Low-Dose Ketamine for Burns

(IMPROVE Trial)

Overseen By David M Hill, Pharm.D.

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Tennessee

Disqualifiers: Pregnant, Incarcerated, Under 18, 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: Unknown

Duration: 7 days

140 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is low-dose ketamine generally safe for humans?

Research on ketamine, often used for depression, shows it can have temporary side effects like changes in mood or heart rate, but these are usually short-lived. There are rare reports of serious issues like breathing problems, so careful monitoring is recommended during treatment. ^{1 2 3 4 5}

How does low-dose ketamine differ from other treatments for burns?

Low-dose ketamine is unique for burn treatment because it can provide pain relief through different routes, such as intravenous or potentially oral and sublingual, which are being explored for other pain conditions. Its rapid action and potential for fewer side effects compared to traditional pain medications make it a novel option for managing burn pain. ^{3 6 7 8 9}

What is the purpose of this trial?

The current standard of care (SOC) (i.e. fentanyl and midazolam) offers limited efficacy for preventing or relieving pain. Ketamine infusions may provide the benefits of analgesia, minimize adverse events, and reduce opioid use. The purpose of this study is to determine if adding a low dose ketamine infusion during wound care will safely provide pain relief for patients with burn injury.

Eligibility Criteria

This trial is for patients with burn injuries who experience pain during wound care. It aims to see if low-dose ketamine can help manage their pain better than the current standard treatments without increasing opioid use.

Inclusion Criteria

I was admitted for a burn injury.

Exclusion Criteria

Unable or unwilling to consent within 72 hours

Unable to report NRS

I am under 18 years old.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either ketamine infusion or placebo during wound care procedures

7 days

Daily visits for wound care

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Ketamine

Trial Overview The study tests whether a low dose of ketamine, given as an infusion alongside the usual care (like fentanyl and midazolam), can provide better pain relief during burn wound care compared to just using the standard medications alone.

Participant Groups

Group I: Ketamine Experimental Treatment 1 Intervention

Ketamine infusion (0.3 mg/kg/hr) to begin 1 hour before wound care, continuing through and for 1 hour following wound care.

Group II: Placebo Placebo Group 1 Intervention

0.9% saline to begin 1 hour before wound care, continuing through and for 1 hour following wound care.

Who Is Running the Clinical Trial?

University of Tennessee

Lead Sponsor

Trials

202

Recruited

146,000+

Findings from Research

This systematic review analyzed 60 studies on the safety of ketamine for treating depression, revealing that acute doses of ketamine led to more frequent side effects, including psychiatric and cardiovascular issues, compared to placebo.

There is a notable lack of data on the long-term safety and effects of repeated ketamine dosing, highlighting the need for large-scale clinical trials to better understand its safety profile over extended use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side-effects associated with ketamine use in depression: a systematic review. Short, B., Fong, J., Galvez, V., et al.[2019]

Chronic administration of ketamine does not induce widespread neurotoxicity ('Olney's lesions') in rats, unlike the NMDAR antagonist MK-801, which showed dose-dependent lesions with both single and repeat dosing.

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) was found to be safe, as it did not cause any behavioral effects or neurotoxic lesions, suggesting it may be a safer alternative for treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the pharmacokinetics and NMDAR antagonism-associated neurotoxicity of ketamine, (2R,6R)-hydroxynorketamine and MK-801. Morris, PJ., Burke, RD., Sharma, AK., et al.[2022]

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 shows promise as a treatment for treatment-resistant depression (TRD), but its use can lead to common adverse events, which are usually temporary.

A case of apnea during a slow sub-anesthetic infusion of ketamine highlights a rare but serious potential side effect, emphasizing the need for careful monitoring and management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., et al.[2021]

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]

A new lozenge formulation of ketamine, containing 25 mg, demonstrated good chemical stability for at least 14 weeks, making it a viable option for pain management.

The bioavailability of the lozenge was found to be 24% for both oral and sublingual administration, indicating it could effectively deliver ketamine for treating chronic neuropathic pain, although further efficacy studies are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: Preliminary findings from a three-way randomized, crossover study. Chong, C., Schug, SA., Page-Sharp, M., et al.[2021]

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]

In a study of 69 gynecological surgery patients, low dose ketamine (0.15 mg/Kg) administered preoperatively did not provide a preemptive analgesic effect, as indicated by similar pain scores at rest compared to placebo.

However, patients receiving ketamine postoperatively experienced less pain upon movement on the fifth day and required less morphine in the first 6 hours, suggesting that while preemptive use is ineffective, postoperative ketamine can still improve pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of low-dose intravenous ketamine in postoperative analgesia for hysterectomy and adnexectomy]. Gilabert Morell, A., Sánchez Pérez, C.[2013]

In a study involving 11 healthy volunteers, oral S-ketamine showed low bioavailability (8%) and high clearance, indicating that while it is absorbed poorly, it is rapidly eliminated from the body.

The study suggests that small oral doses of S-ketamine could effectively provide analgesic effects through its metabolite norketamine, making it a potential alternative to frequent intravenous dosing for managing chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Fanta, S., Kinnunen, M., Backman, JT., et al.[2018]

References

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

Side-effects associated with ketamine use in depression: a systematic review. [2019]

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

A comparison of the pharmacokinetics and NMDAR antagonism-associated neurotoxicity of ketamine, (2R,6R)-hydroxynorketamine and MK-801. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: Preliminary findings from a three-way randomized, crossover study. [2021]

7. 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]

8. Spain pubmed.ncbi.nlm.nih.gov

[Effect of low-dose intravenous ketamine in postoperative analgesia for hysterectomy and adnexectomy]. [2013]

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

Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. [2018]