Ketamine for Chronic Pain and Depression

(PEAK Trial)

Overseen By Theresa Lii, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Stanford University

Must not be taking: Problematic interactions

Disqualifiers: Pregnant, Breastfeeding, Other trials, others

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: 2

Duration: 1 day

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The goal of this clinical trial is to compare ketamine to a placebo when given as a single infusion during IV sedation in adults with chronic pain and depression. We do not know whether ketamine will be more effective than placebo under these circumstances. This study aims to: * Evaluate whether placebo is non-inferior to ketamine in treating chronic pain and depression, when delivered under propofol sedation * Confirm that propofol sedation is a safe way to keep participants blinded to treatment * Assess patients' comfort with the sedation process to improve future studies * Explore whether patient expectations affects their pain and depression Participants will: * Need to qualify for the study based on stringent medical criteria * Undergo sedation with propofol * Randomly receive either a ketamine or a placebo (saline) infusion during sedation * Complete several study assessments over 5-7 weeks

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it excludes those who regularly use medications that might interact with the study drugs. It's best to discuss your current medications with the study team to see if they might be problematic.

Is ketamine safe for use in humans?

Research shows that ketamine can cause side effects like dissociation (feeling disconnected from reality) and increased blood pressure/heart rate, but these effects are usually temporary. Studies on ketamine for depression suggest it is generally safe and well-tolerated, with careful monitoring. ^{1 2 3 4 5}

How is the drug ketamine unique in treating chronic pain and depression?

Ketamine is unique because it works quickly and can be administered in various ways, including orally, intravenously, and intranasally, making it flexible for different patient needs. It acts on NMDA receptors, which are involved in chronic pain, and has shown potential in treating both pain and depression, especially when other treatments have failed. ^{6 7 8 9 10}

What evidence supports the effectiveness of the drug ketamine for treating chronic pain and depression?

Research shows that ketamine can reduce pain intensity in patients with chronic pain and has been effective in treating severe depression, including treatment-resistant depression. Although more studies are needed, ketamine has shown promise as a quick-acting intervention for both pain and depression. ^{6 9 10 11 12}

Who Is on the Research Team?

Theresa R Lii, MD, MS

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 who have had chronic pain for at least 3 months and are currently experiencing depression. Participants must be able to follow the study's procedures and communicate effectively in English about any adverse events or important clinical information.

Inclusion Criteria

I am comfortable speaking and writing in English.

I have been experiencing chronic pain for at least 3 months.

I can follow the study rules and talk about any health changes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo sedation with propofol and receive a one-time intravenous infusion of either ketamine or placebo

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of pain, depression, and side effects

4 weeks

Multiple assessments at 1, 7, 14, 21, and 28 days post-treatment

Pilot Feasibility Phase

A pilot phase with a smaller group of participants to assess feasibility before the main trial

Not specified

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine

Trial Overview The trial is testing if ketamine is more effective than a placebo (saline) in treating chronic pain and depression when given as a single infusion during sedation with propofol. The study also evaluates patient comfort with sedation and how expectations might influence outcomes.

How Is the Trial Designed?

Group I: Ketamine Active Control 1 Intervention

A one-time intravenous infusion of ketamine (0.5 mg/kg)

Group II: Saline Placebo Group 1 Intervention

A one-time intravenous infusion of normal saline

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

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]

In a 1-year study involving 256 patients with refractory chronic pain, ketamine treatment significantly reduced pain intensity from an average of 6.8 to 5.7 on a 0-10 scale, indicating its efficacy in managing chronic pain.

The study identified three distinct pain trajectories among patients, highlighting that those with neuropathic pain had better outcomes compared to those with fibromyalgia, suggesting the need for tailored treatment approaches based on pain type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for refractory chronic pain: a 1-year follow-up study. Corriger, A., Voute, M., Lambert, C., et al.[2022]

A meta-analysis of 12 studies involving 88 patients indicates that Ketamine significantly reduces neuropathic pain compared to placebo, although the effects are typically short-lived after administration.

Ketamine has shown promise as an alternative to opioids for chronic pain management, with some studies reporting positive long-term outcomes, but further research with larger sample sizes is needed to confirm its efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ketamine for treatment of chronic pain: meta-analysis]. Wiedemann, B.[2019]

In a study of 329 patients with treatment-refractory chronic pain, repeated ketamine administration significantly reduced pain intensity and improved mental and physical health over one year, with a notable effect size of -0.52.

The study found that depression, rather than the dose of ketamine, was the key factor mediating pain relief, suggesting that ketamine's effectiveness in reducing pain is primarily linked to its ability to alleviate depressive symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain. Voute, M., Lambert, C., Pereira, B., et al.[2023]

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]

An extended release oral ketamine tablet was found to be safe and well tolerated in a study of seven patients with treatment-resistant depression/anxiety, with no significant changes in vital signs and only one brief report of dissociation.

All patients experienced over 50% improvements in mood ratings over 96 hours, suggesting that while the onset of mood improvement is slightly delayed compared to injectable forms, this oral formulation could be a promising option for treating resistant depression and anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Glue, P., Medlicott, NJ., Neehoff, S., et al.[2022]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

Subcutaneous (SC) administration of racemic ketamine and esketamine has shown rapid and robust antidepressant effects in both unipolar and bipolar patients, with response and remission rates ranging from 50% to 100% after single or multiple doses.

The studies indicated that SC ketamine is generally well-tolerated, with only transitory side effects, making it a promising and cost-effective treatment option for depression, especially in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. Cavenaghi, VB., da Costa, LP., Lacerda, ALT., et al.[2021]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

In a study of 268 procedures involving 35 children with leukemia, the combination of thiamylal plus pentazocine (TP) provided faster sedation compared to ketamine plus midazolam (KM) during bone marrow aspirations and intrathecal chemotherapy.

While TP was associated with a higher incidence of transient desaturation events, these were manageable with oxygen supplementation, indicating that TP can be a safe and effective alternative for sedation in pediatric oncology procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiamylal Plus Pentazocine Shows Similar Efficacy as Ketamine Plus Midazolam for Painful Procedures in Children With Leukemia. Nakagawa, S., Okamoto, Y., Kodama, Y., et al.[2019]

Ketamine has been shown to have antidepressant effects in palliative care patients, with all 11 studies reviewed reporting positive outcomes, including one randomized controlled trial (RCT).

While ketamine may be effective for treating depression, its efficacy for physical pain relief is less clear, with recent RCTs indicating no significant analgesic effect, although some patients did experience pain relief with specific administration methods like epidural or intrathecal ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature. Goldman, N., Frankenthaler, M., Klepacz, L.[2020]

Chronic neuropathic pain in rats leads to depression-like behaviors, as evidenced by decreased sucrose preference and increased immobility in behavioral tests, indicating a link between pain and depression.

A single low-dose ketamine treatment effectively alleviates depression-like behaviors associated with chronic pain without affecting pain sensitivity, suggesting that its antidepressant effects can occur independently of its pain-relieving properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Wang, J., Goffer, Y., Xu, D., et al.[2022]

Citations

1. England pubmed.ncbi.nlm.nih.gov

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

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

Ketamine for refractory chronic pain: a 1-year follow-up study. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

[Ketamine for treatment of chronic pain: meta-analysis]. [2019]

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

Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain. [2023]

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

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

6. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

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

Thiamylal Plus Pentazocine Shows Similar Efficacy as Ketamine Plus Midazolam for Painful Procedures in Children With Leukemia. [2019]

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

The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature. [2020]

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

A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. [2022]