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

NCT05306899 | Recruiting Phase 3

• 1 other identifier: 21-5523
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 2

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

Keywords

ketamine; migraine; daily headache; chronic pain

Outcome Measures

Primary Outcomes (1)

• Difference in headache days between the 2 groups

  Between-group difference in the number of headache days in the first 4 weeks after the infusion. (Defined as a day in which the headache lasts 4 or more hours, or a headache of any duration for which abortive treatment (anti-inflammatories, triptans, ergot derivatives, opioids) are taken. Patients will be asked to keep track of their headache days in a diary)

  At 4 weeks

Secondary Outcomes (15)

• Impact of ketamine on headache intensity after infusion

  At 1 month, 2 months and 3 months

• Impact of ketamine on headache frequency after infusion

  At 1 month, 2 months and 3 months

• Impact of ketamine on headache duration after infusion

  At 1 month, 2 months and 3 months

• Impact on sleep efficiency after ketamine infusion

  At 1 month, 2 months and 3 months

• Impact on quality of sleep after ketamine infusion

  At 1 month, 2 months and 3 months

Study Arms (2)

Ketamine infusion

ACTIVE COMPARATOR

Intravenous Ketamine

Drug: Ketamine

Placebo infusion

PLACEBO COMPARATOR

Other: 0.9% Saline

Interventions

Ketamine DRUG

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.

Also known as: Ketamine hydrochloride

Ketamine infusion

0.9% Saline OTHER

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.

Also known as: Normal saline

Placebo infusion

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years
• 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)
• Normal liver and kidney function tests

You may not qualify if:

• Pregnant or breastfeeding patients
• Pre-existing renal impairment
• Pre-existing liver impairment
• Chronic benzodiazepine or antipsychotic medication use
• History of cerebrovascular event
• Significant and untreated hypertension or severe cardiac condition
• Hypothyroidism
• Glaucoma
• Concomitant use of strong CYP2B6 or CYP2C8 inhibitor
• Allergy or intolerance to ketamine
• Pheochromocytoma
• Any significant cognitive or language barriers that impede participation
• CGRP antagonist use in 1 month or Onabotulinum-toxin A 3 months before infusion
• Active diagnosis of Post-Traumatic Stress Disorder (PTSD)
• Active diagnosis of Substance Use Disorder

Sponsors & Collaborators

• University Health Network, Toronto: lead
• The Canadian Pain Society: collaborator
• Pfizer: collaborator

Study Sites (2)

Women's College Hospital

Toronto, Ontario, M5S 1B2, Canada

RECRUITING

Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

RECRUITING

Related Publications (4)

• Schwenk ES, Dayan AC, Rangavajjula A, Torjman MC, Hernandez MG, Lauritsen CG, Silberstein SD, Young W, Viscusi ER. Ketamine for Refractory Headache: A Retrospective Analysis. Reg Anesth Pain Med. 2018 Nov;43(8):875-879. doi: 10.1097/AAP.0000000000000827.

  PMID: 29923953 RESULT

• Pomeroy JL, Marmura MJ, Nahas SJ, Viscusi ER. Ketamine Infusions for Treatment Refractory Headache. Headache. 2017 Feb;57(2):276-282. doi: 10.1111/head.13013. Epub 2016 Dec 27.

  PMID: 28025837 RESULT

• Orhurhu V, Orhurhu MS, Bhatia A, Cohen SP. Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesth Analg. 2019 Jul;129(1):241-254. doi: 10.1213/ANE.0000000000004185.

  PMID: 31082965 RESULT

• Hoydonckx Y, Singh M, Gilron I, Khan J, Narouze S, Dahan A, Curtis K, Cao X, Kara J, Bhatia A. Trial protocol for a multicenter randomized controlled trial to assess the efficacy and safety of intravenous ketamine for chronic daily headaches: the "KetHead" trial. Trials. 2023 Mar 1;24(1):155. doi: 10.1186/s13063-023-07186-3.

  PMID: 36855160 DERIVED

MeSH Terms

Conditions

Headache Disorders; Migraine Disorders; Chronic Pain

Interventions

Ketamine; Saline Solution

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Anuj Bhatia, MD, PhD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emad Al Azazi

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2022
• First Posted: April 1, 2022
• Study Start: June 1, 2022
• Primary Completion: February 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: February 5, 2026

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2)