Ketamine for Chronic Daily Headache

(KetHead Trial)

Recruiting at 1 trial location

Overseen By Yasmine Hoydonckx, MD, MSc, FIPP

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University Health Network, Toronto

Must not be taking: Benzodiazepines, Antipsychotics, Opioids, others

Disqualifiers: Pregnancy, Renal impairment, Hypertension, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 1 day

56 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications, such as chronic benzodiazepines, antipsychotics, strong CYP2B6 or CYP2C8 inhibitors, CGRP antagonists within 1 month, Onabotulinum-toxin A within 3 months, and opioids with daily Oral Morphine Equivalents of 80 mg or more.

What evidence supports the effectiveness of the drug ketamine for chronic daily headache?

Research shows that ketamine can be effective for managing chronic pain and depression, which suggests it might help with chronic daily headaches too. Ketamine works by blocking certain receptors in the brain that are involved in pain perception, and it has been used successfully in treating other types of chronic pain. ^{1 2 3 4 5}

How does the drug ketamine differ from other treatments for chronic daily headache?

Ketamine is unique because it can be administered through various routes, including oral, intravenous, and intranasal, and it acts quickly to relieve symptoms. Unlike traditional headache treatments, ketamine works by blocking NMDA receptors in the brain, which may help reduce pain and improve mood. ^{2 3 6 7 8}

What is the purpose of this trial?

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.

Research Team

Yasmine Hoydonckx, MD, MSc, FIPP

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

This trial is for adults over 18 with chronic daily headaches, experiencing long-lasting headache episodes frequently each month. Participants must have normal liver and kidney function. It's not suitable for pregnant or breastfeeding individuals, those with renal or liver issues, certain medication users, people with severe hypertension or heart conditions, glaucoma patients, allergy to ketamine, PTSD sufferers, substance abusers or high-dose opioid users.

Inclusion Criteria

You have been diagnosed with chronic daily headaches with frequent and long-lasting headaches.

Your liver and kidney tests show that they are working normally.

Exclusion Criteria

You have existing liver problems.

You already have kidney problems.

Pregnant or breastfeeding patients

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive high-dose intravenous ketamine or saline infusion under hemodynamic monitoring for six hours

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment using diaries and questionnaires

12 weeks

3 visits (in-person) at 1 month, 2 months, and 3 months

Monitoring

Participants wear an actigraphy device to assess sleep and activity for one month

4 weeks

Treatment Details

Interventions

• 0.9% Saline
• Ketamine

Trial Overview The study tests if a high-dose IV infusion of Ketamine can reduce the frequency and intensity of chronic daily headaches compared to a saline solution placebo. The effects on mood, activity levels, sleep quality and overall life satisfaction will also be evaluated over three months using questionnaires and wearable tech.

Participant Groups

Group I: Ketamine infusion Active Control 1 Intervention

Intravenous Ketamine

Group II: Placebo infusion Placebo Group 1 Intervention

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

The Canadian Pain Society

Collaborator

Trials

4

Recruited

360+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

Oral ketamine is a potentially safe and effective treatment for depression, but it requires higher doses (2.0-2.5 mg/kg) compared to intravenous administration due to lower systemic absorption (20%-25%).

Despite its promise as a more accessible and affordable option for treatment, the current literature on oral ketamine is limited, and further research is needed to understand its pharmacokinetics, safety, and efficacy compared to other administration routes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 2: Practical Considerations. Andrade, C.[2020]

A Phase I study involving 32 patients showed that esketamine (0.5 mg/kg) is generally safe and well-tolerated for use in painless gastroscopy, with no serious adverse events reported.

Esketamine resulted in a shorter recovery time compared to racemic ketamine (9 minutes vs. 13 minutes), making it a potentially more efficient option for anesthesia without gender differences affecting its pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. Wang, J., Huang, J., Yang, S., et al.[2022]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

Oral ketamine shows potential for managing chronic pain due to its NMDA receptor antagonism, but there is insufficient evidence to support its routine use, especially regarding long-term safety and efficacy.

The recommended starting dose for ketamine-naive patients is 0.5 mg/kg for racemic ketamine or 0.25 mg/kg for S-ketamine, but the lack of consistent dose-response data and safety concerns limit its application primarily to add-on therapy for complex chronic pain cases where other treatments have failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of oral ketamine in chronic pain management: a review. Blonk, MI., Koder, BG., van den Bemt, PM., et al.[2013]

Grapefruit juice significantly increases the plasma levels of oral S-ketamine, with a 3-fold increase in the area under the plasma concentration-time curve and a 2.1-fold increase in peak plasma concentration, indicating a strong interaction that could affect dosing.

Due to the increased plasma concentrations, it is recommended that dose reductions of S-ketamine be considered when taken with grapefruit juice to avoid potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-ketamine concentrations are greatly increased by grapefruit juice. Peltoniemi, MA., Saari, TI., Hagelberg, NM., et al.[2021]

A new method using gas chromatography-mass spectrometry (GC-MS) allows for the sensitive detection and measurement of ketamine and its metabolite norketamine in hair samples, with a quantitation limit of 0.05 ng/mg.

In an experiment with 15 cavies, it was found that the concentration of ketamine in hair is directly related to the dosage administered, with higher concentrations observed in black hair compared to brown and white hair, indicating that hair color may influence drug incorporation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hair analysis for ketamine and its metabolites. Xiang, P., Shen, M., Zhuo, X.[2016]

Ketamine administered at a dose of 25 mg/kg in domestic cats showed a rapid distribution phase with a half-life of approximately 67 minutes, regardless of whether it was given intravenously (i.v.) or intramuscularly (i.m.).

The i.m. route resulted in quick absorption, with peak plasma levels reached at 10 minutes and about 92% of the dose being systemically available, indicating effective delivery for immobilization purposes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disposition kinetics of ketamine in the domestic cat. Baggot, JD., Blake, JW.[2013]

Ketamine (KET) has been used recreationally since 1962 due to its rapid onset and unique dissociative effects, but its abuse can lead to serious physical and psychological side effects, particularly urological toxicity.

Methoxetamine (MXE), a newer derivative of KET, offers similar dissociative effects but may have even worse side effects, including mood disturbances and acute cerebellar toxicity, indicating it is not a safer alternative to KET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From "Special K" to "Special M": the evolution of the recreational use of ketamine and methoxetamine. Corazza, O., Assi, S., Schifano, F.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 2: Practical Considerations. [2020]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Use of oral ketamine in chronic pain management: a review. [2013]

5. Germany pubmed.ncbi.nlm.nih.gov

S-ketamine concentrations are greatly increased by grapefruit juice. [2021]

6. Ireland pubmed.ncbi.nlm.nih.gov

Hair analysis for ketamine and its metabolites. [2016]

7. Belgium pubmed.ncbi.nlm.nih.gov

Disposition kinetics of ketamine in the domestic cat. [2013]

8. England pubmed.ncbi.nlm.nih.gov

From "Special K" to "Special M": the evolution of the recreational use of ketamine and methoxetamine. [2022]