Buprenorphine/Naloxone Stabilization and Induction Onto Injection Naltrexone
Buprenorphine/Naloxone Stabilization and Induction Onto Injection Naltrexone
The investigators will randomize 50 opioid-dependent participants who have initially failed
 outpatient induction onto XR-NTX; participants will receive buprenorphine/naloxone on a
 weekly basis for 30 days. Buprenorphine/naloxone will be dispensed weekly during the 30-day
 stabilization and twice weekly during taper phase, and all patients who successfully complete
 the detoxification will be offered induction onto XR-NTX. All participants will receive
 weekly therapy with a study psychiatrist. All participants will receive open-label
 medication. The primary outcome of this study will be percentage of patients successfully
 inducted onto XR-NTX. Secondary outcomes will be time to relapse, defined as opioid use or
 dropout.
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.