid analgesic.

- Current use of any medication that could affect central nervous system blood flow
(e.g. certain cardiovascular medications, triptan migraine medications), unless
approved by the Investigator.

- 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 during screening or prior to
the first scan.