Ibudilast in the Treatment of Medication Overuse Headache

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

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.

Study Overview

• Status: Unknown
• Conditions: Medication Overuse Headache
• Intervention / Treatment: Drug: Ibudilast; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Paul Rolan, MD FRACP; Phone Number: +61 8 8303 4102; Email: paul.rolan@adelaide.edu.au

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Pain and Anaesthesia Research Clinic, Royal Adelaide Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Adelaide
• Collaborators: University of South Australia
• Investigators: Principal Investigator: Paul Rolan, MD FRACP, The University of Adelaide

Publications and helpful links

General Publications

• Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008 Nov 25;71(22):1821-8. doi: 10.1212/01.wnl.0000335946.53860.1d.
• Obermann M, Katsarava Z. Management of medication-overuse headache. Expert Rev Neurother. 2007 Sep;7(9):1145-55. doi: 10.1586/14737175.7.9.1145.
• Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR. Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. ScientificWorldJournal. 2007 Nov 2;7:98-111. doi: 10.1100/tsw.2007.230.

Helpful Links

• Click here for more information about this study: Ibudilast in the Treatment of Medication Overuse Headache

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Anticipated): June 1, 2013
• Study Completion (Anticipated): August 1, 2013

Study Registration Dates

• First Submitted: March 17, 2011
• First Submitted That Met QC Criteria: March 17, 2011
• First Posted (Estimate): March 18, 2011

Study Record Updates

• Last Update Posted (Estimate): February 6, 2013
• Last Update Submitted That Met QC Criteria: February 4, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: Medication overuse headache; ibudilast; glia
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders; Headache; Headache Disorders, Secondary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Ibudilast
• Other Study ID Numbers: U1111-1119-9613; IBU-002 (Other Identifier: The University of Adelaide)