Recruiting
Phase 3

Ketamine

Sponsor:

University Health Network, Toronto

Code:

NCT05306899

Conditions

Chronic Daily Headache

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

Interventions

Ketamine

0.9% Saline

Study Details

Brief summary:

Chronic daily headaches (CDH) poses a significant burden on patients, healthcare systems and the society. Intravenous (IV) ketamine infusion, an intervention that is widely available and scalable, can treat CDH by reversing receptor-mediated sensitization. This study is a multicenter, placebo-controlled, parallel group randomized trial with blinding of participants and observers with the goal of comprehensively assessing the effect of high-dose IV ketamine infusion (1 mg.kg-1.h-1 for six hours) on the frequency and intensity of headaches, mood, activity, sleep, quality of life and safety of ketamine for three months after the interventions. Use of validated questionnaires, wearable technology, a research team that includes investigators with expertise in studying ketamine and in evaluating treatments for CDH and pain syndromes are some of the unique features of this project.

Our study aims to prospectively assess the efficacy and safety of high-dose intravenous ketamine infusions compared to saline infusions in participants with CDH syndrome.

Conditions

Chronic Daily Headache

Study ID

NCT05306899

Start date

Jun 1, 2022

Status verified date

Oct, 2025

Completion date

Jun 1, 2027

Anticipated

Primary completion date

Feb 1, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

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:

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 Design

Enrollment

56 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

active comparator: Ketamine infusion

Intravenous Ketamine at a dose of 1 mg / kg / hour for six hours.

placebo comparator: Placebo infusion

0.9% saline infusion at the same rate as the study drug group for six hours.

Interventions

Ketamine

Bolus of IV Ketamine 1 mg.kg-1 (= 0.1 ml.kg-1) followed by Infusion of Ketamine 1 mg.kg-1.hour-1 (= 0.5 mL.kg-1.hour-1) for 6 hours. All patients will receive IV midazolam 0.04 mg.kg-1 (maximum 3 mg) and subsequently 0.01-0.02 mg.kg-1 every hour to keep participants in a sedated but arousable state (Ramsay Sedation Scale score 3 or 4) to blind the participants and assessors to group allocation. Ondansetron 8 mg and 8 mg of dexamethasone will be administered to prevent nausea, 5000 units of heparin will be given subcutaneously to prevent thrombo-embolic events.

0.9% Saline

Bolus of IV Saline 0.9% of 0.1 ml.kg-1 followed by Infusion of Saline 0.9% of 0.5 mL.kg-1.hour-1 for 6 hours. All patients will receive IV midazolam 0.04 mg.kg-1 (maximum 3 mg) and subsequently 0.01-0.02 mg.kg-1 every hour to keep participants in a sedated but arousable state (Ramsay Sedation Scale score 3 or 4) to blind the participants and assessors to group allocation. Ondansetron 8 mg and 8 mg of dexamethasone will be administered to prevent nausea, 5000 units of heparin will be given subcutaneously to prevent thrombo-embolic events.

Primary outcome measure

  • Difference in headache days between the 2 groups [ Time Frame: At 4 weeks ]

Central Contacts and Locations

Central contacts

Emad Al Azazi

+1 (416) 603 5800KetHead@uhn.ca

Locations

Women's College Hospital

Recruiting

Toronto, Ontario, Canada, M5S 1B2

Contacts

Didem Bozak

kethead@uhn.ca

Toronto Western Hospital

Recruiting

Toronto, Ontario, Canada, M5T 2S8

Contacts

Emad Al Azazi

+1-416-603-5800kethead@uhn.ca

Principal Investigator:

Anuj Bhatia, MD, PhD

More Information

Sponsor

University Health Network, Toronto

Last update posted

Jun 8, 2026

Last verified

Oct, 2025

Keywords

  • ketamine
  • migraine
  • daily headache
  • chronic pain

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by University Health Network, Toronto on 2026-06-08.