Effects Of Ketamine Research Articles

A Scoping Review: Ketamine for the Prevention of Perioperative Shivering in Patients Undergoing Spinal Anesthesia.

Shivering is a frequently encountered perioperative complication in patients undergoing spinal anesthesia. Numerous different pharmacological agents have been employed to mitigate this issue. This scoping review aims to evaluate the efficacy of ketamine in mitigating the incidence of shivering. This review process utilized PubMed, JAMA, and Cochrane as primary databases. Searches were performed using combinations of key terms: "Ketamine," "Shivering," "Spinal Anesthesia," and "Hypothermia."Reviews of reference lists for additional pertinent data were performed. Whenketamine was compared against a saline control, three out of five studies found ketamine to be more effective (p < 0.05, p < 0.001, p < 0.001) in the prevention of shivering. When compared with tramadol, two studies found ketamine to be more effective (p < 0.001, p < 0.001), one found no difference (p = 0.261), and one found tramadol to be more effective (p < 0.001). Two studies found dexmedetomidine more effective (p < 0.022, p < 0.027) than ketamine and tramadol. When comparing ketamine, ondansetron, and meperidine, all three were effective (p < 0.001) versus saline, with no significant difference between the three. Meperidine demonstrated more efficacy (p < 0.05) in reducing the intensity of shivering than ketamine. Ketamine's effects on hemodynamics were shown to be equivocal or more favorable across several studies.While there is mixed evidence on whether it is better than other treatments, ketamine may have advantages from a hemodynamic standpoint. Dosages of 0.2-0.5 mg/kg with or without a subsequent infusion of 0.1 mg/kg per hour may aid in the prevention of perioperative shivering. Overall, ketamine is a safe and effective drug for the prevention of perioperative shivering. However, other drugs may be equally or more effective; therefore, patient population, hemodynamic status, patient preferences, and provider familiarity with different agents should be considered.

Brain region-specific action of ketamine as a rapid antidepressant.

Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.

Effect of propofol infusion vs ketamine plus dexmedetomidine infusion on the amplitude of motor evoked potential in pediatric patients undergoing tethered spinal cord surgeries; a randomized, double blind controlled study

Background &amp; objective: The use of intraoperative neurophysiologic monitoring (IOM) has increased over the past two decades for the detection and prevention of iatrogenic neurologic injuries. Motor evoked potentials (MEP) are extremely sensitive to changes in physiological variables and inhalational agents reduce MEPs in a dose dependent manner. So IV anesthetics (propofol or ketamine) and opioids (fentanyl or remifentanil), are frequently used in spinal surgeries under MEPs monitoring. We compared the effects of propofol and fentanyl to those of ketamine, dexmedetomidine, and fentanyl in terms of minimizing their effects on MEP amplitude and hemodynamic stability during surgery Methodology: This double blind, randomized, prospective study was conducted on 46 children, who were randomly allocated into 2 groups Ketamine–dexmedetomidine group: (n = 23) Maintenance throughout the procedure, by infusing Dexmedetomidine (0.4 -0.6 μg/.kg /.hr) ketamine, (1 -2m/.kg/.hr.) and giving bolus of fentanyl, (1-2μg/.kg/ ). Propofol-group:(n = 23) Maintenance throughout the procedure, By infusing propofol (100 ug L/kg/min) and giving bolus of fentanyl, (1-2μg/.kg/ ), with keeping mean arterial blood pressure changes within 25% of the baseline in both groups. Results: Right and left quadriceps muscle measurements were insignificantly different between both groups at base line and were significantly higher in Group KD than Group P at skin incision, surgical manipulation and surgical closure. Right and left adductor hallucis muscle measurements were insignificantly different between both groups at base line and were significantly higher in Group KD than Group P at 5 mins, 10 mins, 15 mins, skin incision, surgical manipulation and surgical closure (P value &lt;0.001). Intraoperative fentanyl consumption was significantly lower in Group KD than Group P. Conclusion: The combination of dexmedetomidine and ketamine infusion is efficacious, safe, and has minimal effect on evoked potentials compared with the propofol-based TIVA group during spine pediatrics surgery. In addition, this combination increases the reliability and accuracy of MEP monitoring with hemodynamic stability and adequate post-operative pain relief. Using dexmedetomidine and ketamine infusions during pediatric spine surgery might successfully replace the typical propofol-based TIVA, although more studies are required . Registration: ClinicalTrials.gov registration number NCT05591001. Keywords: Motor evoked potential, dexmedetomidine, ketamine, propofol. Citation: Saleh AH, Hammad SH, Hassan PF. Effect of propofol infusion vs ketamine plus dexmedetomidine infusion on the amplitude of motor evoked potential in pediatric patients undergoing tethered spinal cord surgeries; a randomized, double blind controlled study. Anaesth. pain intensive care 2024;28(4):692−699; DOI: 10.35975/apic.v28i4.2218 Received: May 08, 2023; Reviewed: February 02, 2024; Accepted: July 03, 2924

Combining bioinformatics, network pharmacology and artificial intelligence to predict the target genes of S-ketamine for treating major depressive disorder.

Ketamine has received attention owing to its rapid and long-lasting antidepressant effects; however, its clinical application is restricted by its addictiveness and adverse effects. S-ketamine, which is the S-enantiomer of ketamine, is considered safer and better tolerated by patients than ketamine. This study aimed to identify the key gene targets and potential signalling pathways associated with the mechanism of S-ketamine in major depressive disorder (MDD) treatment. The GSE98793 dataset was extracted from the Gene Expression Omnibus database, and differentially expressed genes were identified in blood samples from patients with MDD and healthy individuals. The hub genes among the differentially expressed genes were identified and enrichment analysis was performed. The therapeutic targets and related signalling pathways of S-ketamine in MDD treatment were analysed. The 3D structures of the target proteins were predicted using AlphaFold2, and molecular docking was performed to verify whether S-ketamine could be successfully docked to the predicted targets. A quantitative polymerase chain reaction was performed to determine the effect of ketamine on the screened targets. Among 228 target genes annotated using pharmacophore target gene analysis, 3 genes were identified and 2 therapeutic signalling pathways were discovered. S-ketamine exerts downregulatory effects on TGM2 and HSP90AB1 expression but exerts an up-regulatory effect on ADORA3 expression. The protein structures of the therapeutic targets were successfully predicted using AlphaFold2. S-ketamine may alleviate depression by targeting specific genes, including TGM2, HSP90AB1 and ADORA3, as well as signalling pathways, including the gonadotropin-releasing hormone and relaxin signalling pathways.

Effect of Ketamine as an Adjuvant to Bupivacaine in Ilioinguinal and Iliohypogastric Nerve Block for Postoperative Analgesia after Inguinal Hernia Repair

Ilioinguinal and Iliohypogastric nerve block is one of the methods exercised widely to reduce postoperative pain after inguinal hernia repair. Several initiatives are ongoing to prolong the duration of postoperative analgesia by adding various adjuvants to the local anaesthetic agents in different nerve blocks. In this study ketamine has been added as an adjuvant to local anaesthetic bupivacaine in Ilioinguinal and Iliohypogastric nerve blocks. Our study aims to evaluate the effect of adding ketamine to local anaesthetic bupivacaine in ultrasound guided Ilioinguinal and Iliohypogastric nerve block in patient scheduled for inguinal hernia repair under subarachnoid block. This randomized control trial was carried out among 94 patients scheduled for elective inguinal hernia repair under subarachnoid block in Dhaka Medical College Hospital, Dhaka, Bangladesh. Two nerves, Ilioinguinal and Iliohypogastric were blocked by 0.25% bupivacaine under ultrasound guidance after the completion of surgery for postoperative analgesia. The study population was divided equally into two groups having 47 patients in each. Patients of group-A was received 20 ml of 0.25% bupivacaine and 2ml normal saline in the block procedure. Another group, group B patients received 20ml of 0.25% bupivacaine and 1mg/kg of ketamine in the same nerve block. Demographic profiles had no significant differences between two groups (p&gt;0.05). Mean duration of the analgesia or the time of first rescue analgesic requirement were significantly higher in ketamine group (595.24±15.90 minutes) than normal saline group (226.4±20.6 minutes). (p&lt;0.05); Postoperative total analgesic (pethidine) requirement within first 24 hours (178.3±18.3 vs. 92.3±15.3) milligrams, (p&lt;0.05) was higher in normal saline group. Our data suggests that ketamine when used as an adjuvant to bupivacaine for ilioinguinal and iliohypogastric nerve block prolongs the time to first analgesic request as well as decreases the analgesic requirement during postoperative period. CBMJ 2024 July: vol. 13 no. 02 P: 203-212

The effect of low-dose ketamine on electroencephalographic spectrum during gynecology surgery under desflurane anesthesia.

The perioperative administration of low-dose ketamine has shown potential in postoperative pain management, opioid sparing, and enhancing pain control. This study aimed to investigate the impact of low-dose ketamine on processed electroencephalography (EEG) signals during anesthesia. Forty patients with American Society of Anesthesiologists physical status I-II undergoing elective gynecological surgery were enrolled. EEG monitoring was initiated upon induction of anesthesia. Anesthesia was maintained with desflurane and alfentanil immediately after induction. Fifteen minutes after induction, the ketamine group received a 0.3 mg/kg bolus followed by 0.05 mg/kg/h infusion until completion of surgery. The control group received equivalent saline. Postoperative assessments included pain score (visual analog scale), morphine usage, and quality of recovery. The ketamine group had significantly higher Patient State Index (PSi) values at 10, 20, and 30 minutes after ketamine administration compared to the controls. Ketamine administration led to significant alterations in EEG patterns, including reduced relative power in delta and theta frequency bands, and increased relative power in beta and gamma frequency bands at 10 minutes post-administration. Relative power in the alpha frequency band significantly decreased at 10, 20, and 30 minutes post-administration. However, there were no differences in intraoperative alfentanil consumption, postoperative morphine usage, and pain scores between the two groups. Low-dose ketamine administration during desflurane anesthesia led to notable changes in EEG patterns and PSi values. These findings provide valuable insights into the impact of ketamine on brain activity, and offer essential information for clinical anesthesiologists.

Investigating the Effects of Rivastigmine and Ketamine on Brine Shrimp Morphology, Mortality, and Acetylcholinesterase Activity

Investigating the Effects of Rivastigmine and Ketamine on Brine Shrimp Morphology, Mortality, and Acetylcholinesterase Activity

Administration of low dose intranasal ketamine exerts a neuroprotective effect on whole brain irradiation injury model in wistar rats.

Exposure to ionizing radiation leads to oxidative stress and neuroinflammation, resulting in neurocognitive impairments. Adverse effects are also associated with glutamate-induced excitotoxicity due to alterations in the composition of glutamate receptors. Ketamine, which is a noncompetitive NMDA glutamate receptor antagonist, has been stated to exert an impact on glutamatergic receptors. This study aims to reveal the possible alleviating or preventive effects of ketamine, which maintains glutamate homeostasis and decreases neurodegeneration, in a radiation-induced neurotoxicity model. Twenty-one female Wistar Queryrats were included in the study and 14 of these underwent whole brain irradiation (IR) with a 20 Gray single dose. Animals were allocated into three groups. Group 1: Normal control; Group 2: Placebo / IR + Saline; Group 3: IR + Ketamine. Ketamine was administered in addition to IR to rats in Group 3. The one-way ANOVA statistical test was used to compare groups. The value of p < 0.05 was considered statistically significant. When administered in addition to irradiation, ketamine treatment significantly increased scores in the three-chamber sociability test, open field test, and passive avoidance learning test. It also raised neuron counts in the hippocampal CA1 and CA3 regions as well as in Purkinje cells, and enhanced levels of brain-derived neurotrophic factor and tyrosine receptor kinase-B. Furthermore, ketamine administration resulted in decreased levels of glial fibrillary acidic protein, malondialdehyde, and tumor necrosis factor-alpha, indicating a reduction in neuroinflammation and oxidative stress. Ketamine exerted a significant protective impact on radiation-induced neurocognitive impairments and enhanced social-memory capacity by reducing neuronal loss, oxidative stress, and neuroinflammation. Our findings suggest that ketamine is beneficial in the treatment or prevention of neurodegeneration via the regulation of the BDNF/TrkB signaling pathway besides decreasing neuroinflammation and blocking NMDA receptors.

Ketamine for Critically Ill Patients with Severe Acute Brain Injury: A Systematic Review with Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials.

Patients with severe acute brain injury have a high risk of a poor clinical outcome due to primary and secondary brain injury. Ketamine reportedly inhibits cortical spreading depolarization, an electrophysiological phenomenon that has been associated with secondary brain injury, making ketamine potentially attractive for patients with severe acute brain injury. The aim of this systematic review is to explore the current literature regarding ketamine for patients with severe acute brain injury. We systematically searched international databases for randomized clinical trials comparing ketamine by any regimen versus placebo, no intervention, or any control drug for patients with severe acute brain injury. Two authors independently reviewed and selected trials for inclusion, extracted data, assessed risk of bias, and performed analysis using Review Manager and Trial Sequential Analysis. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. The primary outcomes were the proportion of participants with an unfavorable functional outcome, the proportion of participants with one or more serious adverse events, and quality of life. We identified five randomized trials comparing ketamine versus sufentanil, fentanyl, other sedatives, or saline (total N = 149 participants). All outcomes were at overall high risk of bias. The proportions of participants with one or more serious adverse events did not differ between ketamine and sufentanil or fentanyl (relative risk 1.45, 95% confidence interval 0.81-2.58; very low certainty). Trial sequential analysis showed that further trials are needed. The level of evidence regarding the effects of ketamine on functional outcome and serious adverse events in patients with severe acute brain injury is very low. Ketamine may markedly, modestly, or not at all affect these outcomes. Large randomized clinical trials at low risk of bias are needed.

Effectiveness of Intramuscular Ketamine as an Adjunct to Standard Care for Reducing Emergence Agitation in Nasal Surgery Patients

Effectiveness of Intramuscular Ketamine as an Adjunct to Standard Care for Reducing Emergence Agitation in Nasal Surgery Patients

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

Distinct alterations in probabilistic reversal learning across at-risk mental state, first episode psychosis and persistent schizophrenia

We used a probabilistic reversal learning task to examine prediction error-driven belief updating in three clinical groups with psychosis or psychosis-like symptoms. Study 1 compared people with at-risk mental state and first episode psychosis (FEP) to matched controls. Study 2 compared people diagnosed with treatment-resistant schizophrenia (TRS) to matched controls. The design replicated our previous work showing ketamine-related perturbations in how meta-level confidence maintained behavioural policy. We applied the same computational modelling analysis here, in order to compare the pharmacological model to three groups at different stages of psychosis. Accuracy was reduced in FEP, reflecting increased tendencies to shift strategy following probabilistic errors. The TRS group also showed a greater tendency to shift choice strategies though accuracy levels were not significantly reduced. Applying the previously-used computational modelling approach, we observed that only the TRS group showed altered confidence-based modulation of responding, previously observed under ketamine administration. Overall, our behavioural findings demonstrated resemblance between clinical groups (FEP and TRS) and ketamine in terms of a reduction in stabilisation of responding in a noisy environment. The computational analysis suggested that TRS, but not FEP, replicates ketamine effects but we consider the computational findings preliminary given limitations in performance of the model.

Use of Dexmedetomidine, Midazolam, and Ketamine in Prevention of Emergence Agitation in Pediatric Patients Undergoing Surgery Under General Anesthesia

Introduction: Emergence agitation (EA) is a problem that often occurs in pediatric patients during recovery from anesthesia. The cause of EA remained unclear, but the combination of etiologies increases the risk of postoperative agitation. The researchers use various drugs such as ketamine, midazolam, and dexmedetomidine to prevent and treat EA. Objective: This review aims to determine the effectiveness of dexmedetomidine, midazolam, and ketamine in preventing emergence agitation in pediatric patients undergoing surgery under general anesthesia. Method: This literature review is a narrative review that looks at the outcomes of randomized controlled trials (RCT) studies that tested how well dexmedetomidine, midazolam, and ketamine worked at keeping pediatric patients from becoming agitated during emergence. Literature was collected through Google Scholar and PubMed using the keywords Pediatric, Children, Dexmedetomidine, Ketamine, Midazolam, Emergence Agitation, Emergence Delirium, Postoperative Agitation, and Postoperative Delirium and published within the last ten years (2011–2021) in English or Indonesian. The researchers excluded articles that were not available in full, as well as literature reviews. Results: Based on the specified database and keywords identified, there were 695 articles. This literature study included thirteen articles that met the inclusion criteria. Ten articles examined the effectiveness of dexmedetomidine, four reviewed the effectiveness of midazolam, and three examined the effectiveness of ketamine. Conclusion: According to the ten reviewed articles, administering dexmedetomidine or ketamine reduced the incidence of emergence agitation in children. However, the administration of midazolam yielded inconsistent results. To evaluate the optimal dosage, route, and timing of dexmedetomidine, midazolam, and ketamine in preventing EA, further studies are necessary.

High-order brain interactions in ketamine during rest and task: a double-blinded cross-over design using portable EEG on male participants

Ketamine is a dissociative anesthetic that induces a shift in global consciousness states and related brain dynamics. Portable low-density EEG systems could be used to monitor these effects. However, previous evidence is almost null and lacks adequate methods to address global dynamics with a small number of electrodes. This study delves into brain high-order interactions (HOI) to explore the effects of ketamine using portable EEG. In a double-blinded cross-over design, 30 male adults (mean age = 25.57, SD = 3.74) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Ketamine induced an increase in redundancy in brain dynamics (copies of the same information that can be retrieved from 3 or more electrodes), most significantly in the alpha frequency band. Redundancy was more evident during resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine’s HOI and experiences of derealization. Ketamine appears to increase redundancy and HOI across psychometric measures, suggesting these effects are correlated with alterations in consciousness towards dissociation. In comparisons with event-related potential (ERP) or standard functional connectivity metrics, HOI represent an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations between electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

Evaluating the Histopathological Effects of Short-term and Long-term Doses of Ketamine Injection on Heart Tissue of Male and Female Rats

Introduction: Ketamine is a general anesthetic drug that acts by inhibiting the NMDA receptoran important component of excitatory neurotransmission. Existing of NMDA receptors all over the central nervous system and the special type of anesthesia induced by ketamine, called dissociative anesthesia has led to its use as an analgesic and also paved the way for abuse. Ketamine affects the cardiovascular system by increasing indices such as heart rate, blood pressure, and cardiac output. Methods: For further evaluation of ketamine effects on heart tissue, we used 15 male and 15 female Wistar rats and divided them into 6 groups, including male and female control groups (MC and FC), male and female short-term exposure (MS and FS), and male and female long-term exposure (ML and FL) to ketamine. Each group included 5 Wistar rats. The ML and FL groups received 75mg of ketamine once a week for 4 weeks in the posterior muscle of the thigh and the MS and FS groups received 25mg of ketamine 3 times a week for 4 weeks at the same site. Results: After preparation of histopathological slides, it was observed that only in the group of female mice receiving long-term ketamine, empty spaces and intercellular distances increased, and in the group of male mice receiving long-term ketamine, in addition to the increase of intercellular spaces, tissue accumulations were also observed in the heart tissue. Conclusion: This study showed that long-term ketamine injection in both sexes can cause some qualitative changes in heart tissue. Expanding the duration of long-term exposure to ketamine and more studies based on sexes can lead to more findings.

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine’s molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

Potential effect of ketamine in treatment for dextromethorphan use disorder exploding in Japanese young population

In Japan, the landscape of clinical practice for substance use disorder is changing significantly, primarily due to an increase in patients using over-the-counter drugs. A major concern is the rising number of patients misusing dextromethorphan (DXM). These patients with DXM use disorders often have severe trauma-related and mood symptoms, and therefore try to cope with those symptoms by self-medicating with DXM. In this article, we propose that ketamine, which has similar psychopharmacological effects to DXM, may be a useful alternative pharmacological treatment for these patients.

Low-dose ketamine as an adjunct to morphine: A randomized controlled trial among patients with and without current opioid use.

Pain is a common complaint among patients presenting to the emergency department (ED), yet pain treatment is frequently suboptimal. The aim of this study was to determine the effectiveness of low-dose ketamine (LDK) as an adjunct to morphine versus morphine alone for treatment of acute pain among ED patients with and without current opioid use. Adult patients presenting with acute pain of ≥5 on a numeric rating scale (0-10) who were deemed by their treating ED physician to require intravenous opioids were randomized to receive either 0.1 mg/kg ketamine (treatment group) or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain was measured at baseline (T0) and 10, 20, 30, 45, 60, and 120 min after randomization. The primary outcome was pain reduction from T0 to T10. Secondary outcomes included pain intensity over 120 min, need of rescue opioids, side effects, and patient and provider satisfaction. A total of 116 patients were included from May 2022 to August 2023. Median (IQR) age was 51 (36.5-67) years; 58% were male and 36% had current opioid use. Pain reduction from T0 to T10 was greater in the LDK group (4 [IQR 3-6]) compared to the placebo group (1 [IQR 0-2]; p = 0.001). Pain intensity was lower in the LDK group at T10, T20, and T30, compared to the placebo group. There was a higher risk of nausea, vomiting, and dissociation in the LDK group during the first 10 min. LDK may be effective as an adjunct analgesic to morphine for short-term pain relief in treatment of acute pain in the ED for both patients with and without current opioid use.

Effects of Dexmedetomidine and Ketamine on Oxidative Stress Markers in Patients Undergoing Lower Extremity Surgery: A Randomized, Double-Blind Study

Effects of Dexmedetomidine and Ketamine on Oxidative Stress Markers in Patients Undergoing Lower Extremity Surgery: A Randomized, Double-Blind Study

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.