Hydroxynorketamine for Neuropathic Pain

(HNK Trial)

Overseen By Daniel Torrez, BS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Rush University Medical Center

Disqualifiers: Severe illness, Fibromyalgia, Mental illness, others

Compensation: Varies

Number of Visits: 8

Duration: 15 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called (2R,6R)-hydroxynorketamine, which may reduce pain and improve quality of life for individuals with neuropathic pain in their arms or legs. Participants will receive three different infusions over a 15-week period: the new treatment, ketamine (an anesthetic), and a saline solution, to determine which is most effective. The trial seeks individuals who have experienced chronic neuropathic pain for more than three months and are interested in exploring whether this new treatment can alleviate their pain and enhance their daily activities and sleep. Consider joining to contribute to advancements in pain treatment research. As a Phase 1, Phase 2 trial, this study aims to understand how the treatment works in people and measure its effectiveness in an initial group.

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.

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

Research has shown that (2R,6R)-hydroxynorketamine, a byproduct of ketamine, was well-tolerated in previous studies. Safety research indicates it has very few side effects, with no serious side effects reported at any dose tested.

Ketamine is already used to treat long-term nerve pain, and studies have demonstrated its ability to greatly reduce pain. While effective, ketamine can cause side effects like dizziness and confusion, but these are usually manageable. It has been used safely in medical settings for many years.

Overall, both treatments in this trial have demonstrated good safety records in past studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about (2R,6R)-hydroxynorketamine for neuropathic pain because it offers a novel approach compared to standard treatments like gabapentin or pregabalin. Unlike these typical treatments, which often target calcium channels, (2R,6R)-hydroxynorketamine acts on the NMDA receptor pathway. This unique mechanism may lead to faster pain relief and potentially fewer side effects. Additionally, this compound is a metabolite of ketamine, which has shown rapid antidepressant effects, suggesting it may have additional benefits beyond pain management.

What evidence suggests that this trial's treatments could be effective for neuropathic pain?

This trial will compare the effectiveness of (2R,6R)-hydroxynorketamine, ketamine, and saline for neuropathic pain. Research has shown that (2R,6R)-hydroxynorketamine, a byproduct of ketamine, reduces pain sensitivity more effectively than ketamine, particularly in cases of sudden and long-lasting pain. Studies have found that it helps relieve mechanical allodynia, which is pain from typically non-painful stimuli, and remains effective over time. Ketamine has significantly reduced pain in people with chronic nerve pain compared to standard treatments. It provides short-term relief, but its effects can diminish with repeated use. Both treatments show promise for pain relief, but (2R,6R)-HNK might offer longer-lasting benefits. ^{1 2 6 7 8}

Who Is on the Research Team?

Asokumar Buvanendran, MD

Principal Investigator

Rush University Medical Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• (2R,6R)-hydroxynorketamine
• Ketamine
• Saline

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.

How Is the Trial Designed?

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+

Congressionally Directed Medical Research Programs

Collaborator

Trials

59

Recruited

10,600+

Published Research Related to This Trial

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]

(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]

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]

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]

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]

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]

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]

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]

Hydroxynorketamines (HNKs), metabolites of ketamine, have been found to exert significant antidepressant effects in preclinical models, particularly (2R,6R)-HNK, which shows robust behavioral actions and limited side effects.

HNKs appear to work by modulating glutamatergic neurotransmission and influencing various brain regions, suggesting potential therapeutic applications for conditions like depression, PTSD, and chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. Highland, JN., Zanos, P., Riggs, LM., 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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1347861325000817

(2R,6R)-hydroxynorketamine Reverses Mechanical and ... Furthermore, (2R,6R)-HNK remained effective after daily treatment for 7 days with no indication of a loss of effect. Nevertheless, it is unknown ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30640662/

Efficacy of the ketamine metabolite (2R,6R) Conclusions: This study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10013843/

Target deconvolution studies of (2R,6R)-hydroxynorketamine In sum, our results indicate that (2R,6R)-HNK does not share pharmacological or behavioral profile similarities with ketamine or its enantiomers. However, it ...

4. withpower.com withpower.com/trial/phase-2-neuralgia-2024-40d86

Hydroxynorketamine for Neuropathic Pain (HNK Trial) The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) was found to be more effective than ketamine in relieving mechanical allodynia in various pain ...

5. researchgate.net researchgate.net/publication/330379630_Efficacy_of_the_ketamine_metabolite_2R6R-hydroxynorketamine_in_mice_models_of_pain

(PDF) Efficacy of the ketamine metabolite (2R,6R) Conclusions This study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it ...

6. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3391

A Phase 1 Assessment of the Safety, Tolerability ... (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10721716/

Hydroxynorketamine in Murine Pain Models - PMC We have demonstrated that (2R,6R)-HNK has analgesic effects in murine pain models (plantar incision (PI), spared nerve injury (SNI), and tibial fracture (TF)).

8. researchgate.net researchgate.net/publication/382564694_A_Phase_1_Assessment_of_the_Safety_Tolerability_Pharmacokinetics_and_Pharmacodynamics_of_2R6R-Hydroxynorketamine_in_Healthy_Volunteers

(PDF) A Phase 1 Assessment of the Safety, Tolerability ... Safety assessments showed RR‐HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of ...