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

Official title

A Multi-center Randomized Controlled Trial of Efficacy and Safety of Intravenous Ketamine for Chronic Daily Headaches: The KetHead Study

Overview

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.

Detailed description

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.

Interventions

• Drug 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 hepar
• Other 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 subcut

Primary outcome measures

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

Secondary outcome measures (12)

• Impact of ketamine on headache intensity after infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact of ketamine on headache frequency after infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact of ketamine on headache duration after infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact on sleep efficiency after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact on quality of sleep after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact on physical activity after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact after ketamine infusion on daily activity [Time frame: At 1 month, 2 months and 3 months]
• Impact of on emotional well being (for catastrophizing) after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact of on emotional well being for anxiety after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact of on emotional well being for depression after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]
• Impact of ketamine infusion on patient satisfaction [Time frame: At 1 month, 2 months and 3 months]
• Impact on quality of life after ketamine infusion [Time frame: At 1 month, 2 months and 3 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Canada · 2 centers

• Women's College Hospital — Toronto
• Toronto Western Hospital — Toronto

Publications

• 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
• 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
• 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
• Vekhova KA, Namiot ED, Jonsson J, Schioth HB. Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations. Clin Pharmacol Ther. 2025 Feb;117(2):374-386. doi: 10.1002/cpt.3478. Epub 2024 Oct 20. PMID 39428602
• 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

Identifiers

NCT: NCT05306899 · 21-5523

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗