Investigating the Analgesic Potential of (2R,6R)-HNK in Acute Pain in Healthy Volunteers

Background:

Opioid drugs are often prescribed for acute and chronic pain. But these drugs are addictive, and they lead to more than 14,000 overdose deaths in the United States each year. Researchers want to find new drugs that relieve pain but are not addictive. This study will test whether a single dose of an experimental drug called (2R,6R)-hydroxynorketamine (HNK) can help reduce short term pain in healthy adults. HNK is related to ketamine. Studies suggest HNK might be as effective as ketamine at reducing pain but that it might have fewer side effects. In this study we will test how HNK affects pain and emotion. The results of this study may help us understand whether HNK has pain relieving effects and how it works in the brain, which could inform future pain treatments.

Objective:

To test the study drug [(2R,6R)-hydroxynorketamine (HNK)] for treating acute pain in healthy people.

Eligibility:

Healthy people aged 18 to 60 years.

Design;

Up to 92 healthy volunteers between 18 and 60 years old without chronic pain or psychiatric conditions will participate in the study. The study will take place at the NIH Clinical Center in Bethesda, Maryland. Each participant s involvement will last up to two months. The overall study is expected to last about three years (36 months).

The study has 2 parts.

In part 1, participants will have up to 2 clinic visits. They will be screened and have blood draws to make sure they're eligible for the study. They will complete sensory testing and have MRI brain scans.

Sensory testing involves feeling and rating painful and non-painful sensations. These may include hot or cold temperatures, pinches or squeezes, and being touched with brushes or pinpricks.

Eligible participants will have an imaging scan that shows brain activity: During the scan, they will rate heat, hear pleasant or unpleasant sounds, and view unpleasant or pleasant pictures.

After completing part 1, eligible participants will be invited to part 2, which includes overnight stays at NIH.

In part 2, participants will be assigned to either a treatment group or a no-treatment group.

The treatment group will have 2 overnight visits of 2 nights each. The visits will be 1 to 3 weeks apart. For one of the visits, treatment group participants will receive the study drug HNK. For the other visit, they will receive a placebo. A placebo looks just like the study drug but contains no medicine. HNK and placebo are given through a tube inserted into a vein in the arm. The sensory tests, blood draws, and MRI scans will be repeated at each visit. Participants will not be told whether they got the drug or placebo on each visit.

The nontreatment group will have 1 overnight visit. They will not receive the drug or placebo. The sensory tests, blood draws, and MRI scans will be repeated.

Participants cannot drink alcohol, use recreational drugs, or take certain other kinds of medicine or supplements during the study.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: (2R,6R)-Hydroxynorketamine; Drug: Placebo

Detailed Description

Study Description:

This is a randomized, double-blind, placebo-controlled, single-site crossover study.

This experimental study will assess the analgesic efficacy and mechanisms of a single infusion of 0.5 mg/kg (2R,6R)-HNK, an enhancer of synaptic glutamate release. We hypothesize that HNK infusion will elicit acute and long-lasting analgesia and that HNK will alter brain responses to noxious stimuli in a pain-specific manner. We will also include a natural history (i.e., No Treatment) control group to isolate placebo effects. The study includes both inpatient and outpatient visits.

Objectives:

Primary Objective:

To evaluate the ability of (2R,6R)-HNK, an enhancer of synaptic glutamate release, to reduce acute pain during quantitative sensory testing (QST). The efficacy of a single infusion of (2R,6R)-HNK will be compared to placebo in a crossover design.

Secondary Objectives:

• To determine the time course of analgesic efficacy of (2R,6R)-HNK immediately following infusion, after 4-5 hours, and one day later compared to placebo, as assessed by change from baseline on QST outcomes.
• To evaluate the effects of (2R,6R)-HNK on nociceptive brain responses, as assessed by brain responses to thermal stimulation in the Neurologic Pain Signature (NPS) in comparison to placebo during functional magnetic resonance imaging (fMRI).
• To evaluate whether analgesic effects of (2R,6R)-HNK are specific to pain, by comparing effects of (2R,6R)-HNK relative to placebo on pain-related neural activation and emotion-related neural activation during fMRI scanning.
• To evaluate the magnitude of placebo analgesia by comparing the placebo condition with a natural history (No Treatment) control group.

Endpoints:

Primary Endpoint:

Ratings of nociceptive stimuli during QST.

Secondary Endpoints:

• Ratings of nociceptive stimuli during QST one day after infusion.
• Scores on validated acute pain questionnaires (McGill Pain Questionnaire, Brief Pain Inventory, Patient Global Impression of Change).
• NPS pattern expression based on fMRI response to painful, relative to nonpainful, stimulation.
• FMRI activation in response to unpleasant, relative to neutral, emotional images.
• Incidence and nature of adverse events; vital signs; weight and body mass index (BMI) changes; physical examination changes; clinical laboratory evaluations; Electrocardiogram (ECG).

Surrogate Markers of Drug Effect, Target Engagement, and Analgesic Response:

-Change in peripheral biomarkers, including autonomic nervous system and NPS.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lauren Y Atlas, Ph.D.; Phone Number: (301) 827-0214; Email: lauren.atlas@nih.gov
• Study Contact Backup: Name: Xue S Davis; Phone Number: (301) 827-8646; Email: xue.davis@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov
      • Contact: Xue Davis; Phone Number: (240) 671-2064; Email: xue.davis@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Aged 18-60
4. In good general health as evidenced by medical history
5. Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen
6. For females of reproductive potential: Use of highly effective contraception starting at the time of enrollment and agreement to use such a method during study participation and for an additional four weeks after the end of participation
7. For males of reproductive potential: Use of condoms or other effective contraceptive methods from the time of enrollment, and for an additional 90 days after the end of participation
8. Agreement to adhere to Lifestyle Considerations throughout study duration
9. Ability of participant to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:00

1. Current use of disallowed concomitant medications.
2. Presence of ferromagnetic devices or any devices that could pose a risk relating to the safety of the fMRI procedure, including implanted cardiac pacemaker or auto-defibrillator, insulin pump, ferromagnetic metal in the cranial cavity or eye (e.g. aneurysm clip, implanted neural stimulator, cochlear implant, ocular foreign body), and irremovable body piercings.
3. Pregnancy or lactation.
4. Has a clinically important acute or active chronic disease
5. Has a history of any clinically important cardiovascular findings

6. Has a history of serious medical illness, including but not limited to the following body systems and organs or those that in the judgment of the Principal Investigator and Medical Advisory Investigator pose a risk to the participant s ability to safely participate in the study:

   1. Hepatic diseases (e.g. active viral hepatitis infection or cirrhosis of the liver)
   2. Cardiovascular disease (including ischemic heart disease, coronary artery disease, congestive heart failure, poorly controlled hypertension due to risk of further blood pressure elevation and increase in demand on cardiac function from study drug)
   3. Renal/urologic (e.g chronic kidney disease or acute kidney injury, history of bladder dysfunction due to theoretical risk of ketamine-induced cystitis)
   4. Endocrinologic (including diabetes due to association with progressive abnormality of the microvasculature and nervous system)
   5. Central nervous system disorder, neuromuscular disease, or other neurologic disorder (e.g. stroke, brain damage, elevated intraocular pressure or history of or presence of diseases that are associated with elevated intracranial pressure).
   6. Pulmonary disease (e.g., asthma, emphysema, chronic bronchitis)
7. Has a clinically important vital sign, ECG, or clinical laboratory finding.
8. Has a major medical condition or medical history that in a clinician's assessment could affect heat sensitivity, pain thresholds, or somatosensation (e.g., Raynaud s disease, peripheral neuropathy, or circulatory disorder)
9. Has a significant current psychiatric condition (including mood disorders, anxiety disorders, or substance use disorders) or has a history of psychosis, hospitalization for a mental health condition, or recurrent psychiatric episodes.
10. Has a current chronic pain condition or has had chronic pain in the past (painful condition lasting more than six months).
11. Has a dermatological condition that might influence cutaneous sensibility such as scars or burns, or has a tattoo in the testing region
12. Unable to comply with study procedures or follow-up visits.
13. Those with an abnormality on a structural MRI.
14. Individuals who are left-handed (based on self-report or score on handedness questionnaire).
15. Participants who are currently using drugs (except for caffeine, nicotine, or cannabis) must not have used illicit substances or known drugs of abuse in the two weeks prior to screen and must have a negative drug urine test at baseline and on each research visit prior to infusion. Cannabis use is exclusionary if the use is daily, or if participants are unable to abstain during the study, or if function of daily life is impaired by use as determined by a clinician.
16. Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes.
17. Participants with unstable clinical hyperthyroidism or hypothyroidism.
18. Participants with one or more seizures without a clear and resolved etiology.

19. Clinically significant abnormal laboratory tests specifically defined by:

    1. Alkaline phosphatase (Alk Phos) > 150 U/L
    2. Alanine aminotransferase (ALT) >55 U/L
    3. Aspartate aminotransferase (AST) > 34 U/L
    4. Total bilirubin (TB) > 1.2 mg/dL
    5. Direct bilirubin (DB) > 0.5 mg/dL
    6. 25-hydroxyvitamin D < 20 ng/mL
    7. Folate < 2ng/mL
    8. Vitamin B12 < 200 pg/mL
20. Positive Human Immunodeficiency Virus (HIV) test.
21. Participants with Coronavirus Disease 2019 (COVID-19) or suspected COVID-19.
22. NIH employee who is a subordinate/relative/co-worker of any investigator on the protocol.
23. Inability to read and understand English. Non-English speakers will not be eligible as most of the required monitoring and rating instruments are not validated in languages other than English.
24. Participants may not use any prescription or nonprescription drugs including OTC, herbal medicine, or dietary supplements within 14 days or 5 half-lives, whichever is longer, prior to drug administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: (2R,6R)-HNK; Participants receive a single intravenous infusion of (2R,6R)-hydroxynorketamine (HNK) at a dose of 0.5 mg/kg over approximately 40 minutes during an inpatient research visit. Pain responses and brain activity are assessed before and after infusion using quantitative sensory testing (QST) and functional MRI (fMRI).	Drug: (2R,6R)-Hydroxynorketamine; Experimental, non opioid ketamine metabolite administered as a single intravenous infusion at a dose of 0.5 mg/kg over approximately 40 minutes to evaluate analgesic effects in acute experimental pain.
No Intervention: No Treatment<TAB>; Participants do not receive a drug or placebo infusion. They undergo baseline and follow up pain testing and imaging assessments to characterize the natural history of pain responses and isolate placebo effects.
Placebo Comparator: Placebo; Participants receive a single intravenous infusion of placebo (saline) matched in volume and infusion duration (approximately 40 minutes) to the active drug. Pain and brain responses are assessed using the same procedures as the experimental condition.	Drug: Placebo; Intravenous saline solution matched in volume and administration schedule to the active drug, administered as a single infusion over approximately 40 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain ratings during quantitative sensory testing (QST)	Change in pain intensity ratings in response to experimentally induced nociceptive stimuli during quantitative sensory testing (QST), comparing (2R,6R)-hydroxynorketamine (HNK) with placebo in a randomized, double blind crossover design, controlling for baseline pain sensitivity.	3-5 hours after infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability	Incidence and nature of adverse events; changes in vital signs, weight and body mass index, physical examination findings, clinical laboratory results, and electrocardiogram (ECG) parameters following HNK compared with placebo.	From infusion through end of study participation (up to 2 months)

Collaborators and Investigators

• Sponsor: National Center for Complementary and Integrative Health (NCCIH)
• Investigators: Principal Investigator: Lauren Y Atlas, Ph.D., National Center for Complementary and Integrative Health (NCCIH)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): June 17, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: March 31, 2026
• First Submitted That Met QC Criteria: March 31, 2026
• First Posted (Actual): April 1, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: April 29, 2026

More Information

Terms related to this study

• Keywords: Pain; fMRI; Quantitative Sensory Testing; (2R,6R)-hydroxynorketamine; Ketamine metabolite; Non opioid analgesic; HydroxyNorKetamine (HNK)
• Additional Relevant MeSH Terms: Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; 6-hydroxynorketamine
• Other Study ID Numbers: 10002520; 002520-AT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De identified individual participant data (IPD) generated in this study will be shared in accordance with NIH Data Management and Sharing (DMS) Policy and HEAL Initiative requirements. Shared data may include demographic variables, quantitative sensory testing (QST) outcomes, pain questionnaire scores, autonomic measures, and processed neuroimaging derived measures (e.g., Neurologic Pain Signature and Negative Affect Signature expression). Personally identifiable information (PII) will not be shared.@@@@@@@@@@@@Data may be made available to other researchers through NIH approved data repositories or other open data repositories after de identification. Data sharing will occur following completion of primary analyses and publication of primary study results, subject to applicable approvals and data use agreements.
• IPD Sharing Time Frame: De identified individual participant data will be shared after publication of the primary study results or no later than 12 months after study completion, whichever occurs first. Data will remain available for secondary research for at least 6 years following completion of the primary endpoint, in accordance with NIH Data Management and Sharing (DMS) Policy and HEAL Initiative requirements.
• IPD Sharing Access Criteria: De identified individual participant data (IPD) and supporting materials will be shared with qualified researchers for non commercial scientific research through NIH approved data repositories or secure data sharing platforms, in accordance with NIH Data Management and Sharing (DMS) Policy and HEAL Initiative requirements. Access may require submission of a data use request describing the proposed analyses and data security protections. Requests will be reviewed by the study Principal Investigator and/or designated NIH officials to ensure consistency with participant consent and protection of participant privacy. No personally identifiable information will be shared, and data access may be subject to a data use agreement restricting re identification and requiring appropriate data citation.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No