A Phase 3 interventional study of Ketamine and 0.9% Saline in Chronic Daily Headache, sponsored by University Health Network, Toronto. Recruiting at 2 sites in Canada. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-06-08.
Sponsored by University Health Network, Toronto · Phase 3, Interventional, and Treatment
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.
The KetHead study is designed as a multi-center, placebo-controlled, superiority randomized controlled trial with two parallel groups and blinding of participants and outcome assessors. It will be conducted at two chronic pain centers, Toronto Western Hospital and Sinai Health System. Eligible patients will be identified and enrolled in the pain clinics. Randomization will take place upon patient enrollment. Treating physicians, patients, close contacts, study coordinators and primary outcome assessors will be blinded to treatment allocation.
Interventions common to both arms Participating patients will receive the infusion at the pain infusion unit at Toronto Western Hospital, under hemodynamic monitoring, supervised by an Anesthesiologist. At the start of the infusion, 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)22 to blind the participants and assessors to group allocation. Eight mg of ondansetron and 8 mg of dexamethasone will be administered to all participants to prevent nausea, 5000 units of heparin will be given subcutaneously to prevent thrombo-embolic events. Medications will be administered by an Anesthesiologist.
A. Intervention group: For individuals randomized to the IV Ketamine group, 1 mg.kg-1 bolus will be given. This will be prepared as a syringe of 10 cc of Ketamine 10 mg/ml. This is followed by an infusion of 1 mg.kg-1.hour-1 (ketamine diluted in saline to 2 mg/mL at 0.5 mL.kg-1.hour-1) for six hours.
B. Control group: For individuals in the saline infusion group, an IV bolus of 0.9% saline will be given. The volume will be the same as that of the ketamine bolus for that weight, to prevent unblinding of participants and assessors. This will be followed by an infusion 0.5 mL.kg-1.hour-1 of saline for six hours. The rate of the infusion will be the same as that of a ketamine infusion for that weight to prevent unblinding of participants and assessors.
Study personnel will assess patient and collect data throughout their enrollment in the study.
During the trial, patients will be instructed to use a pain and migraine diary for collection of migraine days, pain scores and rescue pain medication during the 12 weeks after infusion.
Patients will be assessed for collection of outcomes immediately after the infusion and at 1-month, 2-months and 3-months after infusion.
Participants in both arms will wear the actigraphy device starting on the day of infusion for one month to longitudinally assess the impact of the study treatments on sleep and activity.
145 studies on the registry are indexed under Headache Disorders; 37 are open to participants now.
This study's planned enrollment of 56 is close to the median of 60 across 98 interventional studies indexed under Headache Disorders.
Browse Headache Disorders studies →University Health Network, Toronto is the lead sponsor of 1,438 studies on the registry; 297 are open to participants now.
Of its 17 completed or terminated interventional studies of FDA-regulated products, 3 (18%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion criteria:
Intravenous Ketamine at a dose of 1 mg / kg / hour for six hours.
Drug: Ketamine
0.9% saline infusion at the same rate as the study drug group for six hours.
Other: 0.9% Saline
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
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
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)
Time frame: At 4 weeks
Impact of ketamine on headache intensity after infusion
Impact of ketamine on headache intensity at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using Numerical Rating Scale (0-10)
Time frame: At 1 month, 2 months and 3 months
Impact of ketamine on headache frequency after infusion
Impact of ketamine on headache frequency at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, as number of headache episodes per day
Time frame: At 1 month, 2 months and 3 months
Impact of ketamine on headache duration after infusion
Impact of ketamine on duration of headache at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, from the headache diary maintained by patient
Time frame: At 1 month, 2 months and 3 months
Impact on sleep efficiency after ketamine infusion
Impact of ketamine on efficiency of sleep at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, measured with an actigraphy device
Time frame: At 1 month, 2 months and 3 months
Impact on quality of sleep after ketamine infusion
Impact of ketamine on quality of sleepat one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, assessed with the PSQI (Pittsburgh Sleep Quality Index) questionnaire
Time frame: At 1 month, 2 months and 3 months
Impact on physical activity after ketamine infusion
Impact of ketamine on physical activity at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, measured with actigraphy device
Time frame: At 1 month, 2 months and 3 months
Impact after ketamine infusion on daily activity
Impact of ketamine on seven daily activities (e.g. general activity, walking, mood etc.) at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, measured with Brief Pain Inventory (BPI) scale
Time frame: At 1 month, 2 months and 3 months
Impact of on emotional well being (for catastrophizing) after ketamine infusion
Impact of ketamine on emotional well being at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using the PCS (pain catastrophizing scale) scale
Time frame: At 1 month, 2 months and 3 months
Impact of on emotional well being for anxiety after ketamine infusion
Impact of ketamine on emotional well being at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using anxiety (GAD7- Generalized Anxiety Disorder-7) scale
Time frame: At 1 month, 2 months and 3 months
Impact of on emotional well being for depression after ketamine infusion
Impact of ketamine on emotional well being at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using depression (PHQ9-Patient Health Questionnaire9) questionnaire
Time frame: At 1 month, 2 months and 3 months
Impact of ketamine infusion on patient satisfaction
Impact of ketamine on patient satisfaction at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using global improvement (PGIC) scales
Time frame: At 1 month, 2 months and 3 months
Impact on quality of life after ketamine infusion
Impact of ketamine on quality of life at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using EQ-5D (European Quality of life) questionnaire
Time frame: At 1 month, 2 months and 3 months
Impact of ketamine infusion on analgesic consumption
Impact of ketamine on analgesic consumption at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using name and dose of the analgesic use
Time frame: At 1 month, 2 months and 3 months
Side effects after ketamine infusion
Side effects after the ketamine infusion as assessed using Bowdle questionnaire
Time frame: Immediately after infusion and after 1 week
Side effects after ketamine infusion
Dissociative side effects assessed after the ketamine infusion, using the CADSS (Clinician Administered Dissociative States Scale) checklist
Time frame: Immediately after the infusion
Plan to share: No — Study results will first be disseminated at the local, national and international conferences and submitted for publication in a peer-reviewed journal.
Started Jun 2022 (actual). Primary completion is estimated for Feb 2027, 56 months after the start.
How these figures are worked out, and which studies are left out of them.
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drug tested here: Ketamine
University Health Network, Toronto →