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

NCT07504601 | Not Yet Recruiting Phase 2 FDA Drug

• 2 other identifiers: 10002520002520-AT
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Healthy Volunteers

Keywords

fMRI; Pain; Quantitative Sensory Testing; Ketamine metabolite; Non opioid analgesic; HydroxyNorKetamine (HNK); (2R,6R)-hydroxynorketamine

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Safety and tolerability

  From infusion through end of study participation (up to 2 months)

Study Arms (3)

(2R,6R)-HNK

EXPERIMENTAL

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

No Treatment<TAB>

NO INTERVENTION

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

PLACEBO COMPARATOR

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

Interventions

(2R,6R)-Hydroxynorketamine DRUG

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.

(2R,6R)-HNK

Placebo DRUG

Intravenous saline solution matched in volume and administration schedule to the active drug, administered as a single infusion over approximately 40 minutes.

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Aged 18-60
• In good general health as evidenced by medical history
• Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen
• 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
• 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
• Agreement to adhere to Lifestyle Considerations throughout study duration
• Ability of participant to understand and the willingness to sign a written informed consent document

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:00
• Current use of disallowed concomitant medications.
• 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.
• Pregnancy or lactation.
• Has a clinically important acute or active chronic disease
• Has a history of any clinically important cardiovascular findings
• 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:
• Hepatic diseases (e.g. active viral hepatitis infection or cirrhosis of the liver)
• 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)
• Renal/urologic (e.g chronic kidney disease or acute kidney injury, history of bladder dysfunction due to theoretical risk of ketamine-induced cystitis)
• Endocrinologic (including diabetes due to association with progressive abnormality of the microvasculature and nervous system)
• 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).
• Pulmonary disease (e.g., asthma, emphysema, chronic bronchitis)
• Has a clinically important vital sign, ECG, or clinical laboratory finding.
• 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)

Sponsors & Collaborators

• National Center for Complementary and Integrative Health (NCCIH): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Pain

Interventions

6-hydroxynorketamine

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Lauren Y Atlas, Ph.D.

  National Center for Complementary and Integrative Health (NCCIH)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xue S Davis

CONTACT

(301) 827-8646; xue.davis@nih.gov

Lauren Y Atlas, Ph.D.

CONTACT

(301) 827-0214; lauren.atlas@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2026
• First Posted: April 1, 2026
• Study Start (Estimated): June 17, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2031
• Last Updated: June 12, 2026

Record last verified: 2026-04-29

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• 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.
• 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.

Locations

US (1)