Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double‐Blind, Randomized, Placebo‐Controlled Pilot Trial of Efficacy and Safety

Johnson, Jacinta; Kwok, Yuen Hei; Sumracki, Nicole M.; Hutchinson, Mark R.; Johnson, Kirk W.; Williams, Dean C.; Tuke, Jonathan; Rolan, Paul

doi:10.1111/head.12655

Cited by 18 publications

(12 citation statements)

References 50 publications

(81 reference statements)

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“…Our results are in agreement with a recently published finding by our group, which found ibudilast to have no effect in reducing headache index or in reducing opioid intake in medi cation overuse headache patients 41. However, the study also measured toll-like receptor (TLR) reactivity from peripheral blood mononuclear cells and found ibudilast to significantly reduce the proinflammatory cytokine (interleukin 1β) levels from ex vivo stimulation with TLR-2 or TLR-4 agonists.…”

Section: Discussionsupporting

confidence: 92%

A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine

Kwok¹,

Swift²,

Gazerani³

et al. 2016

JPR

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BackgroundChronic migraine (CM) is problematic, and there are few effective treatments. Recently, it has been hypothesized that glial activation may be a contributor to migraine; therefore, this study investigated whether the potential glial inhibitor, ibudilast, could attenuate CM.MethodsThe study was of double-blind, randomized, placebo-controlled, two-period crossover design. Participants were randomized to receive either ibudilast (40 mg twice daily) or placebo treatment for 8 weeks. Subsequently, the participants underwent a 4-week washout period followed by a second 8-week treatment block with the alternative treatment. CM participants completed a headache diary 4 weeks before randomization throughout both treatment periods and 4 weeks after treatment. Questionnaires assessing quality of life and cutaneous allodynia were collected on eight occasions throughout the study.ResultsA total of 33 participants were randomized, and 14 participants completed the study. Ibudilast was generally well tolerated with mild, transient adverse events, principally nausea. Eight weeks of ibudilast treatment did not reduce the frequency of moderate to severe headache or of secondary outcome measures such as headache index, intake of symptomatic medications, quality of life or change in cutaneous allodynia.ConclusionUsing the current regimen, ibudilast does not improve migraine with CM participants.

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Section: Discussionsupporting

confidence: 92%

A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine

Kwok¹,

Swift²,

Gazerani³

et al. 2016

JPR

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“…For example, minocycline treatment results in pain attenuation in the clinic [ 150 ], but PPF shows no pain attenuation in human trials [ 147 ]. Administration of ibudilast has been shown to attenuate peripheral nerve injury-induced and paclitaxel-induced pain in an animal study [ 151 ]; however, this effect is not observed in a clinical trial [ 152 ]. Although most animal studies have demonstrated that glial modulation is efficacious in treating neuropathic pain [ 153 ], future studies in humans must (1) characterize the effects of glial modulation on glial activation and pain severity and (2) optimize the administration route and application time in order to identify the most promising translational applications of glial modulation in human neuropathic pain [ 154 ].…”

Section: Clinical Applications and Limitations Of Glial Activationmentioning

confidence: 99%

Neuronal-Glial Interactions Maintain Chronic Neuropathic Pain after Spinal Cord Injury

2017

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The hyperactive state of sensory neurons in the spinal cord enhances pain transmission. Spinal glial cells have also been implicated in enhanced excitability of spinal dorsal horn neurons, resulting in pain amplification and distortions. Traumatic injuries of the neural system such as spinal cord injury (SCI) induce neuronal hyperactivity and glial activation, causing maladaptive synaptic plasticity in the spinal cord. Recent studies demonstrate that SCI causes persistent glial activation with concomitant neuronal hyperactivity, thus providing the substrate for central neuropathic pain. Hyperactive sensory neurons and activated glial cells increase intracellular and extracellular glutamate, neuropeptides, adenosine triphosphates, proinflammatory cytokines, and reactive oxygen species concentrations, all of which enhance pain transmission. In addition, hyperactive sensory neurons and glial cells overexpress receptors and ion channels that maintain this enhanced pain transmission. Therefore, post-SCI neuronal-glial interactions create maladaptive synaptic circuits and activate intracellular signaling events that permanently contribute to enhanced neuropathic pain. In this review, we describe how hyperactivity of sensory neurons contributes to the maintenance of chronic neuropathic pain via neuronal-glial interactions following SCI.

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“…Of interest for the treatment of opioid withdrawal, another study in a rat model of diarrhea-predominant irritable bowel syndrome found that pioglitazone significantly reduced defecation frequency, produced a shift from watery stool to hard stool, and increased nociceptive thresholds [30]. On the other hand, clinical trials in humans failed to demonstrate sufficient efficacy of pioglitazone on the oxycodone abuse liability of nondependent opioid users [31] and in the treatment of opioid use withdrawal. Together with the observations made with SJP-005, this encourages further research into the antinociceptive properties and potential opioid sparing properties of PPAR-γ agonists.…”

Section: Discussionmentioning

confidence: 99%

A Comparison of the Antinociceptive Properties of SJP-005 and Morphine in Rats

Verster

Scholey

Dahl³

et al. 2021

Pharmaceutics

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SJP-005 (a combination of ketotifen and ibuprofen) is being developed as a potential treatment for pain and for opioid use disorder. It is therefore important to investigate the potential antinociceptive properties of SJP-005. Two studies were conducted to evaluate the potential effects of SJP-005 in rats. Study 1 applied the von Frey test to examine the antinociceptive effect of morphine with and without SJP-005 in adjuvant-induced hypersensitivity to tactile stimulation. In a double-blind, between-groups design, groups of rats (n = 10 each) received morphine at 3, 10, or 30 mg/kg bodyweight (bw) (subcutaneous injection) with or without SJP-005 (oral). Mechanic allodynia and paw volume were assessed before and after treatment. Study 2 utilized the hot plate test. Using a crossover design, groups of rats (n = 10 each) received either morphine at 3, 10, or 30 mg/kg bw (subcutaneous injection) preceded by oral administration of placebo (Week 1) or SJP-005 (Week 2). In Study 1, in the von Frey up-and-down test, Δ paw withdrawal responses in Group 1 (3 mg/kg bw morphine) were significantly lower compared to those in Group 4 (3 mg/kg bw morphine plus SJP-005), whereas the differences in Δ paw withdrawal between Group 2 and Group 5 (10 mg/kg bw morphine with and without SJP-005) and between Group 3 and Group 6 (10 mg/kg bw morphine with and without SJP-005) did not reach statistical difference. Trendline analysis of the dose–response relationship for the morphine + placebo groups and morphine + SJP-005 groups revealed no significant differences in the intercepts and slopes. In Study 2, no significant differences were observed on hot plate performance between morphine and morphine in combination with SJP-005. In conclusion, the findings in the von Frey up-and-down test (Study 1) suggest that animals can withstand higher levels of painful stimuli when SJP-005 is co-administered. This may also suggest a possible opioid sparing effect. However, in the hot plate test (Study 2), animals did not respond more adaptively to stronger painful stimuli after co-administering SJP-005. These observations warrant further investigation of the antinociceptive properties of SJP-005.

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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

Cited by 18 publications

References 50 publications

A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine

A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine

Neuronal-Glial Interactions Maintain Chronic Neuropathic Pain after Spinal Cord Injury

A Comparison of the Antinociceptive Properties of SJP-005 and Morphine in Rats

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