Investigating the Analgesic Potential of (2R,6R)-HNK in Acute Pain in Healthy Volunteers
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Pain ratings during quantitative sensory testing (QST)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •INCLUSION CRITERIA:
- •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 years
- •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
排除标准
- •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)
- •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.
- •Has a current chronic pain condition or has had chronic pain in the past (painful condition lasting more than six months).
- •Has a dermatological condition that might influence cutaneous sensibility such as scars or burns, or has a tattoo in the testing region
- •Unable to comply with study procedures or follow-up visits.
- •Those with an abnormality on a structural MRI.
- •Individuals who are left-handed (based on self-report or score on handedness questionnaire).
- •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.
- •Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes.
- •Participants with unstable clinical hyperthyroidism or hypothyroidism.
- •Participants with one or more seizures without a clear and resolved etiology.
- •Clinically significant abnormal laboratory tests specifically defined by:
- •Alkaline phosphatase (Alk Phos) > 150 U/L
- •Alanine aminotransferase (ALT) >55 U/L
- •Aspartate aminotransferase (AST) > 34 U/L
- •Total bilirubin (TB) > 1.2 mg/dL
- •Direct bilirubin (DB) > 0.5 mg/dL
- •25-hydroxyvitamin D < 20 ng/mL
- •Folate < 2ng/mL
- •Vitamin B12 < 200 pg/mL
- •Positive Human Immunodeficiency Virus (HIV) test.
- •Participants with Coronavirus Disease 2019 (COVID-19) or suspected COVID-
- •NIH employee who is a subordinate/relative/co-worker of any investigator on the protocol.
- •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.
- •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.
研究组 & 干预措施
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
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.
干预措施: Placebo (Drug)
(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).
干预措施: (2R,6R)-Hydroxynorketamine (Drug)
结局指标
主要结局
Pain ratings during quantitative sensory testing (QST)
时间窗: 3-5 hours after infusion
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.
次要结局
- Safety and tolerability(From infusion through end of study participation (up to 2 months))