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Kirk W. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence
Neuropsychopharmacology, 2017Co-Authors: Verena E Metz, Kirk W. Johnson, Jermaine D Jones, Jeanne Manubay, Maria A Sullivan, Shanthi Mogali, Andrew Segoshi, Gabriela Madera, Sandra D ComerAbstract:Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of Ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of Ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate–severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers ( n =11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active Ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active Ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo Ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active Ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active Ibudilast condition. Our data suggest that Ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.
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Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2017Co-Authors: Verena E Metz, Kirk W. Johnson, Jermaine D Jones, Jeanne Manubay, Maria A Sullivan, Shanthi Mogali, Andrew Segoshi, Gabriela Madera, Sandra D ComerAbstract:Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence
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the effects of Ibudilast a glial activation inhibitor on opioid withdrawal symptoms in opioid dependent volunteers
Addiction Biology, 2016Co-Authors: Ziva D. Cooper, Kirk W. Johnson, Jermaine D Jones, Maria A Sullivan, S.k. Vosburg, Diana Martinez, Martina Pavlicova, Andrew Glass, Jeanne M. Manubay, P.a. SacconeAbstract:Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, Ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive Ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two Ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with Ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.
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Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double-Blind, Randomized, Placebo-Controlled Pilot Trial of Efficacy and Safety.
Headache, 2015Co-Authors: Jacinta L. Johnson, Kirk W. Johnson, Yuen H. Kwok, Nicole M. Sumracki, James E. Swift, Mark R. Hutchinson, Desmond B. Williams, Jonathan Tuke, Paul RolanAbstract:Background Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, Ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized Ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. Objective To determine if treatment with Ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. Methods Participants with MOH who were using opioids were randomized via computer-generated code to Ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood samples for immune biomarker analyses were collected before and after treatment in a subgroup of participants. Results Thirty-four participants were randomized, 13 of 15 randomized to Ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs Ibudilast 77 [72] groups, difference −15, CI −65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs Ibudilast 24.5 [6.2], difference −1.5, CI −7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs Ibudilast 19 [24.3], difference 1.6, CI −31.5 to 34.8 mg morphine equivalent) were observed between placebo and Ibudilast groups. Conclusions Using the current dosing regimen, Ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if Ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.
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The effects of Ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid‐dependent volunteers
Addiction biology, 2015Co-Authors: Ziva D. Cooper, Kirk W. Johnson, Jermaine D Jones, Maria A Sullivan, S.k. Vosburg, Diana Martinez, Martina Pavlicova, Andrew Glass, Jeanne M. Manubay, P.a. SacconeAbstract:Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, Ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive Ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two Ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with Ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.
Masunari Shibata - One of the best experts on this subject based on the ideXlab platform.
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Ibudilast a phosphodiesterase inhibitor protects against white matter damage under chronic cerebral hypoperfusion in the rat
Brain Research, 2003Co-Authors: Hideaki Wakita, Hidekazu Tomimoto, Ichiro Akiguchi, Jin Xi Lin, Masafumi Ihara, Ryo Ohtani, Masunari ShibataAbstract:Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-alpha is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by Ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-alpha production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg Ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of Ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg Ibudilast ameliorated these lesions (p<0.001). Without an alterations in laboratory blood data, 60 mg/kg Ibudilast exhibited percent reduction of the white matter lesions ranging between 50% and 70%, which was more effective than 30 mg/kg Ibudilast (p<0.05). The TNF-alpha immunoreactive glia decreased in number in the 60 mg/kg Ibudilast-treated group as compared to the vehicle-treated group (p<0.001). These results indicate a dose-dependent protective effect of Ibudilast against cerebrovascular white matter lesions and suggest a potential use for Ibudilast in the treatment of vascular dementia.
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Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat
Brain research, 2003Co-Authors: Hideaki Wakita, Hidekazu Tomimoto, Ichiro Akiguchi, Jin Xi Lin, Masafumi Ihara, Ryo Ohtani, Masunari ShibataAbstract:Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-alpha is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by Ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-alpha production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg Ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of Ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg Ibudilast ameliorated these lesions (p
Akio Suzumura - One of the best experts on this subject based on the ideXlab platform.
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Ibudilast a nonselective phosphodiesterase inhibitor regulates th1 th2 balance and nkt cell subset in multiple sclerosis
Multiple Sclerosis Journal, 2004Co-Authors: Juan Feng, Akio Suzumura, S Sakoda, Tatsuro Misu, Kazuo Fujihara, Yuji Nakatsuji, Hikoaki Fukaura, Seiji Kikuchi, Kunio Tashiro, Naoto IshiiAbstract:We investigated the immunoregulatory effects of Ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4- cells revealed that the Ibudilast monotherapy significantly reduced tumour necrosis factor-a and interferon (IFN)-g mRNA and the IFN-g/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.
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Neuroprotective role of phosphodiesterase inhibitor Ibudilast on neuronal cell death induced by activated microglia
Neuropharmacology, 2004Co-Authors: Tetsuya Mizuno, Tohru Kurotani, Yukio Komatsu, Jun Kawanokuchi, Hideki Kato, Norimasa Mitsuma, Akio SuzumuraAbstract:Abstract The phosphodiesterase inhibitor, Ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of Ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-γ. To examine the mechanisms by which Ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following Ibudilast treatment. In a dose-dependent manner, Ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, Ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-γ stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that Ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.
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Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis.
Multiple sclerosis (Houndmills Basingstoke England), 2004Co-Authors: Juan Feng, Akio Suzumura, S Sakoda, Tatsuro Misu, Kazuo Fujihara, Yuji Nakatsuji, Hikoaki Fukaura, Seiji Kikuchi, Kunio Tashiro, Naoto IshiiAbstract:We investigated the immunoregulatory effects of Ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4- cells revealed that the Ibudilast monotherapy significantly reduced tumour necrosis factor-a and interferon (IFN)-g mRNA and the IFN-g/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.
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Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS
Brain Research, 1999Co-Authors: Akio Suzumura, A Ito, M Yoshikawa, M SawadaAbstract:Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of Ibudilast on TNFα production by murine microglia and astrocytes. Some actions of Ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by Ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that Ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of Ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, Ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.
M Sawada - One of the best experts on this subject based on the ideXlab platform.
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Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS.
Brain research, 1999Co-Authors: A Suzumura, A Ito, M Yoshikawa, M SawadaAbstract:Tumor necrosis factor alpha (TNFalpha) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFalpha production in the CNS for future treatment of these pathological conditions, we examined the effects of Ibudilast on TNFalpha production by murine microglia and astrocytes. Some actions of Ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by Ibudilast. Ibudilast significantly and selectively suppressed TNFalpha production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that Ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 microM or higher concentrations to effectively suppress TNFalpha production in vitro, the combination of Ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFalpha and nitric oxide production by microglia at 1 microM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, Ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFalpha may play a causative role.
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Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS
Brain Research, 1999Co-Authors: Akio Suzumura, A Ito, M Yoshikawa, M SawadaAbstract:Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of Ibudilast on TNFα production by murine microglia and astrocytes. Some actions of Ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by Ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that Ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of Ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, Ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.
P.a. Saccone - One of the best experts on this subject based on the ideXlab platform.
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Effects of Ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.
Drug and alcohol dependence, 2017Co-Authors: Ziva D. Cooper, Jermaine D Jones, Jeanne Manubay, Maria A Sullivan, K.w. Johnson, S.k. Vosburg, Diana Martinez, P.a. Saccone, Sandra D ComerAbstract:Abstract Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of Ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30 mg, PO, QID) for two weeks and received placebo Ibudilast (0 mg, PO, BID) during the 1st week (days 1–7). On day 8, participants (N = 10/group) were randomized to receive Ibudilast (20 or 40 mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50 mg/70 kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4 °C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40 mg BID Ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p ≤ 0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p ≤ 0.05); Ibudilast did not consistently affect these ratings. These findings suggest that Ibudilast may enhance opioid-induced analgesia. Investigating higher Ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.
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the effects of Ibudilast a glial activation inhibitor on opioid withdrawal symptoms in opioid dependent volunteers
Addiction Biology, 2016Co-Authors: Ziva D. Cooper, Kirk W. Johnson, Jermaine D Jones, Maria A Sullivan, S.k. Vosburg, Diana Martinez, Martina Pavlicova, Andrew Glass, Jeanne M. Manubay, P.a. SacconeAbstract:Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, Ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive Ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two Ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with Ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.
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The effects of Ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid‐dependent volunteers
Addiction biology, 2015Co-Authors: Ziva D. Cooper, Kirk W. Johnson, Jermaine D Jones, Maria A Sullivan, S.k. Vosburg, Diana Martinez, Martina Pavlicova, Andrew Glass, Jeanne M. Manubay, P.a. SacconeAbstract:Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, Ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive Ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two Ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with Ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.
