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Background: Among chronic opioid users, the association between decreasing or increasing preoperative opioid utilization and postoperative outcomes is unknown. The authors hypothesized that decreasing utilization would be associated with improved outcomes and increasing utilization with worsened outcomes.Methods: Using commercial insurance claims, the authors identified 57,019 chronic opioid users (10 or more prescriptions or 120 or more days supplied during the preoperative year), age 18 to 89 yr, undergoing one of 10 surgeries between 2004 and 2018. Patients with a 20% or greater decrease or increase in opioid utilization between preoperative days 7 to 90 and 91 to 365 were compared to patients with less than 20% change (stable utilization). The primary outcome was opioid utilization during postoperative days 91 to 365. Secondary outcomes included alternative measures of postoperative opioid utilization (filling a minimum number of prescriptions during this period), postoperative adverse events, and healthcare utilization.Results: The average age was 63 ± 13 yr, with 38,045 (66.7%) female patients. Preoperative opioid utilization was decreasing for 12,347 (21.7%) patients, increasing for 21,330 (37.4%) patients, and stable for 23,342 (40.9%) patients. Patients with decreasing utilization were slightly less likely to fill an opioid prescription during postoperative days 91 to 365 compared to stable patients (89.2% vs. 96.4%; odds ratio, 0.323; 95% CI, 0.296 to 0.352; P < 0.001), though the average daily doses were similar among patients who continued to utilize opioids during this timeframe (46.7 vs. 46.5 morphine milligram equivalents; difference, 0.2; 95% CI, -0.8 to 1.2; P = 0.684). Of patients with increasing utilization, 93.6% filled opioid prescriptions during this period (odds ratio, 0.57; 95% CI, 0.52 to 0.62; P < 0.001), with slightly lower average daily doses (44.3 morphine milligram equivalents; difference, -2.2; 95% CI, -3.1 to -1.3; P < 0.001). Except for alternative measures of persistent postoperative opioid utilization, there were no clinically significant differences for the secondary outcomes.Conclusions: Changes in preoperative opioid utilization were not associated with clinically significant differences for several postoperative outcomes including postoperative opioid utilization.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Objectives: To identify perioperative practice patterns that predictably impact postoperative pain. Background: Despite significant advances in perioperative medicine, a significant portion of patients still experience severe pain after major surgery. Postoperative pain is associated with serious adverse outcomes that are costly to patients and society. Methods: The presented analysis took advantage of a unique observational data set providing unprecedented detailed pharmacological information. The data were collected by PAIN OUT, a multinational registry project established by the European Commission to improve postoperative pain outcomes. A multivariate approach was used to derive and validate a model predictive of pain on postoperative day 1 (POD1) in 1008 patients undergoing back surgery. Results: The predictive and validated model was highly significant (P ¼ 8.9E-15) and identified modifiable practice patterns. Importantly, the number of nonopioid analgesic drug classes administered during surgery predicted decreased pain on POD1. At least 2 different nonopioid analgesic drug classes (cyclooxygenase inhibitors, acetaminophen, nefopam, or metamizol) were required to provide meaningful pain relief (>30%). However, only a quarter of patients received at least 2 nonanalgesic drug classes during surgery. In addition, the use of very short-acting opioids predicted increased pain on POD1, suggesting room for improvement in the perioperative management of these patients. Although the model was highly significant, it only accounted for a relatively small fraction of the observed variance. Conclusion: The presented analysis offers detailed insight into current practice patterns and reveals modifications that can be implemented in today's clinical practice. Our results also suggest that parameters other than those currently studied are relevant for postoperative pain including biological and psychological variables. [ABSTRACT FROM AUTHOR]

Abstract: Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12–60% of the observed response variance. Significant familial effects accounting for 24–32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype. [Copyright &y& Elsevier]

Abstract: It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in “acute tolerance.” The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the μ-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5–24% for analgesia, 20–48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects. [Copyright &y& Elsevier]

Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid-associated hyperalgesia has been attributed to a pain facilitating system involving the N-methyl-D-aspartate (NMDA)-receptor. In humans little direct evidence documents opioid-associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo-controlled design to test in opioid-naïve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90-min infusion with the mu-opioid agonist remifentanil, and whether co-administration of the NMDA-receptor antagonist S-ketamine would prevent such hyperalgesia. We found that a skin area with pre-existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co-administration of the NMDA-receptor antagonist S-ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short-term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA-receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration. [ABSTRACT FROM AUTHOR]

Experimental pain models inducing hyperalgesia, i.e. an increased sensitivity to noxious stimuli often present in clinical pain, are important tools for studying antinociceptive drug profiles. The correct interpretation of results obtained in these models necessitates their mechanistic understanding. This study evaluated the freeze lesion, an experimental model of hyperalgesia, in humans. Twelve healthy subjects were tested with mechanical (brush, punctuated and blunt) and electrical (5, 250, and 2000 Hz sine wave current) stimuli before and after freezing the skin, and during a computer-controlled infusion of the mu-opioid agonist remifentanil targeting five different plasma concentrations between 0 and 6 ng/ml in a two-staged, single occasion, randomized, and double blind study design. Pharmacodynamic modeling techniques were used to describe the effect of freezing and drug administration on the mechanical and electrical pain thresholds. Freezing the skin resulted in hyperalgesia to blunt and punctuated stimuli and lowered the respective pain threshold by 29 and 73%. Hyperalgesia to brushing or electrical stimuli was not detected. Remifentanil attenuated hyperalgesia to blunt stimuli about twice as potently as hyperalgesia to punctuated stimuli, as indicated by a significantly steeper linear relationship between the remifentanil plasma concentration and the increase of the pain threshold to blunt stimuli. Remifentanil attenuated electrical pain with greater potency for low frequency stimulation. The potency difference of remifentanil suggests that different neuronal mechanisms mediate hyperalgesia to blunt and punctuated stimulation. Absence of brush-evoked and electrical hyperalgesia is compatible with the view that mechanical hyperalgesia to blunt and punctuated stimulation of the freeze lesion is predominantly caused by a peripheral mechanism. [ABSTRACT FROM AUTHOR]

The article focuses on a cohort study published within the issue of the periodical which used a single-cell mass cytometry approach to characterize the phenotype and function of major innate and adaptive immune responses in patients who suffered from traumatic injury. It mentions individualized risk stratification based on the deep immune profiling of critically ill patients and characterization of intracellular expression of over 20 cytokines at the single-cell level.

The authors discuss the study "Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery," by R. W. Loftus, M. P. Yeager, J. A. Clark, et al. which appeared within the issue. They compare the findings of the study with other studies that have investigated ketamine as an adjunctive analgesic in the perioperative period. They conclude that the study failed to answer important questions including the dose and infusion duration of ketamine and the specific benefits and possible risks of using an adjunct analgesics and gabapentin.

The author reflects on the studies by Eisenach and colleagues which examine the analgesic effects of ketorolac, a nonsteroidal antiinflammatorydrug (NSAID), in alleviation of pain. He notes that the result demonstrates the ineffectiveness of intrathecal ketorolac in alleviating brief pain evoked in unaltered tissue. He cites that the results of the study raise concerns on the clinical utility of NSAIDs for pain management but do not rule out its effectiveness for certain pain conditions.

Objective: The longitudinal assessment of physical function with high temporal resolution at a scalable and objective level in patients recovering from surgery is highly desirable to understand the biological and clinical factors that drive the clinical outcome. However, physical recovery from surgery itself remains poorly defined and the utility of wearable technologies to study recovery after surgery has not been established., Background: Prolonged postoperative recovery is often associated with long-lasting impairment of physical, mental, and social functions. Although phenotypical and clinical patient characteristics account for some variation of individual recovery trajectories, biological differences likely play a major role. Specifically, patient-specific immune states have been linked to prolonged physical impairment after surgery. However, current methods of quantifying physical recovery lack patient specificity and objectivity., Methods: Here, a combined high-fidelity accelerometry and state-of-the-art deep immune profiling approach was studied in patients undergoing major joint replacement surgery. The aim was to determine whether objective physical parameters derived from accelerometry data can accurately track patient-specific physical recovery profiles (suggestive of a 'clock of postoperative recovery'), compare the performance of derived parameters with benchmark metrics including step count, and link individual recovery profiles with patients' preoperative immune state., Results: The results of our models indicate that patient-specific temporal patterns of physical function can be derived with a precision superior to benchmark metrics. Notably, 6 distinct domains of physical function and sleep are identified to represent the objective temporal patterns: ''activity capacity'' and ''moderate and overall activity (declined immediately after surgery); ''sleep disruption and sedentary activity (increased after surgery); ''overall sleep'', ''sleep onset'', and ''light activity'' (no clear changes were observed after surgery). These patterns can be linked to individual patients preopera-tive immune state using cross-validated canonical-correlation analysis. Importantly, the pSTAT3 signal activity in monocytic myeloid-derived suppressor cells predicted a slower recovery., Conclusions: Accelerometry-based recovery trajectories are scalable and objective outcomes to study patient-specific factors that drive physical recovery., Competing Interests: R.F., F.V., E.G., N.S., I.M., A.L.C., M.B., T.P., M.X., D.D.F., C.E., P.S., D.F.A., J.I.H., S.B.G., B.G., M.S.A., and N.A. contributed to conception and design. E.G., X.G., A.T., M.T., B.G., M.S.A, and N.A. acquired the data. R.F., F.V., A.C., B.G., M.S.A, and N.A. analyzed the data and interpreted the results. R.F., F.V., B.G., M.S.A., and N.A. wrote the manuscript with input from all authors. The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of this study was to determine whether single-cell and plasma proteomic elements of the host's immune response to surgery accurately identify patients who develop a surgical site complication (SSC) after major abdominal surgery., Summary Background Data: SSCs may occur in up to 25% of patients undergoing bowel resection, resulting in significant morbidity and economic burden. However, the accurate prediction of SSCs remains clinically challenging. Leveraging high-content proteomic technologies to comprehensively profile patients' immune response to surgery is a promising approach to identify predictive biological factors of SSCs., Methods: Forty-one patients undergoing non-cancer bowel resection were prospectively enrolled. Blood samples collected before surgery and on postoperative day one (POD1) were analyzed using a combination of single-cell mass cytometry and plasma proteomics. The primary outcome was the occurrence of an SSC, including surgical site infection, anastomotic leak, or wound dehiscence within 30 days of surgery., Results: A multiomic model integrating the single-cell and plasma proteomic data collected on POD1 accurately differentiated patients with (n = 11) and without (n = 30) an SSC [area under the curve (AUC) = 0.86]. Model features included coregulated proinflammatory (eg, IL-6- and MyD88- signaling responses in myeloid cells) and immunosuppressive (eg, JAK/STAT signaling responses in M-MDSCs and Tregs) events preceding an SSC. Importantly, analysis of the immunological data obtained before surgery also yielded a model accurately predicting SSCs (AUC = 0.82)., Conclusions: The multiomic analysis of patients' immune response after surgery and immune state before surgery revealed systemic immune signatures preceding the development of SSCs. Our results suggest that integrating immunological data in perioperative risk assessment paradigms is a plausible strategy to guide individualized clinical care., Competing Interests: Conflicts of Interest and Source of Funding: This work was supported by the Stanford Department of Anesthesiology, Pain and Perioperative Medicine, the Stanford Department of Surgery, the national institute of health (NIH) R35GM137936 (BG), R35GM138353 (NA), NS114926 (MSA), AG065744 (MSA), the Fluegel Research Fund (KR), and the Center for Human Systems Immunology (BG). A provisional patent application that covers aspects of the subject matter of the article has been filed (S31-07151.PRO, title: systems and methods to generate a surgical risk score and uses thereof, co-inventors: B.G., J.H., K.R., N.A., M.S.A.). The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Animal studies suggest that increased circulating estrogen and progesterone, and activation of the endorphin system cause prenancy-induced antinociceptive effects. Human studies have provided inconsistent results and have often lacked a nonpregnant control group. In this study, we compared sensitivity to experimental heat and cold pain in pregnant and nonpregnant women. Nineteen healthy nonpregnant female volunteers and 20 pregnant women at term were enrolled. Pain threshold and tolerance were examined using experimental heat-induced pain and cold pressor pain models. Subjects were evaluated pre- and 1-2 days post-delivery (pregnant), or on consecutive days (nonpregnant). Heat pain tolerance was significantly increased in the pregnant women during pre and postdelivery when compared with nonpregnant controls (50.0 +/- 1.0 vs 49.0 +/- 1.2 and 50.1 +/- 0.7 vs 49.2 +/- 1.2 degrees C; mean +/- sd). However, pain induced by the cold pressor test was endured for a similar amount of time by both study groups. Pregnancy-induced analgesic effects at term can be detected in a model of experimental heat pain. These effects persist during the first 24-48 h after delivery. Experimental heat pain is a suitable modality for further characterizing the phenomenon of pregnancy-induced analgesia in humans.

Background: Activation of the complement system is one component of the inflammatory response. Various components of the complement system participate in killing foreign organisms, recruiting immune cells, enhancing edema, and stimulating cytokine formation. Complement-mediated enhancement of the inflammation surrounding surgical incisions may increase pain., Methods: In these studies, the authors used a murine hind paw incisional model to study the role of the complement C5a receptor in supporting incisional inflammation. At baseline and at various time points after incision, they measured the effects of a highly selective C5a receptor antagonist on nociceptive thresholds, edema formation, and cytokine production in the skin surrounding the incision. They also measured changes in C5a receptor expression near the incisions., Results: The once-daily injection of the C5a receptor antagonist AcF-[OPdChaWR] reduced mechanical allodynia and edema in the incised hind paw. A multiplexed cytokine assay revealed that 8 of the 18 cytokines examined showed significant increases in skin tissue abundance after incision. Distinct time courses for the patterns of elevation were seen, though some degree of resolution occurred for all cytokines within 96 h. For 7 of these 8 cytokines, the C5a receptor antagonist reduced the enhancement of expression. In addition, the authors found that the C5a receptor messenger RNA level increased 15-fold in the skin surrounding the incisions within 24 h and then slowly declined., Conclusions: The tissue directly surrounding incisions in mouse hind paws undergoes large changes in the content of specific cytokines in addition to demonstrating edema and nociceptive sensitization. By blocking the receptor for one component of the complement system, C5a, all of these changes can be reduced. Complement receptor inhibitors may constitute a novel group of compounds useful in reducing the pain and swelling of surgical incisions.

Unlabelled: Most published studies suggesting that epidural fentanyl acts predominantly at spinal sites administered the drug as a bolus injection, whereas most studies suggesting that it acts predominantly at supraspinal sites administered the drug as an infusion. In this study we tested the hypothesis that the mode of administration (bolus versus infusion) of epidural fentanyl determines its site of action. Ten healthy volunteers were enrolled in this randomized, double-blinded, cross-over study. On separate study days fentanyl was administered into the epidural space as a bolus (0.03 mg followed by 0.1 mg 210 min later) and as an infusion (0.03 mg/h followed by 0.1 mg/hr 210 min later for 200 min). Using a thermal and electrical experimental pain model, the heat ( degrees C) and electrical current (mA) causing maximum tolerable pain were assessed repetitively over a period of 420 min. The analgesic efficacy measures were obtained at a lumbar and a cranial dermatome. Plasma fentanyl concentrations were determined throughout the study. Epidural bolus administration of fentanyl resulted in segmental analgesia (leg > head), whereas the epidural infusion of fentanyl produced nonsegmental analgesia (leg = head). There was a significant linear relationship between the analgesic effect and the plasma concentration of fentanyl for the epidural infusion but not for the epidural bolus administration of fentanyl. These findings support our hypothesis and might explain the apparent conflict in the literature regarding the site of action of epidural fentanyl., Implications: In an experimental pain study in volunteers, epidural fentanyl caused segmental analgesia when administered as a bolus and nonsegmental systemic analgesia when administered as a continuous infusion. This finding may help resolve the long-standing controversy surrounding the site of action of epidural fentanyl.

Unlabelled: We have previously demonstrated that continuous epidural infusions of fentanyl without local anesthetics elicit analgesia by a systemic mechanism. In this study, we examined the hypothesis that, in the presence of epidural bupivacaine, continuous infusions of epidural fentanyl elicit analgesia by a spinal mechanism. Forty-eight nulliparous women in active labor participated in this prospective, randomized, double-blinded study. Women received lumbar epidural analgesia with 20-30 mL bupivacaine 0.125% until pain free. Subjects were then randomized to either IV or epidural (EPI) fentanyl infusion groups. Each infusion delivered fentanyl 30 microg/h. All women received an epidural infusion of bupivacaine at a rate of 20 mL/h, the concentration of which was determined by the response of the previous woman in the same group to the analgesic regimen used. Unlike previous studies that assessed the minimum local analgesic concentration (MLAC) for bolus administration at the initiation of analgesia, this study assessed MLAC(infusion) for the maintenance of analgesia throughout the first stage of labor. MLAC(infusion) was determined using the up-down sequential analysis described by Dixon and Massey. The MLAC(infusion) of epidural bupivacaine was 0.063% (95% confidence interval, 0.058-0.068) and 0.019% (95% confidence interval, 0.000-0.038) in the IV and EPI groups respectively. A continuous infusion of fentanyl was more than three times as potent when administered by the epidural than by the IV route. This marked increase in potency for the epidural route is highly suggestive for a predominantly spinal mechanism of action for infused epidural fentanyl under the conditions of this study., Implications: This study determined the median effective concentration for epidural infusions of bupivacaine during labor analgesia. Coadministered epidural fentanyl infusions were more than three times more potent than IV fentanyl infusions, suggesting a predominantly spinal mechanism of opioid action under these study conditions.