Evaluation of Doxazosin to Alter the Abuse of Oxycodone

Healthy, adult men and women, aged 21 to 59 years, who abuse opioids and are physically
dependent on them will be recruited to participate in a study to examine the ability of
doxazosin, an alpha-1 adrenergic receptor antagonist, to alter the abuse liability of
oxycodone. After participants complete the screening process, they will be scheduled for
admission onto the General Clinical Research Unit on 5-South where they will reside during an
8-week study . During Weeks 1-2, participants will be stabilized on morphine and the first
dose of doxazosin (0 or 16 mg/day; active doxazosin will be started at 4 mg and increased by
4 mg every 3 days; dosing will occur at 8pm each evening). During the stabilization periods,
participants will be treated for emergent withdrawal symptoms with supplemental medications
until withdrawal symptoms have dissipated.

During Weeks 3-4, either active or placebo oxycodone will be available (order of testing
active or placebo oxycodone will be randomized). During active oxycodone weeks, participants
will receive a sample dose of intransasal (IN) oxycodone (0, 12.5, 25, 50, or 100 mg/70kg)
during morning sessions on Monday-Friday. The sampled reinforcer will be available during
afternoon choice sessions using a modified progressive ratio self-administration procedure.
During placebo oxycodone weeks, participants will receive a sample dose of placebo oxycodone
(0 mg/70kg) during morning sessions on Monday-Thursday followed by afternoon choice sessions.
On Friday, participants will receive 25 mg IN oxycodone during a sample session (the
oxycodone dose on Fri morning will always be active). When self-administering oxycodone,
participants will be instructed to insufflate the entire dose through one or both nostrils
within 5-10 seconds. Following the sample session on Fri, participants will complete a cue
exposure session during which they will be presented with neutral cues followed by drug cues.
This procedure will allow the investigators to determine whether the study medication affects
reactivity to drug-related cues after a period of no oxycodone availability. After the cue
exposure session on Fri, participants will be given the opportunity to self-administer
oxycodone. To summarize, Weeks 1-2 and 5-6 will be stabilization weeks (0 or 16 mg doses of
doxazosin administered in random order) and Weeks 3-4 and 7-8 will be test weeks under each
of the doxazosin maintenance doses. At the conclusion of the study, participants will be
given an exit interview during which the study will be described. Those who are interested in
treatment for their drug use at the end of the study will be offered referrals to studies at
our Substance Treatment and Research Service or other treatment providers. Within 1 week
after discharge, investigators will assess adverse events, pregnancy (using a urine pregnancy
test), general health (complete blood count, blood chemistry, urinalysis, blood pressure,
heart rate, body weight, EKG), and suicide (Columbia Suicide Severity Rating Scale).

Participants must meet all of the following inclusion criteria to be enrolled into the
study:

1. 21-59 years of age. Ascertained by: Self-reported age and/or verification with legal
identification.

2. Diagnostic criteria for Opioid Use Disorder moderate-severe (304.00) as per DSM-V
Ascertained by: Clinical interviews (telephone, psychologist, nurse, physician),
naloxone challenge test/visual evidence of opioid withdrawal.

3. No current or past diagnosis of schizophrenia, schizoaffective disorder, or other
psychotic disorder; bipolar I or bipolar II disorder, other major mood, psychotic, or
anxiety disorder that might interfere with the study. Ascertained by: Clinical
interview with physician or nurse.

4. Physically healthy. Ascertained by: Clinical interview with physician, laboratory
tests (urinalysis, blood chemistry, 12-lead ECG), physical examination, self-reported
medical history.

5. Able to perform study procedures. Ascertained by: Practice session or Clinical
Judgement (Psychologist or Physician)

6. Normal body weight. Ascertained by: Body Mass Index <30.

7. Current or history of intranasal opioid use. Ascertained by: Clinical interviews
(telephone, psychologist, and psychiatric NP, or physician).

8. Current intranasal or intravenous use of opioids in amounts and/or frequencies that
meet or exceed those used in the proposed study (e.g., 3-4 tablets of a prescription
opioid medication per day or 1-2 bags of heroin per day). Ascertained by: Clinical
interviews (telephone, psychologist, psychiatric NP, or physician)

9. If female and using oral contraceptives, must use alternative forms of contraception
as well (e.g. condoms in combination with spermicide). Ascertained by: Clinical
interviews (telephone, psychologist, nurse, physician), physical examination.

10. Has not participated in another opioid laboratory study within the past 3 months.
Ascertained by: Clinical interviews (psychologist physician, or psychiatric NP),
review of laboratory records.

Participants will be excluded from study participation if they meet any of the following
exclusion criteria:

1. Meeting DSM-V criteria for substance use disorder (moderate-severe) on drugs other
than opioids, nicotine or caffeine (must be less than 500 mg caffeine daily).
Ascertained by: Clinical interview with physician or psychiatric NP, urine screen,
observation.

2. Participants requesting treatment. Ascertained by: Self-report during interview.

3. Treatment with any investigational drug during the last 30 days. Ascertained by:
Self-report during interview.

4. Participants on parole or probation. Ascertained by: Self-report during interview,
criminal background check upon admission.

5. Currently pregnant or trying to conceive, or currently lactating. Ascertained by:
Blood pregnancy testing at screening, on admission and (beta hCG), and self-report
during interview and study visits.

6. Current or recent history of significant violent or suicidal behavior and/or
suicidal/homicidal risk. Ascertained by: Clinical interview with a psychiatrist or
psychiatric NP, and C-SSRS, MINI, and Beck Depression Inventory (based on current
state and history).

7. Cannot read or understand the self-report assessment forms unaided, or are so severely
disabled that they cannot comply with the requirements of the study. Ascertained by:
Clinical interview (psychologist, physician, or psychiatric NP), or practice session.

8. Elevated liver function tests (i.e., AST and ALT > 3 times the upper limit of normal
(ULN); bilirubin > 2x ULN; hepatitis B or chronic hepatitis C). Ascertained by:
Laboratory tests.

9. Physical disorders that might make participation hazardous such as AIDS, cancer,
baseline hypotension, orthostatic hypotension or syncope, hypertension (blood pressure
> 140/90), uncontrolled diabetes, pulmonary hypertension or heart disease (please note
that participants will be asked about previous visits to a cardiologist, chest pain,
or strong palpitations; if these exist, they will be referred to a cardiologist and
excluded unless cleared for participation by a cardiologist). Ascertained by: Clinical
interview (psychologist, physician, or psychiatric NP) physical examination, 12-lead
ECG.

10. Current major Axis I psychopathology other than opioid use disorder (e.g., mood
disorder with functional impairment or suicide risk, schizophrenia), that might
interfere with ability to participate in the study. Ascertained by: Clinical
interviews (psychologist, physician, or psychiatric NP).

11. Sensitivity, allergy, or contraindication to opioids, doxazosin, adrenergic
antagonists or agonists, or similar compounds. Ascertained by: Clinical interview
(psychologist, physician, or psychiatric NP).

12. Planning to conceive within 6 months of study participation. Ascertained by: Clinical
interview (psychologist, physician, or psychiatric NP).

13. Use of any prescription, over-the-counter medication that affects CYP3A4 activity are
prohibited for at least 7 days prior to the anticipated study start date; or the use
of phosphodiesterase inhibitors and MAOIs 14 days prior to the study. Ascertained by:
Medical History, Clinical Interview ((psychologist, physician, or psychiatric NP).