Hydroxynorketamine for Neuropathic Pain

(HNK Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Asokumar Buvanendran, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Rush University Medical Center

Disqualifiers: Severe illness, Fibromyalgia, Mental illness, others

Trial Summary

What is the purpose of this trial?

The goal of this randomized double blind three way (1:1:1) cross over clinical trial is to evaluate the effectiveness and duration of analgesia of a single infusion of (2R,6R)-HNK 0.5mg/kg compared with ketamine 0.5mg/kg and saline with a 5-week interval between treatments on pain, pain qualities, physical function, pain interference, sleep disturbance and quality of life in subjects with neuropathic pain of the extremities. The questions that this study will address are: 1. What is the analgesic efficacy of (2R,6R)-HNK on pain intensity and pain qualities in patients with chronic (\>3 month) neuropathic pain (NP). 2. What will be the effective duration of a single infusion of (2R,6R)-HNK in patients with NP. 3. Will (2R,6R)-HNK reduce pain related effects including interference in daily activities of life, sleep disturbances and change the qualities of pain reported by patients. Participants will receive each of the three study drugs in a random order at 5-week intervals over a 15 week period. The drug will be administered as a 45-minute infusion. Participants will complete quantitative sensory and pain evaluations and complete patient reported pain outcomes prior to receiving the first study drug and at 7, 14 and 21 and 35 days following study drug administration.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications for chronic neuropathic pain. You should continue taking your scheduled medications throughout the study period, but if you experience pain relief, you may choose not to take as-needed medications.

What data supports the effectiveness of the drug Hydroxynorketamine for treating neuropathic pain?

Research suggests that ketamine, which is related to hydroxynorketamine, can help reduce neuropathic pain. Studies show that ketamine, an NMDA receptor antagonist, may provide pain relief and improve quality of life for patients with neuropathic pain. ^{1 2 3 4 5}

How is the drug (2R,6R)-hydroxynorketamine different from other treatments for neuropathic pain?

(2R,6R)-hydroxynorketamine is unique because it provides pain relief without the significant side effects associated with ketamine, and it works through a different mechanism involving AMPA receptors. Unlike ketamine, it has a longer-lasting effect and a better safety profile, making it a promising non-opioid option for treating neuropathic pain. ^{6 7 8 9 10}

Research Team

Asokumar Buvanendran, MD

Principal Investigator

Rush University Medical Center

Eligibility Criteria

Adults aged 18-80 with chronic neuropathic pain in the extremities, who can read/write English and have a BMI of 18-35 kg/m². Participants should not have widespread pain conditions like fibromyalgia, mental illness, or severe medical issues. They must not be allergic to ketamine, pregnant, or using certain substances prior to drug administration.

Inclusion Criteria

I choose not to take pain medication if I feel better.

Ability to read and write English sufficiently to complete study related procedures

I have been diagnosed with neuropathic pain based on a specific questionnaire.

Exclusion Criteria

Inability to effectively communicate with research staff

I have not had a serious illness in the last 2 weeks.

I have a known liver condition.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive each of the three study drugs (ketamine, (2R,6R)-HNK, and saline) in a random order at 5-week intervals over a 15-week period. Each drug is administered as a 45-minute infusion.

15 weeks

3 visits (in-person) for drug administration, multiple follow-up assessments

Follow-up

Participants are monitored for safety and effectiveness after each treatment, with evaluations at 7, 14, 21, and 35 days following each drug administration.

35 days per treatment cycle

4 visits (in-person) per treatment cycle

Safety Assessment

Baseline and ongoing safety assessments including blood chemistry, liver function tests, complete blood count, and ECG are conducted.

Throughout the study

Treatment Details

Interventions

• (2R,6R)-hydroxynorketamine (NMDA Receptor Antagonist)
• Ketamine (NMDA Receptor Antagonist)
• Saline (Other)

Trial Overview The trial is testing the effectiveness of (2R,6R)-hydroxynorketamine compared to ketamine and saline for reducing neuropathic pain. Patients will receive each treatment through an infusion over a cross-over design with intervals of five weeks between treatments.

Participant Groups

Group I: (2R,6R)-hydroxynorketamine Experimental Treatment 1 Intervention

(2R,6R)-hydroxynorketamine 0.5mg/kg 45 minute infusion x 1

Group II: Ketamine Active Control 1 Intervention

Ketamine 0.5mg/kg 45 minute infusion x 1

Group III: Saline Placebo Group 1 Intervention

Saline 45 minute infusion x 1

Who Is Running the Clinical Trial?

Rush University Medical Center

Lead Sponsor

Trials

448

Recruited

247,000+

Dr. Omar B. Lateef

Rush University Medical Center

Chief Executive Officer since 2022

MD from Des Moines University, Fellowship in Pulmonary and Critical Care Medicine at Rush University Medical Center

Dr. Paul E. Casey

Rush University Medical Center

Chief Medical Officer since 2021

MD, MBA

Congressionally Directed Medical Research Programs

Collaborator

Trials

59

Recruited

10,600+

Colonel Mark G. Hartell

Congressionally Directed Medical Research Programs

Director, Congressionally Directed Medical Research Programs since 2022

PhD in Analytical Chemistry from Auburn University, MS in Biophysical Chemistry from Ohio State University, BS in Chemistry from State University of New York at Oswego

Dr. Sarah Goldman

Congressionally Directed Medical Research Programs

Chief Medical Officer since 2023

MD

Findings from Research

Ketamine shows potential for treating chronic neuropathic pain (NP), particularly in patients with conditions like central sensitization or opioid-induced hyperalgesia, although large-scale randomized controlled trials have not consistently demonstrated its efficacy.

Observational studies and case series indicate that ketamine can provide effective pain relief for some patients with NP, suggesting that future research should focus on well-defined patient groups to better assess its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature. Kamp, J., Van Velzen, M., Olofsen, E., et al.[2019]

Adding ketamine to standard treatment for neuropathic pain significantly reduces pain intensity both one week and 30 days after treatment, based on a meta-analysis of 18 randomized controlled trials with 706 participants.

While ketamine effectively alleviates pain, it also increases the risk of adverse effects, particularly psychedelic experiences, highlighting the need for careful consideration of its use in pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ketamine in the Treatment of Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Guimarães Pereira, JE., Ferreira Gomes Pereira, L., Mercante Linhares, R., et al.[2022]

In a 2-week study involving 103 patients with neuropathic pain unresponsive to standard treatments, intravenous ketamine infusion significantly reduced pain severity, with average pain scores dropping from 7.20 to 5.46 on a visual analog scale (P < 0.001).

The treatment was generally well tolerated, with common adverse effects including dizziness and snoring, but no significant associations were found between patient demographics (age, sex) and the effectiveness of the analgesic effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic effects of ketamine infusion therapy in korean patients with neuropathic pain: A 2-week, open-label, uncontrolled study. Kang, JG., Lee, CJ., Kim, TH., et al.[2021]

Preemptive administration of intrathecal ketamine significantly reduced neuropathic pain behaviors in rats for at least 2 weeks after surgery, indicating its efficacy in pain management.

The study suggests that the mechanism of action for intrathecal ketamine involves the prevention of spinal cord sensitization, which is crucial for managing neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Burton, AW., Lee, DH., Saab, C., et al.[2019]

Topical application of ketamine ointment (0.25%-1.5%) showed significant pain relief and reduced swelling in 4 out of 5 patients with acute early dystrophic stage of complex regional pain syndrome type I (CRPS I) after 1 to 2 weeks of treatment.

The treatment was less effective in patients with chronic atrophic stage of CRPS I and in those with complex regional pain syndrome type II (CRPS II), indicating that ketamine's benefits may be limited to specific stages of neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. Ushida, T., Tani, T., Kanbara, T., et al.[2019]

The ketamine metabolite (2R,6R)-hydroxynorketamine ([2R,6R]-HNK) shows significant analgesic effects in chronic pain models, with a greater antiallodynic effect observed in neuropathic pain compared to acute pain, indicating its potential as a pain management option.

The analgesic action of (2R,6R)-HNK is dependent on AMPA receptors, as evidenced by decreased pain relief when an AMPA blocker was administered, and it also influences various protein pathways in the hippocampus related to pain modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models. Das, V., Basovich, MB., Thomas, CJ., et al.[2023]

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) effectively reversed mechanical hypersensitivity in mice with localized inflammatory pain, showing significant pain relief within 1 hour and lasting over 24 hours after administration.

The analgesic effects of (2R,6R)-HNK were comparable to the non-steroidal anti-inflammatory drug carprofen and were found to be dependent on the AMPA receptor, indicating a specific mechanism of action for pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(2R,6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain. Yost, JG., Browne, CA., Lucki, I.[2022]

(2R,6R)-hydroxynorketamine (HNK), a metabolite of ketamine, shows promise as a pain treatment with a better safety profile, as it does not cause side effects like dystaxia even at high doses.

In a study with C57BL/6J mice, (2R,6R)-HNK provided effective pain relief 24 hours after administration and reversed mechanical allodynia as effectively as gabapentin in the short term, but with longer-lasting effects, suggesting it could be a valuable non-opioid analgesic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antinociceptive and Analgesic Effects of (2R,6R)-Hydroxynorketamine. Yost, JG., Wulf, HA., Browne, CA., et al.[2023]

The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) was found to be more effective than ketamine in relieving mechanical allodynia in various pain models, including neuropathic pain, CRPS1, and postoperative pain, with significant pain relief lasting several days after administration.

In contrast to ketamine, which did not provide sustained analgesia, (2R,6R)-HNK demonstrated prolonged pain relief with multiple injections, suggesting it could be a promising non-opioid treatment option for chronic pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain. Kroin, JS., Das, V., Moric, M., et al.[2019]

References

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

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature. [2019]

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

Efficacy and Safety of Ketamine in the Treatment of Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. [2022]

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

Analgesic effects of ketamine infusion therapy in korean patients with neuropathic pain: A 2-week, open-label, uncontrolled study. [2021]

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

Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. [2019]

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

A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models. [2023]

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

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. [2023]

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

(2R,6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain. [2022]

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

Antinociceptive and Analgesic Effects of (2R,6R)-Hydroxynorketamine. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain. [2019]