Ibudilast in the Treatment of Medication Overuse Headache

Study Overview
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Brief Summary
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The purpose of this study is to determine if ibudilast is effective in reverting patients with medication overuse headache suffering chronic daily headache back to their original episodic headache pattern.

Detailed Description
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It has been established that excessive intake of medications used to treat primary headaches, particularly those containing opioids, can induce a form of secondary headache, known as medication overuse headache (MOH). Despite the significant clinical impact of this condition the mechanisms behind MOH remain poorly understood, guidelines for treatment are lacking, and relapse is common. Recently, it has been recognised that repeated opioid exposure can facilitate pain by activating glia, the immunocompetent cells of the central nervous system, resulting in opioid-induced hyperalgesia (OIH). The investigators hypothesise that MOH represents a form of OIH in this susceptible patient group - repeated activation of nociceptive pathways by frequent headaches interacts with the opioid induced pro-inflammatory actions of activated glia to produce chronic daily headache (CDH). This double-blind, randomised, placebo controlled pilot study will investigate the use of ibudilast, a know attenuator of glial activation, in the treatment of medication overuse headache.

Official Title
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Ibudilast in the Treatment of Medication Overuse Headache: A Double-blind, Randomised, Placebo-controlled Pilot Study

Conditions
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Medication Overuse Headache

Intervention / Treatment
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* Drug: Ibudilast
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Regular use, for at least 3 months, of opioid-containing analgesics on ≥ 10 days/month Headache present on at least 15 days/month, for at least 2 months Headache developed or markedly worsened during medication overuse Primary indication for analgesics is headache disorder Exclusion criteria: Unable to provide written informed consent Age < 18 years at time of screening Unable to read and write in English Receiving tramadol regularly Taking triptans > 4 days/month Taking opioids for reasons other than headache (e.g. other pain conditions, cough, bowel motility) Severe psychiatric disorders Other chronic pain conditions likely to interfere with qualitative sensory testing (e.g. trigeminal neuralgia, arthritis) Diabetic neuropathy Recent or current active infection, determined to be clinically significant by the Principal investigator Known active inflammatory diseases such as rheumatoid arthritis History of cerebrovascular disorder Recent history of significant trauma, as determined by the Principal Investigator including major surgery within the previous 2 months Recent history of drug or alcohol abuse Spinal cord injury Any clinically significant findings on screening blood sample results Current malignancy Known hypersensitivity to ibudilast or excipients in Pinatos® formulation Renal or hepatic impairment, defined as baseline GFR (as calculated by the Cockcroft-Gault equation) of < 60 mL/min or LFTs > 3 times the upper limit of normal For females of childbearing potential: Pregnancy Lack of adequate contraception (abstinence, double barrier method, intrauterine device, surgical sterilization (self or partner), hormonal contraceptive methods (oral, injected, or implanted) Breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibudilast<br>To receive ibudilast 40mg twice daily for 8 weeks. | Drug: Ibudilast<br>* Ibudilast 4 x 10 mg capsules, orally, twice daily for 8 weeks.<br>|
| Placebo Comparator: Placebo<br>To receive placebo twice daily for 8 weeks. | Drug: Placebo<br>* Placebo 4 capsules, orally, twice daily for 8 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache Index | Headache Index as calculated by the summation of headache duration (hours) X headache intensity (11-point numerical rating scale), over the final two weeks of treatment. | 2, 4, 8, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Medication frequency | Defined as number of days acute headache medication taken over the previous month. | 2, 4, 8, 24 weeks | 
| Headache frequency | Defined as number of days with headache over the previous month | 2, 4, 8, 24 weeks | 
| Duration of headache | Average duration of headache in hours over previous 2 weeks | 2, 4, 8, 24 weeks | 
| Intensity of headache | Average intensity of headache assessed by numerical rating scale over previous 2 weeks | 2, 4, 8, 24 weeks | 
| Frequency of probable migraine attacks | Defined as number of probable migraine attacks (using International Classification of Headache Disorders, second edition, criteria for diagnosis of migraine/migraine with aura) over previous month | 2, 4, 8, 24 weeks | 
| Headache related impact on quality of life | As assessed via the six-item the Headache Impact Test | 2, 4, 8, 24 weeks | 
| Allodynia symptom checklist score | Assesses presence of cutaneous allodynia during activities of daily living | 2, 4, 8, 24 weeks | 
| Von Frey filament test | To assess sensitivity to static mechanical cutaneous allodynia | 2, 4, 8, 24 weeks | 
| Brush allodynia test | To assess sensitivity to dynamic mechanical cutaneous allodynia | 2, 4, 8, 24 weeks | 
| Response rate | Response defined as ≥ 30% reduction in headache days/month or headache index from baseline. Expressed as percentage of patients who saw a ≥ 30% reduction in headache index after ibudilast treatment (at week 8) and NNT, number of patients treated to see 1 patient respond. | 2, 4, 8, 24 weeks | 
| Relapse rate | Expressed as the percentage of patients who were initially classed as responders (at weeks 8) who no longer meet the criteria for responders at 6 months | 2, 4, 8, 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medication overuse headache, ibudilast, glia