title: Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double-Blind, Randomized, Placebo-Controlled Pilot Trial of Efficacy and Safety.
abstract: 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.
authors.affiliation: Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.
authors.forename: Jacinta L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.
authors.forename: Yuen H
authors.initials: YH
authors.lastname: Kwok
authors.affiliation: Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Sumracki
authors.affiliation: Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Swift
authors.affiliation: Discipline of Physiology, University of Adelaide, Adelaide, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.affiliation: XOMA Corp., Berkeley, CA, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Johnson
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Desmond B
authors.initials: DB
authors.lastname: Williams
authors.affiliation: School of Mathematical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Tuke
authors.affiliation: Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.|Pain and Anaesthesia Research Clinic, Royal Adelaide Hospital, Adelaide, Australia.|Pain Management Unit, Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rolan
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D051271:Headache Disorders, Secondary / Q000188:drug therapy*; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009457:Neuroglia / Q000187:drug effects; D010865:Pilot Projects; D011725:Pyridines / Q000627:therapeutic use*; D012372:ROC Curve; D014665:Vasodilator Agents / Q000627:therapeutic use*; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D011725:Pyridines; D014665:Vasodilator Agents; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
keywords: cytokines; glia; ibudilast; medication overuse headache; opioid; opioid-induced hyperalgesia