NCT07504601

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

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 92 (estimated)
• Sponsor: National Center for Complementary and Integrative Health (NCCIH) · NIH
• Sex: All
• Age: 18 Years – 60 Years
• Healthy volunteers: Accepted

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 a study drug \[(2R,6R)-hydroxynorketamine (HNK)\] for treating 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 testsing and have MRI scans. Sensory tests involve rating painful and nonpainful stimuli, includeincluding being touched with a hot or cold probe, brushes or pinpricks, and pinches or squeezes. 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 nontreatment group. The treatment group will have 2 overnight visits of 2 nights each. The visits will be 1 to 3 weeks apart. For 1 visit, participants will receive HNK. For the other, 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 medicine or supplements during the study.

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: 1. To determine the time course of analgesic efficacy of (2R,6R)-HNK immediately following infusion, after 4-5 hours (1), and one day later compared to placebo, as assessed by change from baseline on QST outcomes. 2. 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; (2)) in comparison to placebo during functional magnetic resonance imaging (fMRI). 3. 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. 4. 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 (3), Brief Pain Inventory (4), Patient Global Impression of Change (5)). * 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.

Conditions

• Pain
• Healthy Volunteers

Interventions

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

Timeline

• Start date: 2026-06-15
• Primary completion: 2030-12-31
• Completion: 2031-12-31
• First posted: 2026-04-01
• Last updated: 2026-04-01

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study