Buprenorphine/Naloxone Stabilization and Induction Onto Injection Naltrexone
Condition: Opioid Dependence
MeSH terms: Opioid-Related Disorders
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Buprenorphine/naloxone
Intervention type(s): Drug
Intervention description(s): 30 day oral Buprenorphine/naloxone
Other intervention name(s): Suboxone
Intervention MeSH terms: Buprenorphine; Buprenorphine, Naloxone Drug Combination; Naloxone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment