Effects of Ibudilast on Oxycodone Self-administration in Opioid Abusers

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by New York State Psychiatric Institute
Sponsor:
Collaborators:
MediciNova
Information provided by (Responsible Party):
New York State Psychiatric Institute
ClinicalTrials.gov Identifier:
NCT01740414
First received: November 26, 2012
Last updated: March 20, 2014
Last verified: March 2014
  Purpose

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. A secondary aim is to verify the ability of the drug to decrease opioid withdrawal symptoms during the initial inpatient detoxification.

This study will include two, 20-day phases. During Phase 1, participants will be detoxified, 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.


Condition Intervention Phase
Opioid Abuse
Opioid Dependence
Drug: MN-166 (formerly AV411)
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: Effects of Ibudilast (MN-166, Formerly AV411), a Glial Activation Inhibitor, on Oxycodone Self-administration in Opioid Abusers

Resource links provided by NLM:


Further study details as provided by New York State Psychiatric Institute:

Primary Outcome Measures:
  • pain intensity [ Time Frame: 41 days ] [ Designated as safety issue: No ]
    Cold Pressure Test, Pain Intensity and Bothersome Scale, Cold Pressure Test Visual Analog Scale, Short-Form McGill Pain Questionnaire


Secondary Outcome Measures:
  • positive subjective effects to oxycodone [ Time Frame: 41 days ] [ Designated as safety issue: No ]
    Subjective Opiate Withdrawal Scale, Modified Clinical Global Impressions Scale, VAS Mood and Craving Scales, Clinical Opiate Withdrawal Scale


Other Outcome Measures:
  • breakpoint values in progressive ratio drug self-administration procedure [ Time Frame: 41 days ] [ Designated as safety issue: No ]
    amount of drug versus money chosen in self administration task (choice session)

  • opioid withdrawal symptoms [ Time Frame: 41 days ] [ Designated as safety issue: No ]
    opioid withdrawal signs assessed by pupil diameter photographs and questionnaires (Subjective/Clinical Opiate Withdrawal Scale), VAS Mood and Craving Scales, Modified Clinical Global Impressions Scale)


Estimated Enrollment: 24
Study Start Date: November 2012
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: MN-166 (formerly AV411)
patient is receiving study drug (MN-166)
Drug: MN-166 (formerly AV411)
in one study arm, 50mg MN-166 BID are administered daily for 20 days
Other Name: ibudilast
Placebo Comparator: Placebo
Patient is receiving placebo
Drug: placebo
In the placebo arm, the patients receive placebo for 20 days
Other Name: placebo

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 study will include two, 20-day phases. During Phase 1, participants will be detoxified, randomized to receive placebo or 50 mg MN-166 BID (po at 0800 and 2000 hr), and then stabilized on the medication. Thereafter, participants will complete laboratory sessions. Subsequently, during Phase 2, participants will cross over to the other treatment arm (Pbo to MN-166 or MN-166 to Pbo), stabilize, and complete laboratory sessions.

Days 1-11 of Phase 1 will include a morphine taper and withdrawal assessment, while days 12-20 of each phase will consist of 6 laboratory sessions (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. We further hypothesize that participants randomized to receive the active dose of MN-166 will exhibit fewer opioid withdrawal symptoms during and subsequent to the morphine taper than those assigned to placebo MN-166.

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.

  Eligibility

Ages Eligible for Study:   21 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults between the ages of 21 and 55
  • Current opioid dependence according to DSM-IV criteria
  • currently not seeking treatment

Exclusion Criteria:

  • Female patients that are currently pregnant, or breastfeeding. Lack of effective birth control.
  • Participants who have a positive history of neurological illness (including epilepsy) or those who have received anticonvulsant therapy during the past 5 years.
  • Liver disease requiring medication or medical treatment, and/or aspartate or alanine aminotransferase levels greater than 3 times the upper limit of normal.
  • Gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medication or medical treatment.
  • Neurological or psychiatric disorders including psychosis, bipolar disorder, organic brain disease, any seizure history or other disorders that require treatment or that could make study compliance difficult.
  • Positive tuberculosis (PPD) TB skin test, clinical history, and chest X-ray indicative of active tuberculosis. (Individuals with a positive PPD test and negative chest X-ray who are not symptomatic for tuberculosis, and do not require antituberculosis therapy will be eligible to participate. Participants will be asked if they ever tested positive for tuberculosis. If so, they will not be given a PPD and chest X-ray and clinical history will be used for evaluation purposes).
  • Presence or positive history of severe medical illness or cardiovascular disease or heart abnormality, such as low hemoglobin (Hb < 13 gm/dL in males, Hb < 11 gm/dL in females) with evidence of acute or chronic blood loss, or BP > 140/90.
  • Participants on any current psychoactive prescription medications that may interfere with the study measures.
  • Current physical dependence on any substance, other than opioids, nicotine or caffeine (ex., methadone, benzodiazepines, LAAM, marijuana, alcohol, etc.).
  • Participants for whom detoxification is not "clinically recommended" such as those with a significant history of overdose following detoxification.
  • Participation in an investigational drug study within the past 3 months.
  • Hypersensitivity to any of the medications used in this study.
  • Current (within the last 3 months) chronic pain.
  • Platelet and white blood cell count that are not within the normal range (platelet = 120 x103/μl -400 x103/μl; WBC= 3.5 x106/μl -10.8x106/μl).
  • Use of Theophylline (PDE-3 inhibitor) or Roflumilast (PDE-4 inhibitor).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01740414

Contacts
Contact: Sandra D Comer, PhD 646-774 ext 6146 comersa@nyspi.columbia.edu
Contact: Maria Sullivan, MD 646-774 ext 6152 sulliva@nyspi.columbia.edu

Locations
United States, New York
New York State Psychiatric Institute Recruiting
New York, New York, United States, 10032
Contact: Sandra D Comer, PhD    646-774-6146 ext 6146    comersa@nyspi.columbia.edu   
Contact: Maria Sullivan, MD    646-774-6152 ext 6152    sulliva@nyspi.columbia.edu   
Principal Investigator: Sandra D Comer, PhD         
Sub-Investigator: Maria Sullivan, MD         
Sub-Investigator: Jermaine D Jones, PhD         
Sub-Investigator: Verena E Metz, PhD         
Sponsors and Collaborators
New York State Psychiatric Institute
MediciNova
Investigators
Principal Investigator: Sandra D Comer, PhD Department of Psychiatry, Columbia University and NYSPI
  More Information

No publications provided

Responsible Party: New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT01740414     History of Changes
Other Study ID Numbers: 6021, P50DA009236
Study First Received: November 26, 2012
Last Updated: March 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by New York State Psychiatric Institute:
prescription opioid abuse
pain
opioid withdrawal
oxycodone
ibudilast

Additional relevant MeSH terms:
Ibudilast
Substance-Related Disorders
Opioid-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Oxycodone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Bronchodilator Agents
Autonomic Agents
Anti-Asthmatic Agents
Respiratory System Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Hematologic Agents
Vasodilator Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on September 11, 2014