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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether high-dose intravenous ketamine infusions can reduce the frequency and intensity of chronic daily headaches (CDH). Ketamine may alter how the brain processes pain, potentially improving mood, activity, sleep, and overall quality of life. Participants will receive either ketamine or a placebo (a treatment with no active drug) to compare effects. Those with long-lasting headaches on most days for three or more months might be suitable candidates. The trial will also assess the safety of ketamine over a three-month period after treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine is generally safe for people, though it can cause side effects. Common side effects include vivid dreams or hallucinations, which some may find pleasant, while others may not. Other possible side effects are confusion, slurred speech, and dizziness.

Ketamine has shown promise in treating headaches and chronic pain. Its use in hospitals for pain relief and anesthesia suggests safety for these purposes. However, individual reactions can vary. Consulting a healthcare provider is essential to understand how this treatment might work for each person. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for chronic daily headaches?

Unlike the standard treatments for chronic daily headache, which typically involve oral medications like triptans or beta-blockers, ketamine is administered via intravenous infusion. This delivery method allows ketamine to act quickly, offering potential relief much faster than traditional oral medications. Researchers are particularly excited about ketamine because it works on the brain's NMDA receptors, a different mechanism from most headache treatments. This unique action could provide new hope for patients who haven't responded to existing therapies.

What evidence suggests that ketamine might be an effective treatment for chronic daily headache?

Research has shown that ketamine might help treat chronic headaches. In one study, 76% of people with chronic cluster headaches experienced significant improvement after receiving ketamine through an IV. Early research also suggests that ketamine can aid those with severe, ongoing migraines. Another study found that using ketamine as a nasal spray reduced headache pain and improved quality of life. In this trial, participants will receive either a ketamine infusion or a placebo infusion to evaluate ketamine's potential in managing chronic daily headaches. ^{6 7 8 9 10}

Who Is on the Research Team?

Anuj Bhatia, MD, PhD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8769496/

Ketamine for Refractory Chronic Migraine

Retrospective evidence suggests that a 5-day infusion of (R,S)-ketamine may be beneficial in the treatment of refractory chronic migraine, but prospective ...

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practicalneurology.com

practicalneurology.com/diseases-diagnoses/headache-pain/headache-horizons-emerging-use-of-ketamine-for-the-treatment-of-migraine-and-other-headache-disorders/32171/

Ketamine for Headache Relief: New Insights

In another study of 17 individuals with chronic cluster headache, 76% of participants responded to IV ketamine, and there was a significant ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03896256

Ketamine for Refractory Chronic Migraine: a Pilot Study

Preliminary studies have shown that ketamine might be effective for patients with refractory chronic migraine, which is a severe type of headache.

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trialsjournal.biomedcentral.com

trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07186-3

the “KetHead” trial - Trials Journal - BioMed Central

This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion.

5.

rapm.bmj.com

rapm.bmj.com/content/48/12/581

Real-world study of intranasal ketamine for use in patients ...

Intranasal ketamine served as an acute treatment for refractory chronic migraine by reducing headache intensity and improving quality of life with relatively ...

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2017/016812s043lbl.pdf

KETALAR (ketamine hydrochloride) injection

THE PSYCHOLOGICAL MANIFESTATIONS VARY IN SEVERITY BETWEEN PLEASANT DREAM-LIKE. STATES, VIVID IMAGERY, HALLUCINATIONS, AND EMERGENCE DELIRIUM. IN SOME CASES.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8520840/

Efficacy of ketamine in the treatment of migraines and other ...

The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ketamine on migraines and other primary headache disorders compared to ...

8.

rxlist.com

rxlist.com/ketalar-drug.htm

Ketalar (Ketamine Hydrochloride Injection): Side Effects, ...

Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever ...

9.

mayoclinic.org

mayoclinic.org/drugs-supplements/ketamine-injection-route/description/drg-20075559

Ketamine (injection route) - Side effects & uses

Ketamine injection is used alone or together with other medicines to produce loss of consciousness before and during surgery or a medical procedure.

10.

practicalneurology.com

practicalneurology.com/diseases-diagnoses/headache-pain/ketamine-for-intractable-headache/31952/

Ketamine for Intractable Headache - - Practical Neurology

Ketamine is a novel treatment for chronic refractory headache not otherwise responsive to standard pharmacotherapy.