Nebulized Ketamine Used for Pain Management of Orthopedic Trauma

BackgroundKetamine is a noncompetitive N-methyl-D-aspartate/glutamate receptor complex antagonist that decreases pain by diminishing central sensitization and hyperalgesia. When administered via i.v. (push-dose, short infusion, or continuous infusion) or intranasal routes, ketamine has shown to be effective in patients with acute traumatic pain. However, when i.v. access is not attainable or readily available, the inhalation route of ketamine administration via breath-actuated nebulizer (BAN) provides a noninvasive and titratable method of analgesic delivery. The use of nebulized ketamine has been studied in areas of postoperative management of sore throat and acute traumatic musculoskeletal and abdominal pain. To our knowledge, this is the first case series describing the use of nebulized ketamine for analgesia and orthopedic reduction.Case SeriesWe describe 4 patients who presented to the emergency department with acute traumatic painful conditions (one patellar dislocation, one shoulder dislocation, and two forearm fractures) and received nebulized ketamine for management of their pain.Why Should an Emergency Physician Be Aware of This?Administration of nebulized ketamine via BAN can be used as analgesic control for musculoskeletal trauma, as it can be administrated to patients with difficult i.v. access, has a rapid onset of analgesic effects with minimal side effects, and remains opioid-sparing.     

Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

Quantitative electroencephalography from freely moving rats is commonly used as a translational tool for predicting drug‐effects in humans. We hypothesized that drug‐effects may be expressed differently depending on whether the rat is in active locomotion or sitting still during recording sessions, and proposed automatic state‐detection as a viable tool for estimating drug‐effects free of hypo‐/hyperlocomotion‐induced effects. We aimed at developing a fully automatic and validated method for detecting two behavioural states: active and inactive, in one‐second intervals and to use the method for evaluating ketamine, DOI, d‐cycloserine, d‐amphetamine, and diazepam effects specifically within each state. The developed state‐detector attained high precision with more than 90% of the detected time correctly classified, and multiple differences between the two detected states were discovered. Ketamine‐induced delta activity was found specifically related to locomotion. Ketamine and DOI suppressed theta and beta oscillations exclusively during inactivity. Characteristic gamma and high‐frequency oscillations (HFO) enhancements of the NMDAR and 5HT_2A modulators, speculated associated with locomotion, were profound and often largest during the inactive state. State‐specific analyses, theoretically eliminating biases from altered occurrence of locomotion, revealed only few effects of d‐amphetamine and diazepam. Overall, drug‐effects were most abundant in the inactive state. In conclusion, this new validated and automatic locomotion state‐detection method enables fast and reliable state‐specific analysis facilitating discovery of state‐dependent drug‐effects and control for altered occurrence of locomotion. This may ultimately lead to better cross‐species translation of electrophysiological effects of pharmacological modulations.     

Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials

BackgroundAt ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR–gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses.MethodsParticipants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery–Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25.ResultsIn the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected.ConclusionsVariation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT02417064","term_id":"NCT02417064"}}NCT02417064 and {"type":"clinical-trial","attrs":{"text":"NCT02418585","term_id":"NCT02418585"}}NCT02418585; www.clinicaltrials.gov     

Molecular mechanisms for the antidepressant-like effects of a low-dose ketamine treatment in a DFP-based rat model for Gulf War Illness

Exposure to organophosphates (OP) during the First Gulf War is among one of the factors for Gulf War Illness (GWI) development in veterans and it has been challenging to treat GWI symptoms with existing therapies. Ketamine produces a rapid-onset and sustained antidepressant response, but there is no evidence whether ketamine treatment is effective for GWI depression. Repeated, low-dose exposure to diisopropyl fluorophosphate (DFP) mimic Gulf War related OP exposures and produces a chronic depressive state in rats. In this study, DFP-exposed rats treated with ketamine (10 mg/kg, i.p.) exhibited antidepressant-like effect on the Forced Swim Test at 1-h. This effect persisted at 24-h post ketamine, a time-point by which it is eliminated from the brain suggesting involvement of mechanisms that affect long-term synaptic plasticity. Western blot analysis showed significantly lower Brain-Derived Neurotrophic Factor (BDNF) levels in DFP rat brains. Ketamine produced a nonsignificant increase in BDNF expression at 1-h but produced a larger, significant (2.2-fold) increase at 24-h in DFP rats. We previously reported chronic hippocampal calcium elevations ([Ca²⁺]_i) in DFP rats. Ketamine-treated DFP rats exhibited significantly lower [Ca²⁺]_i at 1-h but not at 24-h. Interestingly, treatment with ANA-12, a TrkB-BDNF receptor antagonist, in DFP rats blunted ketamine’s antidepressant-like effect at 24-h but not at 1-h. These experiments suggest that in a rat model of DFP-induced depression, inhibition of the NMDAR-Ca²⁺ contributes to the rapid-onset antidepressant effects of ketamine while the antidepressant actions that persisted at 24-h post ketamine administration involve upregulation of BDNF signaling.     

Intravesical hyaluronic acid treatment for ketamine-associated cystitis: Preliminary results

IntroductionLong-term ketamine abuse may cause variable lower urinary tract symptoms (LUTS) and severe cystitis. The clinical features of ketamine-associated cystitis (KC) are very similar to bladder pain syndrome/interstitial cystitis (BPS/IC). Intravesical administration of hyaluronic acid (HA) is one of the regimens for treating BPS/IC. In this study, we aim to investigate whether intravesical HA therapy may improve the LUTS of patients with KC.Materials and methodsFour female patients and one male patient with KC who failed oral medications were enrolled in this study. HA (Cystistat) at a dose of 40 mg in a volume of 50 mL of phosphate-buffered saline was injected into the bladder on a weekly basis for 6 weeks and then monthly for a further 3 months. Response to therapy was evaluated by the visual analog scale (VAS) for pain, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Treatment efficacy was assessed by comparing the pretreatment and posttreatment mean scores of the five questionnaires using the paired t test.ResultsThe mean age of the patients was 22 ± 1.5 years. The mean duration of ketamine abuse was 68 ± 16.7 months. After intravesical HA therapy for 4 weeks, statistically significant mean decreases in VAS (from 7 to 4.4, p = 0.03), IPSS voiding subscore (from 16.2 to 11.6, p = 0.017), and ICSI (from 16.4 to 13.6, p = 0.016) questionnaire scores were seen. However, only ICSI constantly reduced after 4 weeks of treatment.ConclusionIntravesical HA therapy may have short-term benefits for improving bladder pain and voiding symptoms in patients with KC.