Effects of Ibudilast on Oxycodone Self-administration in Opioid Abusers
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Psychiatric, Gastrointestinal |
| Therapuetic Areas: | Gastroenterology, Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 21 - 55 |
| Updated: | 4/21/2016 |
| Start Date: | November 2012 |
| End Date: | December 2016 |
Effects of Ibudilast (MN-166, Formerly AV411), a Glial Activation Inhibitor, on Oxycodone Self-administration in Opioid Abusers
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.
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.
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.
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.
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).
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