Sublingual sufentanil for patient-controlled analgesia during labor induction for pregnancy termination: an effective and well-tolerated approach.

BACKGROUND: Effective pain management during labor induction for pregnancy termination is essential. However, to date, no effective treatment has been identified. The primary aim of this study was to measure the analgesic efficacy of a sufentanil sublingual tablet system during pregnancy termination and patient satisfaction by comparing nulliparous and multiparous women. The secondary aims were to characterize the safety profile by reporting any side effects or adverse events and to determine the need for rescue therapy. METHODS: We conducted an observational, retrospective, single-center study involving 48 women. The data retrieved for analysis included the total and hourly doses of sublingual sufentanil, evaluations of pain management satisfaction using a 5-point rating scale (ranging from 1, indicating "not satisfied" to 5, denoting "completely satisfied"), occurrence of side effects and adverse events, and the rate of rescue analgesic use. Categorical and numerical variables were compared between the two groups, and a correlation analysis was performed. RESULTS: The median total dose of sufentanil required was 60 mcg. Nulliparous women required a higher dose of sufentanil compared with multiparous women (105 mcg vs. 45 mcg; P = 0.01). Additionally, they underwent a longer labor, indirectly measured by the time of device usage (625 min vs. 165 min; P = 0.05). Regarding satisfaction, 40 patients (83.4%) were satisfied or completely satisfied, whereas only 8 patients (16.6%) reported dissatisfaction. Multiparous women exhibited higher satisfaction levels than did nulliparous women (P = 0.03). No adverse events were reported, and the most common side effects were nausea and vomiting (31.2%). Four patients (12%) required acetaminophen due to insufficient analgesia, with only one patient necessitating a switch to intravenous morphine. CONCLUSIONS: Sublingual sufentanil was effective in both nulliparous and multiparous women with minimal side effects. Therefore, sublingual sufentanil can be considered a valid strategy for analgesia during labor induction for pregnancy termination.

Opioid-free anesthesia: a practical guide for teaching and implementation.

Opioid-free anesthesia (OFA) represents an innovative approach that prioritizes patient safety, reduces the risks associated with opioid use, and seeks to enhance recovery. Few descriptions regarding the practical and implementation aspects exist. This review serves as a practical guide on OFA teaching and application. We briefly discuss the historical use of opioids in anesthesia, side effects and their consequences. We discuss pedagogical avenues and challenges, as well as implementation of OFA in less experienced settings. Opioid use in anesthesia originally coexisted with OFA. During the last decades, the advent of multimodal analgesia has resulted in decreased opioid dosages both before and after surgery. Recently, OFA increased in popularity, supported by meta-analyses, due to reduced nausea and vomiting, with a potential, even if limited, impact on pain. OFA, as part of rational prescribing, may contribute to a more patient-centered approach. Different strategies for OFA implementation coexist. Educational aspects, leadership, guidelines, local guidance, and training are all important. We propose a framework for OFA implementation with concrete options, including patient preparation, choice of OFA pharmacological agents (according to type of surgery and patient), and postoperative care. Whilst opioids still have an important place in pain management, they have brought harms that we cannot ignore. Evidence for using opioid-sparing and OFA techniques continues to emerge and there is a need to personalize more approaches. In this review, we provide evidence-based, relatively simple methods that can be used in implementing and delivering OFA.

How to Modulate Peripheral and Central Nervous System to Treat Acute Postoperative Pain and Prevent Pain Persistence.

Chronic postoperative pain (CPSP) is a major issue after surgery, which may impact on patient's quality of life. Traditionally, CPSP is believed to rely on maladaptive hyperalgesia and risk factors have been identified that predispose to CPSP, including acute postoperative pain. Despite new models of prediction are emerging, acute pain is still a modifiable factor that can be challenged with perioperative analgesic strategies. In this review we present the issue of CPSP, focusing on molecular mechanism underlying the development of acute and chronic hyperalgesia. Also, we focus on how perioperative strategies can impact directly or indirectly (by reducing postoperative pain intensity) on the development of CPSP.

Safety of spinal anesthesia and analysis of cerebrospinal fluid in SARS-CoV-2 pregnant women undergoing cesarean section: an observational prospective study.

BACKGROUND: Systemic infection has always been considered a relative contraindication to neuraxial anesthesia, despite the fact that infectious complications are relatively uncommon. Pregnancy-related physiological changes and coronavirus disease (COVID-19) neurotropic features may facilitate the virus' entry into the central nervous system. The principal aim of this study was to test the safety of spinal anesthesia in "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2)-positive pregnant women and to examine cerebrospinal fluid (CSF) characteristics. METHODS: We conducted a prospective observational single-center study in asymptomatic or paucisymptomatic consecutive pregnant SARS-CoV-2 patients who underwent spinal anesthesia for cesarean section. Women with severe infection were excluded because they underwent general anesthesia. At the time of spinal anesthesia, we collected CSF samples, and then we performed a chemical-physical analysis to look for signs of inflammation and for SARS-CoV-2 genome. RESULTS: We included 26 women. No spinal anesthesia complications were reported in the perioperative period and after 2 months. All CSF samples were crystal clear, and all physical-chemical values were within physiological ranges: the median concentration of CSF/plasma glucose ratio was 0.66, IQR 0.5500 (0.6000-0.7100), and the average CSF protein concentration value was 23.2 mg/dl (SD 4.87). In all samples, genomes of SARS-CoV-2 and other neurotropic viruses were not detected. CONCLUSIONS: Spinal anesthesia was safe in SARS-CoV-2 pregnant women with mild disease; no clinical maternal complications were detected, and no CSF changes indicative of inflammatory or infectious diseases that would compromise the safety of the procedure were found.

Prolonged continuous wound infusion of local anesthetic and steroid after major abdominal surgery to reduce opioid consumption: a randomized, double-blind trial.

BACKGROUND: Continuous wound infusion (CWI) is effective for post-operative pain management, but the effect of prolonged infusions and the use of steroids in the infused mixture have never been addressed. We investigate the effect of prolonged CWI with ropivacaine 0.2% (R) over seven days and methylprednisolone (Mp) 1 mg/kg infused in the wound in the first 24 hours. METHODS: This is a randomized, double blind, phase III trial (RCT) in major abdominal surgery with laparotomy. After a 24-hours pre-peritoneal CWI of R-Mp, patients were randomized to receive either R-Mp or placebo for the next 24 hours. Then, patient-controlled CWI with only ropivacaine 0.2% or placebo (according to the randomization group) was planned between 48 hours and seven days after surgery. Morphine equivalents at seven days were analyzed, together with any catheter- or drug-related side effect and PPSP at 3 months. RESULTS: We enrolled 120 patients (63 in the CWI group, 57 in the placebo group). Prolonged CWI did not reduce opioid consumption in the first seven postoperative days (P=0.08). CWI was associated with reduced consumption of non-opioid analgesics (P=0.03). Most of the patients continued to require bolus in the surgical wound beyond 48 hours. PPSP prevalence was not different between groups. CONCLUSIONS: Prolonged infusion with R-Mp is safe and effective but did not reduce opioid consumption in the seven days after surgery or PPSP prevalence.

Erector spinae plane versus fascia iliaca block after total hip arthroplasty: a randomized clinical trial comparing analgesic effectiveness and motor block.

BACKGROUND: Ultrasound-guided supra-inguinal fascia iliaca block (FIB) provides effective analgesia after total hip arthroplasty (THA) but is complicated by high rates of motor block. The erector spinae plane block (ESPB) is a promising motor-sparing technique. In this study, we tested the analgesic superiority of the FIB over ESPB and associated motor impairment. METHODS: In this randomized, observer-blinded clinical trial, patients scheduled for THA under spinal anesthesia were randomly assigned to preoperatively receive either the ultrasound-guided FIB or ESPB. The primary outcome was morphine consumption 24 h after surgery. The secondary outcomes were pain scores, assessment of sensory and motor block, incidence of postoperative nausea and vomiting and other complications, and development of chronic post-surgical pain. RESULTS: A total of 60 patients completed the study. No statistically significant differences in morphine consumption at 24 h (P = 0.676) or pain scores were seen at any time point. The FIB produced more reliable sensory block in the femoral nerve (P = 0.001) and lateral femoral cutaneous nerve (P = 0.018) distributions. However, quadriceps motor strength was better preserved in the ESPB group than in the FIB group (P = 0.002). No differences in hip adduction motor strength (P = 0.253), side effects, or incidence of chronic pain were seen between the groups. CONCLUSIONS: ESPBs may be a promising alternative to FIBs for postoperative analgesia after THA. The ESPB and FIB offer similar opioid-sparing benefits in the first 24 h after surgery; however, ESPBs result in less quadriceps motor impairment.

Simulation-Based Medical Education and Training Enhance Anesthesia Residents' Proficiency in Erector Spinae Plane Block.

Background: Advances in regional anesthesia and pain management led to the advent of ultrasound-guided fascial plane blocks, which represent a new and promising route for the administration of local anesthetics. Both practical and theoretical knowledge of locoregional anesthesia are therefore becoming fundamental, requiring specific training programs for residents. Simulation-based medical education and training (SBET) has been recently applied to ultrasound-guided regional anesthesia (UGRA) with remarkable results. With this in mind, the anesthesia and intensive care residency program of the University of Milano-Bicocca organized a 4-h regional anesthesia training workshop with the BlockSim® (Accurate Srl, Cesena) simulator. Our study aimed to measure the residents' improvement in terms of reduction in time required to achieve an erector spinae plane (ESP) block. Methods: Fifty-two first-year anesthesia residents were exposed to a 4-h training workshop focused on peripheral blocks. The course included an introductory theoretical session held by a locoregional anesthetist expert, a practical training on human models and mannequins using Onvision® (B. Braun, Milano) technologies, and two test performances on the BlockSim simulator. Residents were asked to perform two ESP blocks on the BlockSim: the first without previous practice on the simulator, the second at the end of the course. Trainees were also also asked to complete a self-assessment questionnaire. Results: The time needed to achieve the block during the second attempt was significantly shorter (131 [83, 198] vs. 68 [27, 91] s, p < 0.001). We also observed a reduction in the number of needle insertions from 3 [2, 7] to 2 [1, 4] (p = 0.002), and an improvement aiming correctly at the ESP from 30 (58%) to 46 (88%) (p < 0.001). Forty-nine (94%) of the residents reported to have improved their regional anesthesia knowledge, 38 (73%) perceived an improvement in their technical skills and 46 (88%) of the trainees declared to be "satisfied/very satisfied" with the course. Conclusions: A 4-h hands-on course based on SBET may enhance first-year residents' UGRA ability, decrease the number of punctures and time needed to perform the ESP block, and improve the correct aim of the fascia.

Opioid-Free Anesthesia and Postoperative Outcomes in Cancer Surgery: A Systematic Review.

BACKGROUND: Surgery is an essential component of the treatment of solid tumors, but the perioperative course can be complicated by different factors (including anesthesia). Opioid-free anesthesia (OFA) may mitigate adverse outcomes of opioid-based anesthesia (OBA), but major questions remain on the actual impact in terms of analgesia and the improvement of surgical outcomes. To address this issue, we present a systematic review to evaluate the efficacy of OFA compared to OBA in the specific subset of cancer patients undergoing surgery. METHODS: following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), we searched MEDLINE, Embase and the Cochrane CENTRAL Library to include randomized controlled trials (RCTs) on adults undergoing oncological surgery, comparing OFA and OBA up to March 2022. Additional papers were added from the reference lists of identified sources. Papers were manually reviewed by two independent authors to ascertain eligibility and subsequent inclusion in qualitative analysis. RESULTS: only two studies were eligible according to inclusion criteria. It was not possible to perform any meta-analysis. The two studies included patients undergoing prostate and gynecologic surgery on 177 patients, with significant heterogeneity in the outcomes. CONCLUSIONS: randomized controlled trial specifically addressed to cancer patients are lacking. A knowledge gap exists, neither confirming nor rejecting the capacity of OFA to improve early postoperative outcomes in cancer surgery. Long-term consequences on specific oncological outcomes are far from being elucidated. We expect a growing body of literature in the coming years. Further studies are required with homogeneous methodology and endpoints.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

Opioid free anesthesia: evidence for short and long-term outcome.

The introduction of synthetic opioids in clinical practice played a major role in the history of anesthesiology. For years, anesthesiologists have been thinking that opioids are needed for intraoperative anesthesia. However, we now know that opioids (especially synthetic short-acting molecules) are definitely not ideal analgesics and may even be counterproductive, increasing postoperative pain. As well, opioids have revealed important drawbacks associated to poor perioperative outcomes. As a matter of fact, efforts in postoperative pain management in the last 30 years were driven by the idea of reducing/eliminating opioids from the postoperative period. However, a modern concept of anesthesia should eliminate opioids already intra-operatively towards a balanced, opioid-free approach (opioid-free anesthesia - OFA). In OFA drugs and techniques historically proven for their efficacy are combined in rational and defined protocols. They include ketamine, alpha-2 agonists, lidocaine, magnesium, anti-inflammatory drugs and regional anesthesia. Promising results have been obtained on perioperative outcome. For sure, analgesia is not reduced with OFA, but it is effective and with less opioid-related side effects. These benefits may be of particular importance in some high-risk patients, like OSAS, obese and chronic opioid-users/abusers. OFA may also increase patient-reported outcomes; despite it is difficult to specifically rule out the effect of intraoperative opioids. Finally, few data are available on long-term outcomes (persistent pain and opioid abuse, cancer outcome). New studies and data are required to elaborate the optimal approach for each patient/surgery, but interest and publication are increasing and may open the road to the wider adoption of OFA.

Genetics and Opioids: Towards More Appropriate Prescription in Cancer Pain.

Opioids are extensively used in patients with cancer pain; despite their efficacy, several patients can experience ineffective analgesia and/or side effects. Pharmacogenetics is a new approach to drug prescription based on the "personalized-medicine" concept, i.e., the ability of tailoring treatments to each individual's genetic/genomic profile. Pharmacogenetics aims to identify specific genetic variants that influence pharmacokinetics and pharmacodynamics of drugs, better determining their effectiveness/safety profile. Opioid response is a complex scenario, but some gene variants have shown a correlation with pain sensitivity, as well as with opioid metabolism and clinical efficacy/adverse events. Although questions remain unanswered, some of these gene variants may already be used to identify specific patients' phenotypes that are more prone to experience better clinical response (i.e., better analgesia and/or less adverse events). Once adopted, this approach to opioid prescription may improve a patient's outcome. This review summarizes the available data on genetic variants and opioid response: we will focus on basic pharmacogenetic and its impact in the clinical scenario discussing how they may lead to more appropriate opioid prescription in cancer patients.

Effects of Environmental Factors on Severity and Mortality of COVID-19.

Background: Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. Methods: We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Findings: Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, p < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, p = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Interpretation: Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.

Sublingual sufentanil tablet system for postoperative analgesia after gynecological surgery.

BACKGROUND: Gynecological procedures are among the most frequent surgical interventions, and effective postoperative analgesia is associated with improved patient comfort. Despite the efficacy of neuraxial analgesia, limitations and potential complications have led to seek new strategies for pain relief. A novel, pre-programmed, non-invasive, hand-held system (Sufentanil Sublingual Tablet System [SSTS]) displayed good results in the orthopedic setting. However, it has never been applied in gynecological procedures. METHODS: This retrospective observational case series evaluates receiving SSTS for postoperative analgesia. Data from 42 consecutive patients undergoing open gynecological surgery with Pfannenstiel incision were retrieved from medical charts in two Italian hospitals. RESULTS: The mean age was 49±11 years, and mean BMI was 24.4±4.6 kg/m2. We reported effective relief on both static and dynamic pain all along the perioperative period, with good effect on patient's rehabilitation. Postoperative nausea and vomiting is the most common adverse effect, but the incidence was strongly decreased with medical prophylaxis. SSTS was easy to prepare, use and manage by both patients and care providers. CONCLUSIONS: SSTS may be an interesting option for postoperative analgesia in gynecologic procedures. The efficacy in the management of dynamic pain is an interesting outcome that needs to be compared with the other standards of pain management, such as neuraxial techniques. Rigorous studies are required to give conclusive evidence, but this is the first report, to our knowledge, of SSTS use in open gynecologic procedures. Our preliminary experience encourages the routine application of SSTS in gynecologic surgery and will help designing future randomized controlled trials on the topic.

In vitro and in vivo quantification of chloroprocaine release from an implantable device in a piglet postoperative pain model.

BACKGROUND: The pharmacokinetic properties and clinical advantages of the local anesthetic chloroprocaine are well known. Here, we studied the pharmacokinetic profile of a new hydrogel device loaded with chloroprocaine to investigate the potential advantages of this new strategy for postoperative pain (POP) relief. MATERIALS AND METHODS: We performed both in vitro and in vivo analyses by considering plasma samples of four piglets receiving slow-release chloroprocaine. To quantify chloroprocaine and its inactive metabolite 4-amino-2-chlorobenzoic acid (ACBA), a HPLC-tandem mass spectrometry (HPLC-MS/MS) analytical method was used. Serial blood samples were collected over 108 hours, according to the exposure time to the device. RESULTS: Chloroprocaine was consistently found to be below the lower limit of quantification, even though a well-defined peak was observed in every chromatogram at an unexpected retention time. Concerning ACBA, we found detectable plasma concentrations between T0 and T12h, with a maximum plasma concentration (Cmax) observed 3 hours after the device application. In the in vitro analyses, the nanogel remained in contact with plasma at 37°C for 90 minutes, 3 hours, 1 day, and 7 days. Chloroprocaine Cmax was identified 1 day following exposure and Cmin after 7 days, respectively. Additionally, ACBA reached the Cmax following 7 days of exposure. CONCLUSION: A thorough review of the literature indicates that this is the first study analyzing both in vivo and in vitro pharmacokinetic profiles of a chloroprocaine hydrogel device and is considered as a pilot study on the feasibility of including this approach to the management of POP.

Update on Selective Regional Analgesia for Hip Surgery Patients.

In hip surgery, regional anesthesia offers benefits in pain management and recovery. There are a wide range of regional analgesic options; none have shown to be superior. Lumbar plexus block, femoral nerve block, and fascia iliaca block are the most supported by published literature. Other techniques, such as selective obturator and/or lateral femoral cutaneous nerve blocks, represent alternatives. Newer approaches, such as quadratus lumborum block and local infiltration analgesia, require rigorous studies. To realize long-term outcome benefits, postoperative regional analgesia must be tailored to the individual patient and last longer.

Immune function after major surgical interventions: the effect of postoperative pain treatment.

INTRODUCTION: Impaired immune function during the perioperative period may be associated with worse short- and long-term outcomes. Morphine is considered a major contributor to immune modulation. PATIENTS AND METHODS: We performed a pilot study to investigate postoperative immune function by analyzing peripheral blood mononuclear cells' functionality and cytokine production in 16 patients undergoing major abdominal surgery. All patients were treated with intravenous (i.v.) patient-controlled analgesia with morphine and continuous wound infusion with ropivacaine+methylprednisolone for 24 hours. After 24 hours, patients were randomized into two groups, one continuing intrawound infusion and the other receiving only i.v. analgesia. We evaluated lymphoproliferation and cytokine production by peripheral blood mononuclear cells at the end of surgery and at 24 and 48 hours postoperatively. RESULTS: A significant reduction in TNF-α, IL-2, IFN-γ and lymphoproliferation was observed immediately after surgery, indicating impaired cell-mediated immunity. TNF-α and IFN-γ remained suppressed up to 48 hours after surgery, while a trend to normalization was observed for IL-2 and lymphoproliferation, irrespective of the treatment group. A significant inverse correlation was present between age and morphine and between age and lymphoproliferation. No negative correlation was present between morphine and cytokine production. We did not find any differences within the two groups between 24 and 48 hours in terms of morphine consumption and immune responses. CONCLUSION: A relevant depression of cell-mediated immunity is associated with major surgery and persists despite optimal analgesia. Even though morphine may participate in immunosuppression, we did not retrieve any dose-related effect.