Effects of Ibudilast on Oxycodone Self-administration in Opioid Abusers
Condition: Opioid Abuse; Opioid Dependence
MeSH terms: Opioid-Related Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      Opioid drugs increase glial cell activation which may be related to the abuse liability of
      opioid drugs. Data supporting this hypothesis have demonstrated that glial cell attenuators
      decrease the positive rewarding aspect of opioids in laboratory animals. Ibudilast (MN-166,
      formerly AV411) is a compound that inhibits the activation of glia. Recent preclinical
      studies demonstrate that while ibudilast increases the analgesic effects of opioids, it
      decreases the rewarding effects of such drugs. It has also been shown that ibudilast
      suppresses morphine-induced release of dopamine, a primary neurotransmitter involved in the
      rewarding and reinforcing effects of abused drugs. Additionally, we recently found that
      ibudilast decreases subjective symptoms of opioid withdrawal in opioid dependent humans
      during detoxification.

      Therefore, the primary aim of this 6-7 week inpatient study is to investigate the ability of
      MN-166 to dose-dependently alter the reinforcing, analgesic, subjective, performance, and
      physiological effects of oxycodone, a commonly abused prescription opioid.

      This study includes a 10-day morphine taper phase, followed by two study phases
      (approximately 18 days each) with daily active ibudilast and placebo administration,
      respectively. After the detoxification phase, participants are randomized to receive placebo
      or MN-166, and then be stabilized on the medication. Thereafter, participants will complete
      laboratory sessions. Subsequently, during Phase 2, participants will cross over to the other
      treatment arm, stabilize, and complete laboratory sessions.
    

Detailed description: 
      Opioid drugs increase glial cell activation and consequent cytokine release. These changes in
      glial cell activation may be related to the abuse liability of opioid drugs including heroin
      and prescription opioids. Data supporting this hypothesis have demonstrated that glial cell
      attenuators decrease the positive rewarding aspect of opioids in laboratory animals.
      Ibudilast (MN-166, formerly AV411) is a compound that inhibits the activation of glia and
      thereby inhibits the release of cytokines. Recent preclinical studies demonstrate that while
      ibudilast increases the analgesic effects of opioids, it decreases the rewarding effects of
      such drugs. It has also been shown that ibudilast suppresses morphine-induced release of
      dopamine, a primary neurotransmitter involved in the rewarding and reinforcing effects of
      abused drugs. Additionally, we recently found that ibudilast decreases subjective symptoms of
      opioid withdrawal in opioid dependent humans during detoxification.

      Therefore, the primary aim of this 6-7 week inpatient study is to investigate the ability of
      MN-166 to dose-dependently alter the reinforcing, analgesic, subjective, performance, and
      physiological effects of oxycodone, a commonly abused prescription opioid. A secondary aim is
      to verify the ability of the drug to decrease opioid withdrawal symptoms during the initial
      inpatient detoxification.

      This inpatient study includes a detoxification and two 18-day study phases. Upon study
      initiation, participants are tapered with morphine before study phase 1 starts, when they are
      randomized to receive placebo or 50 mg MN-166 BID (po at 0800 and 2000 hr), and then switched
      and stabilized on the medication. Thereafter, participants will complete 6 laboratory
      sessions over 9-10 days.

      Subsequently, during Phase 2, participants will cross over to the other study arm (Pbo to
      MN-166 or MN-166 to Pbo), stabilize, and complete again 6 laboratory sessions. Days 1-10 of
      the study include a morphine taper, while each of the two subsequent study phases consist of
      a 7-8-day medication switch and stabilization phase, followed by 6 laboratory sessions over
      the next 9-10 days (3 sample sessions and 3 choice sessions). During sample sessions,
      participants will receive one dose of oxycodone (0, 15, or 30 mg/70 kg, PO) that will be
      available during the choice session the following day. At least 72 hrs after the previous
      sample session, the second sample session will be completed, followed by a choice session the
      next day. And then at least 72 hrs after the second sample session, the third and final
      sample session will be completed, followed by the final choice session the next day. The
      analgesic, subjective, performance, and physiological effects of oxycodone will be measured.
      During the choice session, a drug versus money self-administration paradigm will be employed,
      and the progressive ratio that is completed for drug and/or money will be measured.

      We hypothesize that MN-166 will dose-dependently decrease oxycodone self-administration and
      positive subjective responses while increasing the analgesic effects of the drug.

      A secondary additional objective is to collect exploratory information on potential
      predictors of prescription opioid self-administration including genetic polymorphisms,
      neurocognitive functioning, and response to stress. Blood samples will be collected to
      measure various genetic markers hypothesized to contribute to opioid drug effects (e.g.,
      OPRM1, OPRD1, OPRK1, PENK, PDYN, DRD2, CYP3A4, and CYP2D6 genes). Performance on
      neurocognitive tasks and physiological response to the Trier Social Stress Test will be
      assessed in all participants.
    

Intervention name(s): MN-166 (50 mg) First; Placebo First
Intervention type(s): Drug; Drug
Intervention description(s): In this arm of the study participants were first maintained on 50 mg MN-166 BID for approximately 14 days, and were then switched onto placebo maintenance. The subjective and analgesic effects of Oxycodone (0 mg, 15 mg and 30 mg) were tested under each of the two maintenance conditions (Placebo & MN-166).; This arm of the study participants were first maintained on placebo for approximately 14 days, and were then switched onto 50mg MN-166 BID maintenance. . The subjective and analgesic effects of Oxycodone (0 mg, 15 mg and 30 mg) were tested under each of the two maintenance conditions (Placebo & MN-166).
Other intervention name(s): ibudilast/AV411; placebo
Intervention MeSH terms: Ibudilast
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: prescription opioid abuse; pain; opioid withdrawal; oxycodone; ibudilast