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

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.

Inclusion criteria

• 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

Exclusion criteria

• 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
• Patients taking opioid medications with daily Oral Morphine Equivalents ≥80 mg