(2R,6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain.

The ketamine metabolite (2R,6R)-hydroxynorketamine, or (2R,6R)-HNK, was recently reported to evoke antinociception in response to a noxious thermal stimulus in healthy mice and reverse mechanical hypersensitivity in a murine model of neuropathic pain. This study reports the behavioral effects of (2R,6R)-HNK in male and female C57BL/6J mice exposed to a localized inflammatory pain condition and the broad pharmacological mechanism underlying this effect. Hind paw intraplantar injection of λ-carrageenan (CARR) caused inflammation and mechanical hypersensitivity in mice within 2 h, lasting at least 48 h. Administration of (2R,6R)-HNK (10-30 mg/kg i.p.) 2 h following CARR injection significantly reversed mechanical hypersensitivity within 1 h in male and female mice, and the effect persisted for 24 h following a single dose. The magnitude and timing of the analgesic effect of (2R,6R)-HNK were comparable to the non-steroidal anti-inflammatory drug carprofen. The reversal of hypersensitivity by (2R,6R)-HNK was blocked at 4 and 24 h after administration by pretreatment with the AMPA receptor antagonist NBQX and was not accompanied by changes in locomotor activity. These findings reinforce the growing evidence supporting (2R,6R)-HNK as a novel analgesic in multiple preclinical pain models and further support an AMPAR-dependent mechanism of action. SIGNIFICANCE: The ketamine metabolite (2R,6R)-HNK reversed mechanical hypersensitivity associated with localized inflammation with onset less than 1 h and duration greater than 24 h, an effect comparable to the NSAID carprofen. Reversal of mechanical hypersensitivity by (2R,6R)-HNK is AMPAR-dependent.

Antinociceptive and Analgesic Effects of (2R,6R)-Hydroxynorketamine.

Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects. This study compared the profile and potential mechanisms mediating the antinociception activity of ketamine and (2R,6R)-HNK in C57BL/6J mice. Additionally, this study compared the reversal of mechanical allodynia by (2R,6R)-HNK with gabapentin in a model of neuropathic pain. Unlike the near-immediate and short-lived antinociception caused by ketamine, (2R,6R)-HNK produced late-developing antinociception 24 hours following administration. Pharmacological blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) prevented the initiation and expressionof (2R,6R)-HNK antinociception, suggesting the involvement of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-dependent glutamatergic mechanisms in the pain reduction-like responses. Blockade of opioid receptors with naltrexone partially prevented the antinociceptive effect of ketamine but was ineffective against (2R,6R)-HNK. Furthermore, (2R,6R)-HNK did not produce dystaxia, even when tested at doses five times greater than those needed to produce antinociception, indicating a superior safety profile for (2R,6R)-HNK over ketamine. Additionally, (2R,6R)-HNK reversed mechanical allodynia in a spared nerve injury model of neuropathic pain with similar short-term efficacy to gabapentin (within 4 hours) while outperforming gabapentin 24 hours after administration. These findings support the further study of (2R,6R)-HNK as a potentially valuable agent for treating different types of pain and establish certain advantages of (2R,6R)-HNK treatment over ketamine and gabapentin in corresponding assays for pain. SIGNIFICANCE STATEMENT: The ketamine metabolite (2R,6R)-HNK produced antinociception in male and female mice 24 hours after administration via activation of AMPA receptors. The effects of (2R,6R)-HNK differed in time course and mechanism and presented a better safety profile than ketamine. (2R,6R)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2R,6R)-HNK demonstrates the potential for development as a non-opioid analgesic drug.

Management of Emergence Delirium in Adult PTSD Patients: Recommendations for Practice.

Emergence delirium is a known phenomenon which occurs after general anesthesia in approximately 5% of the general population. However, individuals who have been diagnosed with post-traumatic stress disorder may present with symptoms refractory to conventional methods of reorientation. In the past several years, literature has begun to address the problem, but no standardized guidelines exist at present. The authors synthesize the available literature, combining data with evidence-driven principles from multiple disciplines, to submit an initial set of guidelines until research either supports or disproves these recommendations.

The pharmacokinetics of intraosseous atropine in hypovolemic swine.

OBJECTIVE: Compare the pharmacokinetics of atropine administered via the intravenous (IV), intramuscular (IM), and intraosseous (IO) routes in a normovolemic and hypovolemic swine model. DESIGN: Prospective, between subjects, experimental study. SETTING: Vivarium. SUBJECTS: Yorkshire-cross swine (N = 36). INTERVENTION: Atropine was administered via IV, IM, or IO routes to normovolemic and hypovolemic swine. Blood samples were drawn at regular intervals after atropine administration and analyzed for plasma atropine concentration. Pharmacokinetic parameters were obtained from modeling the plasma concentrations. MAIN OUTCOME MEASUREMENTS: Pharmacokinetic parameters, maximum concentration (Cmax) and time to maximum concentration (Tmax). RESULTS: The IV and IO groups in both the normovolemic and hypovolemic models reached peak plasma concentration immediately and had a very rapid distribution phase with no apparent absorption phase for the IO groups. Peak plasma concentration and time to reach peak concentration were both significantly lower for the IM groups. There was a significant increase in absorption time with IM administration in the hypovolemic model compared to the normovolemic model. CONCLUSION: The IO route is an effective method of administering atropine and is comparable to the IV route even under conditions of significant hemorrhage. Therapeutic levels of atropine may be delayed and possibly difficult to obtain via IM injection in the presence of hypovolemic shock.