Buprenorphine/Naloxone Stabilization and Induction Onto Injection Naltrexone

Buprenorphine induction/stabilization/taper: Buprenorphine induction will be conducted at our
STARS clinic and according to current clinical guidelines. Participants who have initially
failed outpatient induction onto XR-NTX will receive buprenorphine/naloxone (BUP) on a weekly
basis that they will take daily, according to the following schedule: 8/2 mg (Days 1-10),
6/1.5 mg (Days 11-15), 4/1 mg (Days 16-20), 3.0/0.75 mg (Days 21-25), 2.0/0.5 mg (Days
26-30).

Participants will attend the clinic twice weekly and will be assessed for opioid and other
substance use (urine toxicology and self-report), vital signs, opioid withdrawal symptoms,
opioid cravings, and dose adjustments of buprenorphine will be made as needed by study
physicians. If a dose reduction is needed, the stabilization and taper schedule will be
adjusted to occur over 30 days.

Participants will be stabilized on, and tapered off, buprenorphine over a 4-week
period.Reductions will occur in a graded fashion, with the stabilization dose reduced to 2
mg. This approach to buprenorphine taper is intended to resemble standard clinical practice,
in which patients seeking transition off buprenorphine undergo a slow taper. A gradual taper
over approximately 4 weeks has established precedent (Sigmon et al. 2013, Ling et al. 2009,
Nielsen et al. 2013) as a well-tolerated taper strategy for transitioning off buprenorphine.
The purpose is in part to provide a slow transition with minimal withdrawal symptoms.
Participants will have at least two study visits a week during the buprenorphine taper, but
may be seen more regularly at STARS if deemed clinically necessary.

Naltrexone induction procedure: Participants who successfully complete the taper must then
complete a two-day washout (abstinence for opioids, buprenorphine). During this 48-hr
period,participants will report to the STARS clinic daily for vital sign monitoring and to
receive ancillary medications (clonidine, clonazepam, zolpidem, prochlorperazine) to
alleviate withdrawal and discomfort as needed. After abstinence of >/=48 hours from the last
buprenorphine dose, to allow for mu receptor availability, participants will begin the
naltrexone induction,using a 4-day ascending taper of oral naltrexone (1, 3, 12, and 25 mg),
followed by injection naltrexone . The administration of naltrexone will occur within a
detoxification suite provided at STARS, consisting of a private room outfitted with two
comfortable reclining lounge chairs for resting, adjustable lighting, and an entertainment
system. Participants will be monitored by clinical staff at least every 1-2 hours with
frequent vital signs checks and withdrawal assessments. A research psychiatrist or study
physician will be present at all times to conduct frequent clinical assessments and provide
adjuvant medications and naltrexone. Patients will be monitored on a daily basis (Monday to
Friday) for up to 8 hours per day. Transportation home by car service will be provided at the
end of the day for any patient deemed to have this clinical need.

On Day 1 of the naltrexone induction,participants are pre-treated with prochlorperazine 10 mg
for nausea, followed be the first dose of naltrexone 1mg. Ascending doses of naltrexone will
then be titrated upward slowly (3mg, 12mg, 25mg). Adjuvant medications will be available to
patients and will include clonidine for myalgias, prochlorperazine for nausea, clonazepam to
reduce anxiety and dysphoria, and trazodone or zolpidem for insomnia. Participants will be
provided take-home doses of adjuvant medications in small doses and on a tapering schedule
for one week post-administration of XR-NTX. Participants will be required to visit the clinic
daily and remain there for at least 1 hour to permit close monitoring, with an option to stay
as long as necessary to achieve relief of symptoms and medical stability prior to being
discharged home.

Once 25 mg of naltrexone has been tolerated, the participant may receive 380 mg IM XR-NTX.

Additionally, for female participants, a urine pregnancy test will be obtained on the day of
XR-NTX administration. Prior to administration of XR-NTX, participants who have been
non-compliant with the oral naltrexone schedule, accompanied by lapses to opioid use, or in
any case for which the challenge appears clinically indicated in the judgment of the study
physician or research team, will receive a naloxone challenge prior to XR-NTX administration.
Referrals to local treatment providers will be arranged for participants who successfully
complete the study and request to continue XR-NTX maintenance

XR-NTX injections: XR-NTX will be administered once naltrexone 25 mg has been tolerated, as
an intramuscular injection (380 mg) in one buttock by one of the research psychiatrists or
research nurses of STARS, who are currently trained and administer XR-NTX in other protocols.
Participants will be observed for at least 2 hours after the first injection. Participants
will be offered a second injection at Week 5 (four weeks post-administration of the first
injection), and a third injection at Week 9. Prior to receiving second and third injections
at STARS, patients will either provide an opioid-negative urine or pass a naloxone challenge
test.

At each STARS visit the patient meets with the research assistant to complete research
ratings, including self-report of withdrawal, mood, and drug use. Blood samples are drawn
according to the protocol for naltrexone serum levels and liver enzymes. The patient provides
a urine sample under observation by a staff member at each visit. STARS is staffed by both
male and female research assistants so that all urines can be appropriately monitored.

All participants will receive a weekly medication adherence-focused psychosocial intervention
informed by relapse prevention strategies we previously developed in Behavioral Naltrexone
Therapy and delivered by the study physician (Rothenberg, Sullivan et al. 2002). We have
developed a relapse prevention approach which includes an emphasis on compliance with NTX.
Participants will receive this therapy during weekly visits in outpatient Weeks 1-12
following induction onto XR-NTX.

Inclusion Criteria:

1. Age 18-60.

2. Meets DSM-IV criteria for current opiate dependence disorder of at least six months
duration, supported by urine toxicology OR COWS score > or =6 OR Naloxone Challenge.

3. Voluntarily seeking treatment for opioid dependence.

4. In otherwise good health based on complete medical history and physical examination.

5. Able to give written informed consent.

6. Failed outpatient induction onto XR-NTX in Protocol #6374.

Exclusion Criteria:

1. Methadone maintenance treatment or regular use of illicit methadone (> 30 mg per
week).

2. Maintenance on, or regular use of, buprenorphine or other long-acting opioid agonists.

3.) Pregnancy, lactation, or failure in a sexually active woman to use adequate
contraceptive methods. 4) Active medical illness which might make participation hazardous,
such as untreated hypertension, acute hepatitis with AST or ALT > 3 times normal, AIDS,
unstable diabetes.

5) Active psychiatric disorder which might interfere with participation or make
participation hazardous, including DSM-5 Schizophrenia or any psychotic disorder, severe
Major Depressive Disorder, or suicide risk or 1 or more suicide attempts within the past
year.

6) Physiologically dependent on alcohol or sedative-hypnotics with impending withdrawal.
Other substance use diagnoses are not exclusionary.

7) History of allergic or adverse reaction to buprenorphine, naltrexone, naloxone,
clonidine, or clonazepam.

8) Chronic organic mental disorder (e.g. AIDS dementia). 9) History of accidental drug
overdose in the last 3 years as defined as an episode of opioid-induced unconsciousness or
incapacitation, whether or not medical treatment was sought or received.

10) Painful medical condition that requires ongoing opioid analgesia or anticipated surgery
necessitating opioid medications.