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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ketamine, administered during sedation, is more effective than a placebo for treating chronic pain and depression. Researchers aim to determine if patients feel comfortable and safe during sedation and how their expectations might influence their pain and depression. Participants will be randomly assigned to receive either a ketamine or placebo infusion and will complete several assessments over 5-7 weeks. Individuals who have experienced daily chronic pain for at least three months and are currently dealing with depression may be suitable for this study. As a Phase 4 trial, this research seeks to understand how the already FDA-approved treatment benefits more patients.

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.

What is the safety track record for ketamine?

Research has shown that ketamine is generally safe as a treatment. Studies have found it effective for managing chronic pain and depression. Its use in helping patients sleep during surgery further supports its safety.

When used short-term for pain relief, ketamine works effectively during administration. However, like any treatment, it can cause side effects. Common side effects include dizziness, nausea, and a faster heartbeat, which are usually mild and temporary.

Overall, ketamine is considered safe in a controlled medical setting. This trial will further explore its safety in individuals with chronic pain and depression. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Ketamine is unique because it offers a fast-acting alternative for managing chronic pain and depression, conditions traditionally treated with medications like opioids or antidepressants, which can take weeks to show effects. Unlike these standard treatments, ketamine works by blocking the NMDA receptor in the brain, which can quickly alleviate symptoms. Researchers are especially excited about ketamine because it can bring relief in just hours, offering hope for those who haven't responded to other therapies.

What evidence suggests that ketamine might be an effective treatment for chronic pain and depression?

Research has shown that ketamine can help manage chronic pain and depression. In studies, up to 46% of patients experienced significant symptom improvements after ketamine treatment. It greatly reduced both pain and depression across various groups. In this trial, participants will receive either a one-time intravenous infusion of ketamine or a placebo comparator of normal saline. While the strongest pain relief occurs during treatment, ketamine consistently alleviated depression symptoms. These findings suggest ketamine could be a promising option for treating chronic pain and depression. ^{3 6 7 8 9}

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

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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Oral ketamine for 6 weeks showed an alleviation of depressive symptoms in chronic pain, and ketamine improved both depression and pain. A recent ...

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KETALAR (ketamine hydrochloride) injection

KETALAR is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or ...

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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.