EVALUATION OF THE (2R,6R)-HYDROXYNORKETAMINE AS A POTENTIAL CLINICAL USEFUL ANALGESIC AGENT: TRANSLATIONAL EXPERIENCE FROM PRECLINICAL TO HUMAN STUDY

Ketamine is rapidly metabolized into over twenty characterized metabolites including the active metabolite (2R,6R)-Hydroxynorketamine (HNK). Preclinical studies indicate that hydroxynorketamines exert antidepressant-relevant behavioral actions and may also have analgesic, anti-inflammatory, and other physiological effects that are relevant for the treatment of a variety of human diseases. In this presentation I will review our translational experience with (2R,6R)-HNK in murine models of clinical pain, culminating in an ongoing clinical trial under an FDA research IND in patients with neuropathic pain. Preclinical studies: We have shown (2R,6R)-HNK has analgesic properties best quantified by reduction in mechanical hyperalgesia in murine models of pain (plantar incision, peripheral nerve injury, tibial fracture and casting, and discogenic pain low-back pain). Evidence of analgesic efficacy was greater with established pain compared to those seen in naive animals. Common to findings in these models was that a brain penetrating  amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) acid receptor blocker abolished analgesic behaviors. Consistent hippocampal protein changes in (2R,6R)-HNK treated animals compared to saline controls were increases in the ratios of GluA1, GluA2 and Kv2.1 but decreased the BDNF to GADPH ratio. Spinal cord and dorsal root ganglion protein changes have also been investigated in some of the models. No significant adverse events were identified in (2R,6R)-HNK treated animals with animals continuing to gain weight throughout the study periods. More recently, we have demonstrated that (2R,6R)-HNK has less effect on motor coordination, balance and endurance than pregabalin at equianalgesic doses and delays the development of morphine tolerance when co-administered. Clinical study: Based on our preclinical experience we proposed a clinical trial of a single dose of (2R,6R)-HNK to obtain clinical evidence of effectiveness in the treatment of neuropathic pain. The study was funded by the Department of Defense Fiscal Year 2022 Chronic Pain Management Research Program (CPMRP) Clinical Exploration Award. The study design was a randomized double blind three way (1:1:1) cross over clinical trial to evaluate the effectiveness and duration of analgesic of a single infusion of (2R,6R)-HNK 0.5mg/kg compared with ketamine 0.5mg/kg and saline with a 5-week interval between treatments on pain, pain qualities, physical function, pain interference, sleep disturbance and quality of life in subjects with neuropathic pain of the extremities. Specific aims of the trial include AIM 1 - To determine if (2R,6R)-HNK will decrease the sensory dimension (intensity) of pain as assessed by the area under the NRS pain scores by time curve, as well as the affective dimension (unpleasantness) of NP (allodynia, hyperalgesia, burning, aching, tingling, lancinating). AIM 2 - To determine if (2R,6R)-HNK will improve physical function, sleep quality and quantity, decrease pain interference and improve quality of life in subjects with NP. AIM 3 - To evaluate the duration of effectiveness of a single (2R,6R)-HNK 0.5 mg/kg infusion administered over 45 minutes on pain, physical function, pain interference and quality of life. We will longitudinally evaluate all subjects daily for 35 days following drug administration for pain intensity and pain qualities. I will review the progress of this study and current status at the time of the presentation.

References

Das V, Basovich MB, Thomas CJ, et al. A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models. Anesth Analg. 2024; 138:1094-1106. Das V, Milejczyk I, Basovich MB, et al. Behavioral and biochemical changes associated with the analgesic effects of (2R,6R)-hydroxynorketamine alone and in combination with meloxicam following disk puncture in mice. Front Pain Res (Lausanne). 2025 ;6:1574474.