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Effects of a single subanaesthetic dose of ketamine on pain and mood after laparoscopic bariatric surgery: A randomised double-blind placebo controlled study
Wang, Jing; Echevarria, Ghislaine; Doan, Lisa; Ekasumara, Nydia; Calvino, Steven; Chae, Floria; Martinez, Erik; Robinson, Eric; Cuff, Germaine; Franco, Lola; Muntyan, Igor; Kurian, Marina; Schwack, Bradley F; Bedrosian, Andrea S; Fielding, George A; Ren-Fielding, Christine J
BACKGROUND:When administered as a continuous infusion, ketamine is known to be a potent analgesic and general anaesthetic. Recent studies suggest that a single low-dose administration of ketamine can provide a long-lasting effect on mood, but its effects when given in the postoperative period have not been studied. OBJECTIVE:We hypothesised that a single low-dose administration of ketamine after bariatric surgery can improve pain and mood scores in the immediate postoperative period. DESIGN/METHODS:We performed a randomised, double-blind, placebo-controlled study to compare a single subanaesthetic dose of ketamine (0.4 mg kg) with a normal saline placebo in the postanaesthesia care unit after laparoscopic gastric bypass and gastrectomy. SETTING/METHODS:Single-centre, tertiary care hospital, October 2014 to January 2018. PATIENTS/METHODS:A total of 100 patients were randomised into the ketamine and saline groups. INTERVENTION/METHODS:Patients in the ketamine group received a single dose of ketamine infusion (0.4 mg kg) in the postanaesthesia care unit. Patients in the placebo groups received 0.9% saline. OUTCOME MEASURES/METHODS:The primary outcome was the visual analogue pain score. A secondary outcome was performance on the short-form McGill's Pain Questionnaire (SF-MPQ). RESULTS:There were no significant differences in visual analogue pain scores between groups (group-by-time interaction P = 0.966; marginal group effect P = 0.137). However, scores on the affective scale of SF-MPQ (secondary outcome) significantly decreased in the ketamine group as early as postoperative day (POD) 2 [mean difference = -2.2 (95% bootstrap CI -2.9 to 1.6), Bonferroni adjusted P < 0.001], compared with placebo group in which the scores decreased only by POD 7. Scores on the total scale of SF-MPQ for the ketamine group were smaller compared with the placebo group (P = 0.034). CONCLUSION/CONCLUSIONS:Although there was no significant difference between ketamine and placebo for the primary outcome measure, patients who received ketamine experienced statistically and clinically significant improvement in their comprehensive evaluation of pain, particularly the affective component of pain, on POD 2. However, future studies are needed to confirm the enduring effects of ketamine on the affective response to postoperative pain. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT02452060.
PMID: 30095550
ISSN: 1365-2346
CID: 3226762
Cortical Pain Processing in the Rat Anterior Cingulate Cortex and Primary Somatosensory Cortex
Xiao, Zhengdong; Martinez, Erik; Kulkarni, Prathamesh M; Zhang, Qiaosheng; Hou, Qianning; Rosenberg, David; Talay, Robert; Shalot, Leor; Zhou, Haocheng; Wang, Jing; Chen, Zhe Sage
Pain is a complex multidimensional experience encompassing sensory-discriminative, affective-motivational and cognitive-emotional components mediated by different neural mechanisms. Investigations of neurophysiological signals from simultaneous recordings of two or more cortical circuits may reveal important circuit mechanisms on cortical pain processing. The anterior cingulate cortex (ACC) and primary somatosensory cortex (S1) represent two most important cortical circuits related to sensory and affective processing of pain. Here, we recorded in vivo extracellular activity of the ACC and S1 simultaneously from male adult Sprague-Dale rats (n = 5), while repetitive noxious laser stimulations were delivered to animalÕs hindpaw during pain experiments. We identified spontaneous pain-like events based on stereotyped pain behaviors in rats. We further conducted systematic analyses of spike and local field potential (LFP) recordings from both ACC and S1 during evoked and spontaneous pain episodes. From LFP recordings, we found stronger phase-amplitude coupling (theta phase vs. gamma amplitude) in the S1 than the ACC (n = 10 sessions), in both evoked (p = 0.058) and spontaneous pain-like behaviors (p = 0.017, paired signed rank test). In addition, pain-modulated ACC and S1 neuronal firing correlated with the amplitude of stimulus-induced event-related potentials (ERPs) during evoked pain episodes. We further designed statistical and machine learning methods to detect pain signals by integrating ACC and S1 ensemble spikes and LFPs. Together, these results reveal differential coding roles between the ACC and S1 in cortical pain processing, as well as point to distinct neural mechanisms between evoked and putative spontaneous pain at both LFP and cellular levels.
PMCID:6492531
PMID: 31105532
ISSN: 1662-5102
CID: 4038782
Neuromodulation for Pain Management
Wang, Jing; Chen, Zhe
Pain is a salient and complex sensory experience with important affective and cognitive dimensions. The current definition of pain relies on subjective reports in both humans and experimental animals. Such definition lacks basic mechanistic insights and can lead to a high degree of variability. Research on biomarkers for pain has previously focused on genetic analysis. However, recent advances in human neuroimaging and research in animal models have begun to show the promise of a circuit-based neural signature for pain. At the treatment level, pharmacological therapy for pain remains limited. Neuromodulation has emerged as a specific form of treatment without the systemic side effects of pharmacotherapies. In this review, we will discuss some of the current neuromodulatory modalities for pain, research on newer targets, as well as emerging possibility for an integrated brain-computer interface approach for pain management.
PMID: 31729677
ISSN: 0065-2598
CID: 4187052
An Update on the Basic and Clinical Science of Ketamine Analgesia
Doan, Lisa V; Wang, Jing
OBJECTIVE:In the context of the current opioid epidemic, there has been a renewed interest in the use of ketamine as an analgesic agent. METHODS:We have reviewed ketamine analgesia. RESULTS:Ketamine is well-known as an antagonist for N-methyl-D-aspartate receptors. In addition, it can regulate the function of opioid receptors and sodium channels. Ketamine also increases signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. These myriad of molecular and cellular mechanisms are responsible for a number of pharmacological functions including pain relief and mood regulation. Clinically, a number of studies have investigated the role of ketamine in the setting of acute and chronic pain, and there is evidence that ketamine can provide analgesia in a variety of pain syndromes. DISCUSSION/CONCLUSIONS:In this review, we have examined basic mechanisms of ketamine and its current clinical use as well as potential novel use in pain management.
PMID: 29927768
ISSN: 1536-5409
CID: 3158292
Supervised Machine Learning Predictive Analytics for Prediction of Postinduction Hypotension
Kendale, Samir; Kulkarni, Prathamesh; Rosenberg, Andrew D; Wang, Jing
WHAT WE ALREADY KNOW ABOUT THIS TOPIC/UNASSIGNED:WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Hypotension is a risk factor for adverse perioperative outcomes. Machine learning methods allow large amounts of data for development of robust predictive analytics. The authors hypothesized that machine learning methods can provide prediction for the risk of postinduction hypotension METHODS:: Data was extracted from the electronic health record of a single quaternary care center from November 2015 to May 2016 for patients over age 12 that underwent general anesthesia, without procedure exclusions. Multiple supervised machine learning classification techniques were attempted, with postinduction hypotension (mean arterial pressure less than 55 mmHg within 10 min of induction by any measurement) as primary outcome, and preoperative medications, medical comorbidities, induction medications, and intraoperative vital signs as features. Discrimination was assessed using cross-validated area under the receiver operating characteristic curve. The best performing model was tuned and final performance assessed using split-set validation. RESULTS:Out of 13,323 cases, 1,185 (8.9%) experienced postinduction hypotension. Area under the receiver operating characteristic curve using logistic regression was 0.71 (95% CI, 0.70 to 0.72), support vector machines was 0.63 (95% CI, 0.58 to 0.60), naive Bayes was 0.69 (95% CI, 0.67 to 0.69), k-nearest neighbor was 0.64 (95% CI, 0.63 to 0.65), linear discriminant analysis was 0.72 (95% CI, 0.71 to 0.73), random forest was 0.74 (95% CI, 0.73 to 0.75), neural nets 0.71 (95% CI, 0.69 to 0.71), and gradient boosting machine 0.76 (95% CI, 0.75 to 0.77). Test set area for the gradient boosting machine was 0.74 (95% CI, 0.72 to 0.77). CONCLUSIONS:The success of this technique in predicting postinduction hypotension demonstrates feasibility of machine learning models for predictive analytics in the field of anesthesiology, with performance dependent on model selection and appropriate tuning.
PMID: 30074930
ISSN: 1528-1175
CID: 3217582
Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex
Zhou, Haocheng; Zhang, Qiaosheng; Martinez, Erik; Dale, Jahrane; Hu, Sile; Zhang, Eric; Liu, Kevin; Huang, Dong; Yang, Guang; Chen, Zhe; Wang, Jing
Chronic pain is known to induce an amplified aversive reaction to peripheral nociceptive inputs. This enhanced affective response constitutes a key pathologic feature of chronic pain syndromes such as fibromyalgia. However, the neural mechanisms that underlie this important aspect of pain processing remain poorly understood, hindering the development of treatments. Here, we show that a single dose of ketamine can produce a persistent reduction in the aversive response to noxious stimuli in rodent chronic pain models, long after the termination of its anti-nociceptive effects. Furthermore, we demonstrated that this anti-aversive property is mediated by prolonged suppression of the hyperactivity of neurons in the anterior cingulate cortex (ACC), a brain region well known to regulate pain affect. Therefore, our results indicate that it is feasible to dissociate the affective from the sensory component of pain, and demonstrate the potential for low-dose ketamine to be an important therapy for chronic pain syndromes.
PMCID:6138720
PMID: 30218052
ISSN: 2041-1723
CID: 3278482
A retrospective study of opioid prescribing patterns at hospital discharge in surgical patients with obstructive sleep apnea
Kendale, Samir M; Wang, Jing; Blitz, Jeanna D; Calvino, Steven; Cuff, Germaine; Barone, Nicholas; Rosenberg, Andrew D; Doan, Lisa
PURPOSE/OBJECTIVE:Obstructive sleep apnea (OSA) is a risk factor for complications with postoperative opioid use, and in those patients with known or suspected OSA, minimization of postoperative opioids is recommended. We hypothesize that despite these recommendations, surgical patients with known or suspected OSA are prescribed postoperative opioids at hospital discharge at similar doses to those without OSA. METHODS:This was a retrospective analysis of the electronic health records of surgical patients from 1 November 2016 to 30 April 2017 at a single academic institution. Patients with a known diagnosis of OSA or a STOP-Bang score ≥ 5 were compared with those without OSA for the amount of postoperative discharge opioid medication using multivariable linear regression. RESULTS:Of the 17,671 patients analyzed, 1,692 (9.6%) had known or suspected OSA with 1,450 (86%) of these patients discharged on opioid medications. Of the 15,979 patients without OSA, 12,273 (77%) were discharged on opioid medications. The total median [interquartile range (IQR)] oral morphine equivalents (OME) for all patients was 150 [0-338] mg and for patients with known or suspected OSA was 160 [0-450] mg, an unadjusted comparison showing an 18% difference in OME (95% confidence interval [CI], 3% to 35%; P = 0.02). The analysis, after adjusting for confounders, showed no significant difference in the amount of opioids prescribed to OSA or non-OSA patients (8% difference in total OME; 95% CI, -6% to 25%; P = 0.26). CONCLUSION/CONCLUSIONS:This study shows that surgical patients at risk for OSA or confirmed OSA are prescribed opioids at similar rates and doses upon discharge despite guidelines that recommend minimizing opioid use in OSA patients. These findings indicate a need to implement different strategies to reduce the prescription of opioids to patients with OSA.
PMID: 29777388
ISSN: 1496-8975
CID: 3120822
Rate and Temporal Coding Mechanisms in the Anterior Cingulate Cortex for Pain Anticipation
Urien, Louise; Xiao, Zhengdong; Dale, Jahrane; Bauer, Elizabeth P; Chen, Zhe; Wang, Jing
Pain is a complex sensory and affective experience. Through its anticipation, animals can learn to avoid pain. Much is known about passive avoidance during a painful event; however, less is known about active pain avoidance. The anterior cingulate cortex (ACC) is a critical hub for affective pain processing. However, there is currently no mechanism that links ACC activities at the cellular level with behavioral anticipation or avoidance. Here we asked whether distinct populations of neurons in the ACC can encode information for pain anticipation. We used tetrodes to record from ACC neurons during a conditioning assay to train rats to avoid pain. We found that in rats that successfully avoid acute pain episodes, neurons that responded to pain shifted their firing rates to an earlier time, whereas neurons that responded to the anticipation of pain increased their firing rates prior to noxious stimulation. Furthermore, we found a selected group of neurons that shifted their firing from a pain-tuned response to an anticipatory response. Unsupervised learning analysis of ensemble spike activity indicates that temporal spiking patterns of ACC neurons can indeed predict the onset of pain avoidance. These results suggest rate and temporal coding schemes in the ACC for pain avoidance.
PMCID:5974274
PMID: 29844413
ISSN: 2045-2322
CID: 3136262
Local field potential decoding of the onset and intensity of acute pain in rats
Zhang, Qiaosheng; Xiao, Zhengdong; Huang, Conan; Hu, Sile; Kulkarni, Prathamesh; Martinez, Erik; Tong, Ai Phuong; Garg, Arpan; Zhou, Haocheng; Chen, Zhe; Wang, Jing
Pain is a complex sensory and affective experience. The current definition for pain relies on verbal reports in clinical settings and behavioral assays in animal models. These definitions can be subjective and do not take into consideration signals in the neural system. Local field potentials (LFPs) represent summed electrical currents from multiple neurons in a defined brain area. Although single neuronal spike activity has been shown to modulate the acute pain, it is not yet clear how ensemble activities in the form of LFPs can be used to decode the precise timing and intensity of pain. The anterior cingulate cortex (ACC) is known to play a role in the affective-aversive component of pain in human and animal studies. Few studies, however, have examined how neural activities in the ACC can be used to interpret or predict acute noxious inputs. Here, we recorded in vivo extracellular activity in the ACC from freely behaving rats after stimulus with non-noxious, low-intensity noxious, and high-intensity noxious stimuli, both in the absence and chronic pain. Using a supervised machine learning classifier with selected LFP features, we predicted the intensity and the onset of acute nociceptive signals with high degree of precision. These results suggest the potential to use LFPs to decode acute pain.
PMCID:5974270
PMID: 29844576
ISSN: 2045-2322
CID: 3136272
Scaling Up Cortical Control Inhibits Pain
Dale, Jahrane; Zhou, Haocheng; Zhang, Qiaosheng; Martinez, Erik; Hu, Sile; Liu, Kevin; Urien, Louise; Chen, Zhe; Wang, Jing
Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC) is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain.
PMCID:5965697
PMID: 29719246
ISSN: 2211-1247
CID: 3061672