Clinical TrialHeadache Disorders (Cluster & Migraine)KetaminePlaceboRecruiting

Multi-center RCT of IV Ketamine Efficacy and Safety in Chronic Daily Headaches

This placebo-controlled trial (n=56) will investigate the efficacy and safety of high-dose intravenous ketamine infusion in treating Chronic Daily Headaches (CDH) syndrome.

Target Enrollment
56 participants
Study Type
Phase III interventional
Design
Randomized, double Blind

Detailed Description

Multicentre, randomised, double-blind, placebo-controlled parallel trial at two Canadian chronic pain centres comparing high-dose IV ketamine versus saline in participants with chronic daily headache.

Active treatment is a 1 mg/kg IV bolus followed by an infusion of 1 mg/kg/hour (6 hours) with sedation (midazolam), antiemetic and prophylactic measures; placebo arm receives volume-matched saline with identical adjunct medications to preserve blinding.

Outcomes include headache frequency and intensity, mood, activity and sleep (actigraphy), quality of life and safety assessed acutely and at 1, 2 and 3 months post-infusion using validated questionnaires and wearable devices.

Study Protocol

Preparation

sessions

Dosing

1 sessions
360 min each

Integration

sessions

Study Arms & Interventions

Ketamine infusion

experimental

IV ketamine bolus followed by 6‑hour infusion with sedation to maintain blinding.

Interventions

  • Ketamine1 mg/kg
    via IV• single infusion• 1 doses total

    Bolus 1 mg/kg then infusion 1 mg/kg/hour for 6 hours; midazolam sedation (0.04 mg/kg then 0.01–0.02 mg/kg/hr), ondansetron 8 mg, dexamethasone 8 mg, heparin 5000 U SC.

Placebo infusion

inactive

Volume‑matched 0.9% saline bolus and 6‑hour infusion with identical sedation regimen.

Interventions

  • Placebo
    via IV• single infusion• 1 doses total

    Volume‑matched saline bolus and infusion to mirror ketamine; same midazolam/ondansetron/dexamethasone/heparin regimen to maintain blinding.

Participants

Ages
18 – 75
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1. Age 18-75 years
  • 2. CDH diagnosis preceding trial enrollment with headache episodes lasting for 4 or more hours occurring on 15 or more days in a month for 3 or more months (International Headache Society-IHS criteria)
  • 3. Normal liver and kidney function tests

Exclusion Criteria

  • Exclusion criteria:
  • 1. Pregnant or breastfeeding patients
  • 2. Pre-existing renal impairment
  • 3. Pre-existing liver impairment
  • 4. Chronic benzodiazepine or antipsychotic medication use
  • 5. History of cerebrovascular event
  • 6. Significant and untreated hypertension or severe cardiac condition
  • 7. Hypothyroidism
  • 8. Glaucoma
  • 9. Concomitant use of strong CYP2B6 or CYP2C8 inhibitor
  • 10. Allergy or intolerance to ketamine
  • 11. Pheochromocytoma
  • 12. Any significant cognitive or language barriers that impede participation
  • 13. CGRP antagonist use in 1 month or Onabotulinum-toxin A 3 months before infusion
  • 14. Active diagnosis of Post-Traumatic Stress Disorder (PTSD)
  • 15. Active diagnosis of Substance Use Disorder
  • 16. Patients taking opioid medications with daily Oral Morphine Equivalents ≥80 mg

Study Details

Locations

Women's College Hospital — Toronto, Ontario, Canada
Toronto Western Hospital — Toronto, Ontario, Canada

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