BackgroundRobotic instruments are increasingly being used in total knee arthroplasty (TKA). The adoption of robotics has allowed surgeons a new level of precision and facilitated the adoption of a kinematic approach in TKA. We sought to examine one surgeon’s transition from a traditional mechanical alignment technique to a modified kinematic approach by comparing short-term recovery outcomes of robotic TKA patients with those who underwent traditionally instrumented TKAs.MethodologyWe examined six-week and six-month postoperative data from 99 traditionally instrumented, mechanically aligned and 66 kinematically aligned robotic TKA patients between January 2021-October 2021 and October 2021-April 2022, respectively. Robotic surgery was performed with VELYS™  a semi-active, imageless, table-affixed, robotic TKA solution.ResultsRobotic and traditionally instrumented TKAs did not differ significantly in any functional outcome measures examined, including pain scores, use of assistive devices, or range of motion at six weeks postoperatively. Robotic TKA patients had a better range of motion in knee flexion than traditional TKA patients at six months postoperatively. There were no differences in surgical complications or rates of manipulation under anesthesia within one year postoperatively. Robotic surgery tourniquet times exhibited a steep drop off and equaled traditional methods after only two robotic surgeries were performed.ConclusionsTransition to a kinematic, semi-active, robotic TKA demonstrated encouraging results by demonstrating acute-period recovery of function consistent with the current standard of care, as well as a better range of motion at six months postoperatively. The learning curve of this new-to-market device was shorter than previous research on the transition to robotic TKA. Clear advantages of transitioning to robotic instrumentation by any specific functional measure are yet to be elucidated. Further randomized trials are necessary to characterize long-term outcomes. Robotic surgical devices have displayed promising results in various surgical fields due to their ability to operate more precisely than even the best-trained surgeons. Total knee arthroplasty (TKA) robots can follow surgical plans that are determined by examining patient anatomy preoperatively with radiographs (image-based systems) or intraoperatively by target mapping bony landmarks (imageless systems). During TKA, robotic devices prevent tibial or femoral cuts that deviate from the surgical plan; thus, these devices facilitate more precise joint alignment angles that are in line with the planned joint axis . ClinicaThe implementation of robotics may be limited initially by the training and learning curve, which manifests itself in extended operative times. An analysis of surgeons transitioning to robotic approaches showed that surgeons took 6-11 surgeries to learn the new techniques and stabilize surgery times . PreviouOur study objective was to determine the effect that transitioning to a novel robotic surgical approach to TKA had on short-term patient recoveries. Additionally, we sought to examine the learning curve of this new-to-market robotic solution and determine differences if any from established research on the transition to robotics. To our knowledge, this study is the first to examine an organic clinical transition to this specific device. Our hypothesis has the following two main elements: transitioning to robotic instrumentation with kinematic alignment would improve short-term patient recoveries, and the device learning curve would be similar to other robotic solutions.Study designThis was a retrospective review of medical records examining patients who received either robot-guided and kinematically aligned TKA procedures or traditionally instrumented mechanically aligned TKA procedures. This study received a patient informed consent exemption from the University of Rochester Office for Human Subject Protection on May 31, 2022 (Study ID: STUDY00007211). These surgeries and the subsequent data collection occurred from January 2021 to October 2021 for the traditionally instrumented TKA procedures and from October 2021 to April 2022 for the robotic instrumentation TKA procedures. This time frame represents the study surgeon’s transition from traditional to robotic TKA, with the complete transition for most TKA cases occurring in early November 2021. All TKAs were performed by the senior author and used the same implant design, the Depuy Attune Cruciate Retaining implant . Robotic instrumentation was conducted with the VELYS™ robotic solution . This robotic solution is new to the market, having just been FDA 501k approved for use in early 2021.Inclusion criteria included patients receiving primary TKA by either traditional instrumentation with mechanical alignment or robotic instrumentation with kinematic alignment. Exclusion criteria included revision surgery, age below 30 or above 89, lack of six-week follow-up data in the form of patient office or telemedicine visit note, prior major knee trauma or arthritis related to traumatic injury, unexpected major deformity to the knee, and unavailability of patient medical records.We identified 69 robotic primary TKAs and 105 traditionally instrumented TKA patients within the study duration. Three robotic and three traditional TKA patients had prior previous major trauma to the knee, and three traditional TKA patients did not have a follow-up at six weeks postoperatively. All identified primary TKA patients were between the ages of 30 and 89, leaving a final sample size of 66 robotic TKA patients and 99 traditionally instrumented TKA patients. We examined typical clinical indicators of short-term recovery following TKA, namely, goniometer-measured range of motion in degrees of flexion and extension, patient use of assistive devices for mobility, pain level, and other patient-reported outcome measures, such as depression scores. All of these data points were collected as standard practice at the patients’ six-week follow-up visit. We also examined rates of surgical complications, including the incidence of infection and hospital readmission within the first six weeks postoperatively. Patient knee pain score was determined by patient self-report of their pain on a 1-10 visual analog scale at their six-week postoperative follow-up. Finally, we examined operative tourniquet time as a proxy measure for surgical efficiency.Surgical techniquesThe traditional technique was measured resection, addressing the femur first. Femoral instrumentation was anterior referencing using an intramedullary guide set at 5° valgus for varus knees and 3-4° valgus for valgus knees. Femoral component rotation referenced the line parallel to the transepicondylar axis. Tibial preparation utilized an extramedullary referencing guide set at neutral, with a 5-7° slope, determined by preoperative radiographic assessment. A standard median parapatellar approach was employed. Balancing and final polyethylene component selection were performed during trial placement.Robotic-assisted, modified kinematic technique aimed to preserve final mechanical alignment between 3° varus and valgus, per long-established recommendations regarding mechanical alignment following TKA . A mediaStatistical analysisAll data collection and statistical analyses were performed using Microsoft Excel® software. Data normality for all continuous variables was established with the Shapiro-Wilk test, with an alpha value of less than 0.05 signifying non-normality. Reported p-values for normally distributed continuous variables are two-tailed t-tests assuming equal variances. Reported p-values for non-normally distributed continuous variables are Mann-Whitney U tests. P-values reported for categorical variables are chi-squared test values. A p-value of 0.05 was used as the cutoff for statistical significance. Power analysis revealed that a sample size of at least 126 subjects would be required to detect a 5° difference in ROM, assuming a two-sided alpha of 0.05 and a desired power of 0.8, and a sample of 80 patients would be required to detect a five-minute change in average operation time. Based on this assessment, we examined patients in the aforementioned time parameter, with a final sample of 165 patients.There were no differences in relevant patient demographics/biometrics between groups Table .A summary of the comparison between traditional instrumentation and robotic instrumentation is presented in Table Data comparing the early to late transition to the robot are summarized in Table Surgery times with the robotic system were similar to traditional instrumentation after the first two surgeries performed. Tourniquet times from robotic surgeries three through 10 were no different from surgeries 11 through 66 Table .Surgery times exhibited a steep drop following the second surgery and essentially equalized with traditional instrumentation methods thereafter Figure .The robot under investigation in this study is unique in that it offers the ability to use a kinematic alignment technique or the traditional mechanical alignment. The study surgeon chose to use kinematic alignment. The current standard in TKA is to restore alignment to a neutral mechanical axis or to a marginally valgus axis. However, in patients presenting with constitutional varus alignment, restoring their joint to a neutral mechanical axis may deviate their limb alignment unnaturally . ConstitOur data suggest two key findings. First, a robotically instrumented, kinematically aligned approach to TKA demonstrated short-term recovery as well as manually instrumented, mechanically aligned TKAs. Second, imageless, semi-active robotic instrumentation demonstrated a short learning curve for our study surgeon.Robotic instrumentation with kinematic alignment had similar short-term recovery as traditional methods. The ability of a patient to walk unassisted is one of the key features of proper recovery following TKA. As such, discontinuation of assistive devices is a litmus test to gauge patient pain and recovery of function. The two patient groups used assistive devices at similar rates six weeks postoperatively, indicating that robotic instrumentation with kinematic alignment did not significantly change patients’ short-term functional status. Additionally, recovery of the full range of motion is another key short-term recovery indicator that was not different between robotic and traditional methods, indicating a similar regain of function. Typical recovery goals for TKA propose that patients should be able to achieve 115° of knee flexion after knee replacement. Previous research has shown that achieving a range of motion of 105° of flexion by one-month post-TKA is associated with meeting the long-term range of motion goals . Converscritical transition robotic TKA patients were no different than the next 46, indicating that any learning curve from the new device had no impact on patients’ acute surgical recoveries. Equal outcomes were achieved starting from the first surgeries. This addresses the common concern that learning a new technique would impact patient recovery, one that dissuades surgeons of all types from adopting new techniques.Previous research has established that surgeons require around 15 uses with robotic instrumentation to achieve similar surgery times to their well-practiced traditional methods . AdditioThe first and most salient limitation of this study was its retrospective nature. Patients were not randomly assigned to groups. Hence, while we found no differences in major patient biometrics/demographics, it cannot be said with certainty that there were no differences between patients receiving traditional or robotic TKAs. The retrospective nature of this study was a benefit in some ways. Primarily because the analysis of the surgeon’s transition was organic and represents how a surgeon’s transition to a new technique would normally occur in clinical practice. The study design of only using one surgeon’s transition also confers strengths and limitations. It limits generalizability to the greater population of arthroplasty surgeons, as this surgeon’s specific skillset and aptitude for robotic methods may be different than other surgeons. However, this design did greatly increase the internal validity of our findings. Examining a single surgeon’s data reduces variability, guaranteeing uniformity of surgical techniques. Additionally, the study design examined only acute-period functional recovery and did not have available data for preoperative values for the range of motion, joint alignment, or pain. We cannot make any claims regarding the effects of these surgical techniques or devices on implant longevity or long-term outcomes. Additionally, we cannot make claims regarding causality. Finally, statistical power may have been limited due to the sample size. While continuous variables were well-powered for this study, categorical variables require much larger samples for adequate power. This was limited by this study’s goal of examining a specific smaller transitional period of patients.Acute-period functional recoveries following robotically instrumented and kinematically aligned TKAs were similar to those from traditionally instrumented TKAs. Patients receiving kinematically aligned, robotic TKAs had better knee flexion at six months postoperatively, although the clinical significance of this difference is yet to be established. Imageless, semi-active robotic instrumentation demonstrated a much shorter learning curve in a single-surgeon analysis than previous research on robotic transitions has shown. This study, while retrospective, remains highly clinically relevant. Analysis of new-to-market surgical technologies to determine any differences in patient functional outcomes, complication rates, and operative efficiency is critical information for other surgeons considering the implementation of these devices and techniques into their practice.


Using the numerical verbal scale, the primary outcome assessed was the patient’s pain in the immediate postoperative period (POI). The secondary outcome comprises the assessment of opioid consumption in the IPP by quantifying the medication used in an equianalgesic dose of morphine expressed in milligrams, in the immediate post-anesthetic recovery period, 6h, 12h, and 24h after surgery.  the EVN scores in the LBA and ESPB group in the POI had a mean of 0,8  vs 0,58  in the post-anesthesia care room (REPAI), 1,06  vs 1,30  in 6 hours of POI, 0,84  vs 1,19  within 12 hours of POI and 0,95  vs 1  within 24 hours of POI, all with p>0.05. Mean opioid consumption in the BAL and ESPB groups in the POI was 12.9 (± 10.4) mg vs 14.9 (±10.2) mg, respectively, with p = 0.416. Sixteen participants in the ESPB group and seventeen in the BAL group did not use opioids during the first 24 hours of the PO analyzed.  local anesthesic block and ESP block techniques showed similar results in terms of low pain scores and opioid consumption during the period evaluated. Therefore, due to the importance of promoting efficient and safe analgesia to the patient, in addition to the concern regarding the use of opioids after surgical procedures, we conducted this comparative study between ESPB anesthetic block and local anesthetic block (LAB), to evaluate pain and opioid consumption in the IPO of patients undergoing these techniques in VATS procedures.This is a randomized, blind clinical trial, carried out at the Hospital Nossa Senhora das Graças (HNSG) in Curitiba, Paraná State, Brazil, approved by the Ethics in Research Committee of the Faculdades Pequeno Príncipe (FPP), under opinion number 4,425,817. This study was previously registered in the Brazilian Clinical Trials Registry system under the reference code U1111-1264-5523.We included patients classified by the American Society of Anesthesiologist (ASA) between 1 and 3, aged 18 years or older, with surgical indication for the treatment of any thoracic diseases, who could be performed by minimally invasive, uni or multiportal techniques, carried out from December 2020 to November 2021.We excluded patients with absolute contraindication to VATS procedures, anesthetic drugs used during the procedure, and analgesic medications used in the postoperative period. We also excluded patients with a history of illicit drug or opioid abuse, with a medical diagnosis of dementia, delirium, or other conditions that affect verbal response, pregnant women, emergency procedures, and patients with difficulty understanding the pain scales used in the protocol.The randomization process was performed using a table of random numbers, where patients who received an odd number were allocated to the intervention group (ESPB), and those who received an even number were allocated to the control group (LAB). Each participant received individualized surgical treatment, using an already established surgical technique, considered safe and effective, according to a specific indication for each case, regardless of the group in which they were allocated.-After initial pre-oxygenation, all patients underwent total intravenous anesthesia, with continuous infusion of remifentanil 0.2-05mcg/kg/min and target-controlled infusion (TCI) propofol at a dose of 2.5-3.5ng/ml, to maintain a bispectral index (BIS) between 40-60. For neuromuscular blockade, cisatracurium was used at induction at a dose of 0.15mg/kg, with further doses of 0.05mg/kg to maintain a sequence of four stimuli (TOF) of 0. All patients in the study were intubated with a double-lumen cuffed endobronchial tube, between 35-39F, maintaining single-lung ventilation during the procedure. The anesthetic blocks used in the study were performed only after general anesthesia, as is already routine in the hospital service, thus maintaining the blinding of the group allocation to patients-Patients randomized to the control group received a solution with 15mg of 0.5mg/ml levobupivacaine (corresponding to 30ml), added to 4mg of 4mg/ml dexamethasone disodium phosphate (corresponding to 1ml) and 150µg of 150µg/ml clonidine hydrochloride (corresponding to to 1ml), which were injected into the surgical incisions using 20 or 22-gauge needles, always by the same team of two surgeons. Complete local block was performed by applying the solution to the skin, costal periosteum, and parietal pleura, approximately five minutes before the surgical incisions to position the trocarsth thoracic vertebra (T4). After, the transducer was slid medially to visualize the T4 transverse process , with a deepening of the pleura in the image.Anesthetic block in patients randomized to the intervention group occurred with the patient in a sitting or lateral decubitus position, after general anesthesia, with a high-frequency linear transducer placed in cephalocaudal or longitudinal orientation over the paramedian line, to visualize the ribs and pleura at the level of the of 4® needle on the skin, with an angle of 30° to 45° about the ultrasound beam, facing the transverse process , administered when requested by the patient, to maintain the verbal score of the pain scale in values less than fourThe primary outcome of this study was the patient’s pain level in the immediate postoperative period and throughout the first 24 hours after the procedure, at specific times, using a verbal numerical scale (VNS). Patients were to measure the pain at four different times, still in the Anesthetic Recovery Unit (REPAI) or at the time of the patient’s arrival at the ICU, at 6, 12, and 24 hours after the procedure. The VNS quantifies the pain on a scale from zero to ten, zero corresponding to absence of pain, and ten, the most intense pain possibleThe secondary outcome was the cumulative consumption of opioids during the first 24 hours of the PO period, expressed as an equianalgesic dose of IV morphine in milligrams (MEQs). Patients who were discharged before 24 hours of PO had MEQs dose evaluated until discharge.Data such as sex, age, initial diagnosis, surgery performed, surgery time in minutes, and PO drain use were also documented and used for comparative measures.The sample size calculation was performed using the Welch-Satterthwaite T-TesttAccording to the study by Zheng et al., the mean pain scores in the postoperative period of patients undergoing VATS procedures was 5.4 points on a scale ranging from 0 to 10For quantitative variables, the distribution of normality was verified using the Shapiro-Wilk test and the results were reported using the mean (± standard deviation) or median (interquartile range). As for qualitative variables, the values of each group were expressed as an absolute number To verify the statistical significance between the data, were applied the Mann-Whitney, t, ANOVA, Kruskal-Wallis, or Friedman tests. For all tests, we considered values of p<0.05 sufficient to reject the null hypothesis and deem the result statistically significant® statistical software, version 2.2.1All statistical analyses and construction of graphs and tables were performed using the JAMOVIThe flowchart of the Consolidated Standards of Reporting Trails (CONSORT)16 of this study is represented in Categorical data such as age, sex, duration of surgery, and type of procedure performed were compared between groups, as shown in The VNS pain scores in both groups throughout the analyzed time interval showed no statistically significant differences, with p values >0.05 at all times, as seen in Sixteen participants in the ESPB group and seventeen in the LAB group did not use opioids during the first 24 hours of the PO analyzed. There was no significant difference in 24-hour opioid consumption between the two groups, with p=0.416.When analyzing only the 21 patients who underwent lobectomies or segmentectomies in the LAB group, the mean pain in the REPAI/ICU was 0.62 (±1.80), and after 24 hours of IPO, 1.14 (±1.93). For the ESPB group, of the 17 patients who underwent the same procedures, the mean pain in the REPAI/ICU was 0.94 (±2.68), and 24 hours after the procedure, 0.94 (±1.34). The mean opioid consumption in these patients was 8.19mg (±8.44) and 7.06mg (±9.49) for the LAB and ESPB groups, respectively. When comparing these variables between groups, there was no statistically significant difference in any of them, with p values >0.05.,,,,ESPB has the ability to block the dorsal and ventral branches of the spinal nerves through the craniocaudal spread of up to four dermatomes above and below the injection site, increasing its analgesic efficiency during surgery and in the postoperative periodWe identified no similar study in the literature, in the form of a randomized clinical trial comparing LAB and ESPB in patients undergoing VATS, evaluating pain and opioid consumption by patients in the IPO.,,In this study, both groups showed similar results in pain control. In both the ESPB and LBA groups, the results pointed to adequate analgesic efficacy after VATS. The VNS pain score recorded by 75.3% patients in both groups was null or did not exceed score 4 at any of the postoperative follow-up moments, corroborating the findings of other researchersth hour of the IPO, the mean pain in VNS found by other authors was 3.33 (±0.48)When analyzing the groups separately according to the data in Of the few studies available that assess the pain of patients in the postoperative period of VATS procedures when submitted to local anesthetic block, most of them analyze only patients who underwent segmentectomies or lobectomies. Based on this principle, from our patients in the LAB group who underwent only these two procedures, the mean pain in the REPAI and in 24 hours of the IPO were 0.62 (±1.80) and 1.14 (±1.93), respectively. When compared to other studies, the average found for REPAI was 8.3 (±2.1) and 2.3 (±1.3) in 24 hours of the IPO5. In addition, regardless of the surgical procedure performed with this type of anesthetic block, we observed no significant difference in postoperative pain control, with the overall mean of pain on the VNS in the REPAI/ICU of 0.8 (±1.89) and 0.95 (±1.88) 24 hours after surgery.Opioid consumption can also be an objective variable for pain assessment, since pain quantification in scales can suffer social, psychological, and cultural interferencesAs for the LAB group, in a clinical study evaluating patients undergoing only lobectomies and segmentectomies who received 0.5% ropivacaine local anesthetic blockade, the mean drug consumption in 24 hours was 42mg (± 29.58)In none of the studies discussed above the non-use of opioids was described by some portion of patients. In our research, seventeen patients from the LBA group and sixteen from the ESPB group did not use this class of drugs during the 24 hours analyzed. During this period, the excessive use of the substance is responsible for important side effects that have a negative impact on the patient’s recovery, such as respiratory depression, increased risk of bleeding, and gastrointestinal disorders,It is important to emphasize that there are limitations in this clinical trial. Despite randomization, there was a difference in the number of patients undergoing different types of surgeries between the study and control groups. It is known that procedures such as lobectomies may be associated with more significant postoperative pain and may influence resultsThere was no statistically significant difference between the groups undergoing LAB and ESPB blocks in terms of postoperative pain control and opioid consumption in the IPO of VATS procedures. Both preemptive anesthesia techniques were effective in pain control and capable of promoting low intravenous use of opioids. Eventual differences between the techniques need to be studied with a greater number of patients and new pain assessment protocols.


Although laparoscopic surgery provides earlier recovery, less morbidity and hospital stay, however, severe pain is still a problem after it. Duloxetine has been recently used in postoperative pain management. We tested perioperative duloxetine to evaluate its effect on patients undergoing laparoscopic colorectal cancer surgery.Sixty patients were enrolled in this study divided into two equal groups; duloxetine group each patient received an oral duloxetine capsule (60 mg) 1st dose at night before surgery, the 2nd dose 1 h preoperative, and the 3rd dose 24 h postoperative. Placebo group received placebo capsules at the same times. The cumulative morphine consumption in 48 h, postoperative VAS score, quality of recovery (QoR-40 score), sedation, and adverse effects were evaluated.P < 0.01). Patients in Duloxetine group were more sedated in all the 48 h postoperatively in comparison to placebo group.Duloxetine group had lower VAS scores compared to placebo group, (3 ± 0.69) VS. (4.17 ± 0.83), (2.5 ± 0.6) VS. (4.3 ± 0.9), (2.2 ± 0.7) VS. (3.9 ± 0.6), (1.6 ± 0.7) VS. (3.6 ± 0.8), (1.1 ± 0.8) VS. (3.7 ± 0.7), (0.7 ± 0.7) VS. (3.5 ± 0.8), (0.6 ± 0.7) VS. (3.5 ± 0.8) respectively, P ˂0.01. The cumulative morphine consumption was significantly reduced in the Duloxetine group compared to the placebo group (4.6 ± 2.9 vs. 11.3 ± 1.7 mg), P < 0.01. The total QoR-40 score for duloxetine group was (180.8 ± 4.5) vs. (156 ± 5.9) in placebo group (Perioperative duloxetine had reduced postoperative pain, decreased opioid consumption, and improved the quality of recovery in patients undergoing laparoscopic colorectal surgery. GLOBOCAN 2018 reported that colorectal cancer (CRC) is the third most deadly and fourth-most common cancer worldwide . The lapMulti-modal analgesia is advocated for perioperative pain management, to reduce opioid use and its associated adverse effects . Multi-mDuloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) commonly prescribed for the treatment of major depression and anxiety; it has also been used in the treatment of chronic pain conditions . DuloxetWe hypothesized that the incorporation of perioperative oral duloxetine doses would produce a reduction in postoperative pain intensity, opioid consumption, and quality of recovery for patients subjected to colorectal surgery.This study is a prospective, randomized, double-blinded, placebo-controlled trial. It was done after obtaining approval from both the local ethics committee and the Institutional Review Board (IRB) from the South Egypt Cancer Institute, Assuit University, Assuit, Egypt and strictly followed the regulations and amendments of Helsinki Declaration. Informed written consent was obtained from all patients. The study was recorded at Clinical trials, identifier: NCT04294953 at 4/3/2020, and conducted according to the Consolidated Standards of Reporting Trials (CONSORT) statement.The inclusion criteria were: adult patients with ASA I-III, aged 18–65 years and, scheduled for laparoscopic colorectal surgery for cancer colon. The exclusion criteria were: Patients that have an allergy to the study drug, abnormal liver or renal function tests, a chronic opioid user (> 3 months), being on gabapentin or pregabalin (> 3 months), antidepressant drugs, patients with psychiatric disorders, pregnant females, unable to express their pain or patient refusal.The primary aim of our study is to evaluate the efficacy of perioperative duloxetine on postoperative morphine consumption after colorectal surgery. The secondary aims include its effect on VAS pain scores and postoperative quality of recovery.Sixty patients were randomized by the use of a computer-generated table of random numbers in a 1:1 ratio into 2 groups and concealed in an opaque and sealed envelope.Each patient received an oral duloxetine capsule of 60 mg 12 h before surgery, the 2nd dose of 60 mg 1 h preoperative and, the 3rd dose of 60 mg 24 h postoperative.Each patient received a placebo capsule at the same scheduled times. The placebo capsule was prepared by the hospital pharmacy to ensure that active duloxetine and placebo capsules were identical.The patient’s follow-up was conducted by an anaesthesia resident blinded to the study. The attending anaesthesiologist, surgeon and data-collecting person were unaware of the patient assignment.All patients were instructed on how to evaluate their pain using VAS   scoring The anaesthetic protocol was standardized for all patients. Basic monitoring  was attached. IV access was inserted and 500 ml of normal saline was given preoperative. Anesthesia was induced with fentanyl  2 µg/kg, propofol  1–2 mg/kg, lidocaine 1.5 mg/kg and rocuronium  0.5 mg/kg was administered to facilitate endotracheal intubation. Anesthesia and muscle relaxant were maintained by isoflurane 1 to 1.5 MAC  in a 50% oxygen/air mixture and rocuronium 0.15 mg/kg respectively. Additional intraoperative analgesia consisting of IV boluses of 25 µg fentanyl was given as determined by fluctuation in vital signs . At the end of the surgery, a dose of paracetamol 1 gm/100 ml IV was given to all patients before extubation. Intravenous neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg) were administered to reverse muscle relaxants.After extubation, patients were transferred to the post-anesthesia care unit (PACU), where a standard analgesic regimen of paracetamol 1 g was given intravenously every 8 h. to all patients. In addition, an intravenous PCA morphine bolus of 3 mg without background infusion and a lockout period of 15 min were given upon patient’s request during the follow up period./Sedation Scale (MOSS/A) ) and were compared using the T-test. Categorical variables are presented as counts (percentages) and were evaluated with the Fisher exact test. Nonparametric correlations using the Spearman rho correlation coefficient between the global QoR-40 and “both opioid consumption and the pain subcomponent of the QoR-40” were performed. The level of rejection of the null hypothesis, using the T-test was set at P value < 0.05 for the postoperative cumulative 48 h morphine consumption.Sixty-six patients were assessed for eligibility to participate in the study. Four patients were inoperable and two patients refused to participate. A final sixty patients were scheduled for laparoscopic colorectal surgery for cancer colon completed this study and equally distributed in two groups (n = 30 patient per group) as shown in flow diagram Fig. . The twoThe duloxetine group had significantly lower pain scores represented by VAS score in the first 48 postoperative hours than the placebo group at all-time intervals: 0–2, 2–4, 4–8, 8–12, 12–24, 24–36 and,36–48, Mean and standard deviation (mean ± SD) (3 ± 0.69) vs. (4.17 ± 0.83), (2.5 ± 0.6) vs. (4.3 ± 0.9), (2.2 ± 0.7) vs. (3.9 ± 0.6), (1.6 ± 0.7) vs. (3.6 ± 0.8), (1.1 ± 0.8) vs.(3.7 ± 0.7), (0.7 ± 0.7) vs. (3.5 ± 0.8), (0.6 ± 0.7) vs. (3.5 ± 0.8) respectively, P value ˂0.01  (25.33 ± 26.20) vs. (74.16 ± 27.45), P value ˂0.01  (4.6 ± 2.9 mg vs. 11.3 ± 1.7 mg), P < 0.01 (Table P < 0.01) at 48 h postoperatively, moreover the individual subcomponents in the QoR-40 showed that the duloxetine group had better results than the placebo group in the psychological support, emotional status, physical comfort, physical independence and, pain (32.2 ± 1.7) vs. (29.2 ± 1.9), (41.9 ± 1.8) vs. (35.4 ± 3.4), (52.3 ± 1.7) vs. (47 ± 3.3), (22.1 ± 1.6) vs. (18.9 ± 1.3), (32 ± 1.6) vs. (25.3 ± 2.3) respectively, P value ˂0.01  of total QoR-40 score for the duloxetine group was (180.8 ± 4.5) compared to (156 ± 5.9) in the placebo group  at 0–2, 2–4, 4–6, 6–12, 12–24 and, 24–48 was 3 (3–4) vs. 4 (4–5), 3 (3–4) vs. 4 (4–5), 3 (2–4) vs. 4 (4–5), 3 (2–4) vs. 4 (4–5), 3 (3–4) vs. 4 (4–5) and, 3 (3–4) vs. 4 (4–5), P value ˂0.01  of Modified Observer’s Assessment of Alertness Concerning the postoperative side effects during the first 48 h, where number and percentage of nausea, vomiting, bradycardia and headache were more in the duloxetine group than the placebo group, 6 (20%) vs. 2 (6.6%), 5 (16.6%) vs. 2 (6.6%), 1 (3.3%) vs. 0 and, 3 (10%) vs. 1 (3.3%) respectively; howerver they did not reach the statistical significance level . Furthermore, Ho and his co-workers [Moreover, in our previous  trials o-workers  gave twoIt is reasonable that if an analgesic could also provide emotional stability, it would be a better adjunct for postoperative recovery. One of the most important findings in our study was the better postoperative quality of recovery, as represented by the total score of 180.8 ± 4.5 in patients who received duloxetine compared with those who received a placebo capsule 156 ± 5.9. It specifically improved the five domains: physical comfort, independence, emotional, psychological, and pain in the quality of recovery score. This improvement in QOR is not only due to less opioid consumption and lower VAS scores but also due to a favorable effect on emotional and psychological status which are of utmost importance in cancer patients undergoing surgery.study; administered Duloxetine 60 mg 2 days before surgery till 2 weeks postoperatively in patients undergoing mastectomy and found that it not only reduced pain postoperatively but also improved chronic pain at 3 months and 6 months postoperatively [Nasr’s ratively .Also, in accordance with our study, a meta-analysis conducted by Zorrilla and partners  approvedIn contrast to our study, Erdmann and his collegues  studied Dose selection in this trial was inspired by our previous study , where t2A and aplha2-norepinephrine receptors, which strengthen the inhibitory descending pain pathways. Prefrontal brain activity, which results in cognitive control of pain, is another central mechanism [It has been proposed that duloxetine exerts its analgesic action through three different processes and locations. The dorsal horn of the spinal cord dopamine, NE, and serotonin levels are raised as a result of its action. These monoamines stimulate the spinal cord’s 5-HTechanism , 28.Follow up period was only 48 h postoperatively; we could not report the effect of duloxetine on chronic pain management. We did not report the effect of duloxetine on the hospital stay period or the intestinal recovery. In further studies, the third group with two doses of Duloxetine group could be added to detect the effect of the dose on the side effects.The perioperative doses of duloxetine 60 mg, the first 12 h preoperatively, a second dose one hour preoperatively, and a third dose 24 h postoperatively had reduced postoperative pain, decreased opioid consumption, and improved the quality of recovery for 48 h postoperatively in patients subjected to laparoscopic colorectal surgery.


Objective: To collect the available evidence about the effectiveness of pain neuroscience education (PNE) on pain, disability, and psychosocial factors in patients with chronic musculoskeletal (MSK) pain and central sensitization (CS). Methods: A systematic review was conducted. Searches were performed on Pubmed, PEDro, and CINAHL, and only randomized controlled trials (RCTs) enrolling patients ≥18 years of age with chronic MSK pain due to CS were included. No meta-analysis was conducted, and qualitative analysis was realized. Results: 15 RCTs were included. Findings were divided for diagnostic criteria . PNE has been proposed as a single intervention or associated with other approaches, and different measures were used for the main outcomes considered. Conclusions, practice implication: PNE is effective in improving pain, disability, and psychosocial factors in patients with fibromyalgia, chronic low back pain (CLBP)—especially if associated with other therapeutic approaches—and also in patients with CFS and CSP. Overall, PNE seems to be more effective when proposed in one-to-one oral sessions and associated with reinforcement elements. However, specific eligibility criteria for chronic MSK pain due to CS are still lacking in most RCTs; therefore, for future research, it is mandatory to specify such criteria in primary studies. Despiteprocess” .Interestingly, most of the patients suffering from MSK pain are unaware of the proper pathway of care to undertake. Therefore, there is a negative impact on pain, disability, and quality of life, with a direct increase in healthcare-related costs for these patients ,11. For Among the most widespread educational techniques, pain neuroscience education (PNE) has been recognized as an effective approach for the management of patients with persistent MSK disorders, showing clinically relevant results on pain, disability, and psychosocial factors—especially as an adjunct to exercise and/or manual therapy ,20,21,22Although PNE seems to be an effective intervention for patients with persistent MSK pain , data abThe primary aim of this systematic review is to collect the available evidence concerning the effectiveness of PNE, specifically in individuals suffering from chronic MSK pain and CS, on clinically relevant outcomes and to provide recommendations for clinicians and upcoming research.This systematic review was conducted based on the PRISMA Statement 2020 . The proOnly randomized controlled trials (RCTs) published in Italian or in English were considered eligible. No further restrictions were applied.Studies enrolling patients ≥18 years of age with persistent MSK pain for at least 3 months due to CS were included . In detaRCTs were excluded if they enrolled patients aged <18 years of age; or acute, subacute, or recurrent pain conditions or with pain of any duration caused by specific pathologies  or patients who had surgical back procedures within a year.No restrictions in terms of publication date have been implemented.RCTs were eligible if interventions were based on PNE proposed in any format. No restrictions were applied in terms of the combination of PNE with other interventions.Educational interventions, waiting lists, placebo interventions, or other active  or passive  approaches were eligible for inclusion.To be included, RCTs had to assess at least 1 of the following outcomes: (1) pain, (2) disability, and (3) psychosocial factors. No restrictions were applied in terms of outcome measures.An electronic search was conducted between May and September 2021 on the following databases: PubMed, PEDro, and CINAHL. Searches were set and managed according to the specific settings of each database. Search strings were composed using MESH —where possible—or free terms and combined with Boolean operators  in line with the PI(C)O model of clinical questions . An additional search on the main 3 databases was conducted between September and October 2022 to add also papers published after the first round of search. Furthermore, all bibliographies of the included studies and all other existing systematic reviews focused on PNE were manually screened to identify other potentially relevant papers.The full search strategy for PubMed is available in After the removal of duplicates, all records were screened for title and abstract. Then, all full-text articles suitable for inclusion were screened according to the inclusion criteria of the present study through the independent analysis of the main two authors (B.L. and V.B.). A third author (L.S.) not involved in the screening process was involved in case of disagreements. The data extraction process was performed independently by the two main authors (B.L. and V.B.) Full-text papers were retrieved thanks to the Library Service of the University of Bologna and through direct e-mail contact with authors.To quantify the inter-rater agreement between the two main authors for full-text selection, Cohen’s Kappa (K) was used. K value was calculated and interpreted according to Altman’s definition : low (k The risk of bias in the included studies was independently assessed by the two main authors (B.L. and V.B.) through the Risk of Bias (RoB) assessment tool of the Cochrane Collaboration , and a tp), and clinical relevance  were reported.Due to the high heterogeneity across the included studies, no meta-analysis was performed, and a qualitative synthesis was conducted in a narrative and tabular format. All data from the included studies related to both between-groups and within-group differences were reported for each outcome. Where possible, punctual estimates, confidence intervals, standard deviation, effect size, statistical significance . Across all RCTs, the study of Téllez et al.  in 2015 Out of 1085 patients recruited, there were 60 (5.53%) drop-outs, and 77 (7.10%) lost to follow-up. Details are specified in The timing of re-assessment significantly varied across the included studies. Follow-ups ranged between a minimum of after-treatment follow-up  and a maOnly two studies ,43 have The mean age of all participants was 45.92 years. Although all participants suffered from persistent MSK pain, diagnostic labels significantly differed. Six studies ,43,44,47PNE was proposed in different modalities in all experimental interventions both alone and in association with other therapeutic approaches. In particular, PNE was proposed as a single intervention ,44,48,49Participants in the control group were subjected to different approaches such as self-management education ,49, educSignificant heterogeneity of outcome measures was found across the included studies for pain, disability, and psychosocial factors. Specifically, pain was assessed with NPRS in three studies ,45,47, NSelection bias was low across the included studies except for two RCTs ,41 with The inter-rater agreement index (B.L. and V.B.) was good (K = 0.70) for full-text selection. Data are detailed in The qualitative synthesis for the effectiveness of PNE was divided for the diagnostic label  and reported both in a narrative and a tabular format. Details are reported in In the treatment of patients with fibromyalgia, PNE had similar clinical results in improving all the considered outcomes if compared with education and relaxation techniques . SimilarIn the single RCT focused on CSP, PNE was more effective than education based on neck/back school in improving PCS values in participants with high CSI scores and improving PDI. In contrast, TSK-17 and IPQR values in both intervention groups, regardless of CSI level, were observed . DetailsCompared with the self-management education of ADL , PNE wasAt the 1-month follow-up, PNE was significantly superior to the “Health Behavior Control” program on PSCOQ and BPI (severity and interference) scores . HoweverIn the study of Bodes et al.  in 2018,The objective of this SR was to collect the available evidence about the effectiveness of PNE in chronic MSK patients due to CS on pain, disability, and psychosocial factors.The risk of bias in most of the studies was low, except the performance bias criterion rated as high risk in all studies. Nevertheless, since a low risk for performance bias may be hard to obtain in physical therapy trials, it does not seem to be a significant factor in downgrading the overall quality of evidence.Overall, PNE seems to be effective both as a single intervention and more effective if proposed in a multidisciplinary program. Furthermore, only in two studies ,48 was Pp-values for FIQ scores (p < 0.001), and no data were specified for the remaining so-defined (in the results section) “significant” differences. At all follow-ups , there were also improvements defined by authors as “clinically relevant,” but no data for clinical relevance were provided. The second study [In the context of FM, PNE proposed in combination with usual treatments for FM was more effective than usual treatments only, as appreciated in two studies with a low to moderate risk of bias ,46. Howend study ,49 do nond study  or self-For CSP patients , resultsFor CFS patients, conflicting results arising from the unique moderate-quality RCT  are striWhen the participants are both FM and CLBP patients , PNE is Overall, among the studies included with patients suffering from CLBP, findings from the included RCTs support the effectiveness of PNE, especially if associated with other therapeutic approaches. However, since results differed in terms of follow-up and outcome measures, further considerations are needed. Firstly, it seems that the PNE procedure does not affect outcomes, and both “culture-sensitive” and “standard” PNE are effective in the short term . SignifiRCTs included in this SR support the effectiveness of PNE in patients with chronic MSK pain due to CS, but the applicability of these results is questionable.In terms of PNE administration, several modalities were proposed across the included RCTs. Furthermore, PNE was more effective throughout one-to-one oral sessions rather than the group- or online- or written-based approaches, and such findings are surely a major strength of PNE and its applicability in clinical practice. In terms of health professionals, PNE administration needs specific training to achieve enough knowledge of contents regarding neuroanatomy, neurophysiology, and pain mechanisms. Explanations proposed to patients must be proposed using understandable and simple language, metaphors, and examples—requiring, again, specific communicative- and educative-based training. Since not all clinicians are confident and trained in communicative skills and pain education, the latter aspect may limit the applicability of promising results of PNE in clinical practice. Moreover, PNE needs to be proposed only to selected patients; therefore, all clinicians should be able to screen patients in terms of pain mechanism and to recognize all the psychosocial factors related to CS—limiting the transferability of results of this systematic review only to those clinicians trained in these terms. Finally, nothing is known about the long-term effectiveness of PNE. The majority of follow-ups were set in the short- and medium-term. For this reason, the applicability of results in the long term is not possible.Based on our findings, an urgent need for specific training in the context of pain education is needed, which should be gathered with other mandatory skills for clinicians in direct-access practice, such as screening for referral ,57,58,59Since our SR specifically addressed the effectiveness of PNE in patients with chronic MSK pain and CS, the consistency of our findings was limited to previous papers that investigated the overall effectiveness of PNE on MSK pain.Overall, the results of this SR are consistent with other previous papers. Indeed, PNE already showed effective results in patients with chronic MSK pain, especially when included in multimodal programs . PreviouTherefore, all results gathered from previous papers are consistently in line with our findings. However, none of the previous SRs specifically focused on chronic MSK pain and CS; for this reason, consistency is still limited, and further research is needed.The first limitation of this SR is the lack of specificity of inclusion criteria of primary studies related to the sample of participants with a dominant CS pain mechanism. Indeed, only two studies ,39 clearTo the best of the authors’ knowledge, this is the first systematic review focused on the effectiveness of PNE in patients with chronic MSK pain and CS; this is a major strength of this work. Furthermore, the accurate research screening process on databases, the manual searches, the double-blind assessment for the risk of bias across the studies, and the good Cohen’s K score for full-text selection are strengths of the methodological quality of this SR.Overall, PNE effectively improves pain, disability, and psychosocial factors in patients with persistent MSK pain and CS. In particular, the one-to-one modality with medium- or long-term sessions with reinforcements (brochures and comprehension exercises) seems to be more effective than remote sessions (telephone and computer) or content-only reading.In patients with FM, PNE showed promising results when included in a multidisciplinary program, compared with usual care, but not in comparison with other educational or self-management techniques. In patients with CSP and CFS, PNE seems reliable to improve clinical outcomes in the short term when proposed individually against other educational or self-management approaches. Moreover, in patients with CLBP, PNE appears to be effective in combination with other treatments, such as manual therapy and mostly therapeutic exercise.PNE is a valuable and effective intervention for clinicians in the treatment of patients with persistent MSK pain and a dominant CS pain mechanism. Furthermore, the effectiveness of PNE is more evident if proposed in association with other therapeutic modalities such as manual therapy, therapeutic exercise, and self-management strategies.It is mandatory for future research to homogenize the inclusion criteria in RCTs in order to improve the specificity of sub-groups of participants with a dominance of the CS pain mechanism. Furthermore, longer follow-ups are needed to assess the long-term benefits of PNE, and more standardization of PNE procedures proposed for chronic MSK with CS is needed to summarize these results in a future meta-analysis quantitatively.


In the present study, specific physiological signals were analyzed to determine, whether a distinction can be made between pre-and post-analgesic administration in a postoperative setting. Explicitly, the significance of the facial EMG regarding the operationalization of the effect of analgesia was tested.In the clinical context, the assessment of pain in patients with inadequate communication skills is standardly performed externally by trained medical staff. Automated pain recognition (APR) could make a significant contribution here. Hereby, pain responses are captured using mainly video cams and biosignal sensors. Primary, the automated monitoring of pain during the onset of analgesic sedation has the highest relevance in intensive care medicine. In this context, facial electromyography (EMG) represents an alternative to recording facial expressions N = 38 patients scheduled for surgical intervention where prospectively recruited. After the procedure the patients were transferred to intermediate care. Biosignals were recorded and all doses of analgesic sedations were carefully documented until they were transferred back to the general ward.before’ and ‘after’ pain medication. We found the highest effect sizes (r = 0.56) for the facial EMG.Almost every biosignal feature is able to distinguish significantly between ‘The results of the present study, findings from research based on the BioVid and X-ITE pain datasets, staff and patient acceptance indicate that it would now be appropriate to develop an APR prototype. This is usually done with external observation scales and is limited to and valid only at the time of assessment. Fine-grained continuous documentation is not possible given the lack of personnel time. Essentially, observational scales rely on a classification of pain components  that areExplicitly, checking pain intensity during the onset of analgesic sedation is of utmost relevance in intensive care medicine to avoid over-or underdosing. Therefore, an automated monitoring of pain could be of highest relevance. The basics for such a method have not been sufficiently investigated so far.zygomaticus major and corrugator supercilii represent an alternative to recording facial expressions via video. They can serve as a substitute by appropriate interpretation of their activities. In general, very few studies have investigated the applications of facial EMGs  and Temperature (TEMP)) were analyzed to determine, whether a substantial distinction can be made between pre-and post-analgesic administration in a postoperative setting. Explicitly, the significance of the facial EMG in operationalization the effect of analgesia was investigated.2.2.1.N = 38  patients were included in the study. The ages ranged from 36 to 81 years, mean age was 62.3 years. Unfortunately, due to COVID-19 restrictions, the target sample size of 50 could not been reached.Patients scheduled for a surgical intervention within the next 3 days with the necessity of post-monitoring in an intermediate care (ICM) unit were prospectively enrolled in the study after completion of a written, informed consent. They had to be at least 18 years old, oriented and capable of providing information. Exclusion criteria were pregnancy, neurological diseases or having a pacemaker or defibrillator. All procedures were carried out in the ICM (35 beds) at the University Medical Center of Ulm, Germany. From September 29th, 2020 to April 13th, 2021, 2.2.After the surgical procedure, the patients were transferred to intermediate care. There, after attaching electrodes to them to acquire and monitor biosignals relevant for the study, recording was started immediately and continued continuously throughout the patient’s stay in the ICM see . All pat2.3.corrugator supercilii and right zygomaticus major muscles to measure the Electromyography of the face. To record the ECG, three Ag/AgCl electrodes were attached to the patients’ upper body. Two more electrodes were attached on the bottom edge of the left hand to capture the SCL. At last, to obtain the peripheral body temperature, a temperature (TEMP) sensor was fixed to the tip of the left little finger with a medical tape. The software offered the possibility of manually setting markers during recording. Each time a pain medication was administered (see 2.2), a corresponding marker was set to mark the exact time in the biosignal recordings.Physiological signals were recorded at a sample rate of 1,024 Hz, using the NeXus-10-amplifier and its associated software “BioTrace+ NX10” from Mind Media.2.4.The processing of all physiological signals and subsequent feature extraction was done utilizing the “MATLAB 2018b” software from MathWorks.TEMP & ECG: We applied a moving average to both of the signals to smoothen their data. For the temperature we chose a 513 data-points and for the ECG a 67 data-points sliding window. In addition, all ECG signals were detrended.SCL: The signal was filtered with a 20 Hz-low-pass filter and also smoothened with a 1,025 data-points sliding window.EMG: The 2 EMG channels were processed with a 3rd-order Butterworth bandpass filter with cut-off frequencies of 20 and 250 Hz. Next, a Hilbert-transformation was performed and absolute values of the resulted signal were obtained. Finally, the data were low-pass filtered with a cut-off frequency of 4 Hz . All windows were visually inspected for artifacts and outliers. If necessary and doable, corrupted segments were corrected, otherwise the data window was discarded. Finally, features were derived that differed in number and type depending on the biosignal. With future machine learning in mind, we chose relevant features for biosignals suggested by Gruss et al. (before’ and ‘after’ pain medication). All specific features are shown in For statistical calculations, we extracted features for all biosignals from relevant data windows. The windows had a length of 60 s and were cut out of the signals directly ‘s et al.  and Werngs see 2.. All wins et al. . They we2.5.before’ and ‘after’ for all biosignals and their associated features. With regard to the repetition of measurements, a Wilcoxon signed-rank test for dependent samples was chosen. A p-value of <0.05 indicated statistical significance. In addition, for each p-value, we calculatedthe associated effect size r using the formula r =Z = teststatistic, N = number of samples. Effect size measures help to assess the practical relevance of the results of statistical tests. Cohen’s classification  and associated p-values were used to assess the association: 0.1 ≤ |ρ| < 0.3 = small, 0.3 ≤ |ρ| < 0.5 = moderate, and |ρ| ≥ 0.5 = strong correlation . A sample always consisted of a ‘before’ event and its related ‘after’ event. For the correlation analyses, there were a total of 310 samples, since both facial EMGs within the same sample always had to be qualitatively usable. before’ and ‘after’ groups for each biosignal feature.After discarding unusable data windows, at least more than 330 samples per biosignal were left to examine statistically significant differences  to large (r ≥ 0.5) effect sizes. The largest effect size within this study was found for feature “f6_EMG” of EMG_corrugator_supercilii with r = 0.56 (p = 0.000). Features “f3_SCL”  and “f1_TEMP”  show high significant differences but have small effect sizes. No differences between the groups were found for features “f2_EMG” of EMG_corrugator_supercilii (p = 0.191) and “f2_EMG” of EMG_zygomaticus_major (p = 0.867). Except for the two features mentioned above, all biosignal activity changed to the expected directions. Muscle and SCL activity turned down, peripheral body temperature slightly increased and heart beat slowed down. All findings strongly indicate a reduced sympathicus activity after pain medication.Almost every feature is able to distinguish significantly between the groups. The Regarding a related activity of the two facial muscles, 4.The fact that analgesia can be directly observed and assessed in a postoperative setting, e.g., with the BPS, is part of the S3-guideline “Analgesia, Sedation and Delirium management in Intensive Care.” That pain intensity has an influence on the autonomic nervous system has been shown in numerous studies (see introduction). However, it has not been operationalized to what extent the activities of biosignals are influenced after an analgesic administration. In this brief report the operationalization of an analgesic effect was proven statistically significant for the recorded biosignals EMG, SCL, ECG, and TEMP. This is an indication that physiological signals are suitable to check for an analgesic effect and should be transferred into an AI-based prototype. This would be a key benefit for clinical staff.Walter et al.  showed tDespite initial skepticism of the authors regarding the (patient) acceptability of the facial EMG sensors, the continuous measurement of facial EMG was shown to be unproblematic.Limitations:The sample is relatively small due to the complexity and duration of measurements and Covid-19 pandemic restrictions.The extent to which a particular analgesic dosage affected the activities of the various biosignals was not investigated.Why feature “f2_EMG”  does not show a significant difference, cannot be verified at the moment.Outlook:Further studies should statistically examine the influence of a certain dosage of analgesics on the sympathetic/parasympathetic response.Findings from research based on the BioVid  & X-ITE sascha.gruss@uni-ulm.de.The datasets presented in this article are not readily available because of data security. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Ethics committee of the Ulm University (No. 441/19). The patients/participants provided their written informed consent to participate in this study.SG: study design, literature search, data analysis, and writing. BS: critical revision and writing. MS and LH: data collection. EB: study design, critical revision, and data interpretation. SW: study design, literature search, and writing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Although the study of the neuroanatomical correlates of depression in Parkinson’s Disease (PD) is gaining increasing interest, up to now the cortical gyrification pattern of PD-related depression has not been reported. This study was conducted to investigate the local gyrification index (LGI) in PD patients with depression, and its associations with the severity of depression.LGI values, as measured using FreeSurfer software, were compared between 59 depressed PD (dPD), 27 non-depressed PD (ndPD) patients and 43 healthy controls. The values were also compared between ndPD and mild-depressed PD (mi-dPD), moderate-depressed PD (mo-dPD) and severe-depressed PD (se-dPD) patients as sub-group analyses. Furthermore, we evaluated the correlation between LGI values and depressive symptom scores within dPD group.Compared to ndPD, the dPD patients exhibited decreased LGI in the left parietal, the right superior-frontal, posterior cingulate and paracentral regions, and the LGI values within these areas negatively correlated with the severity of depression. Specially, reduced gyrification was observed in mo-dPD and involving a larger region in se-dPD, but not in mi-dPD group.The present study demonstrated that cortical gyrification is decreased within specific brain regions among PD patients with versus without depression, and those changes were associated with the severity of depression. Our findings suggested that cortical gyrification might be a potential neuroimaging marker for the severity of depression in patients with PD. It may in vivo. Previous functional MRI studies have suggested abnormal neural activity or connectivity in various brain areas which mainly involve the prefrontal-limbic circuit, the striatal-thalamic-prefrontal circuits and the basotemporal limbic circuits (Since the advent of magnetic resonance imaging (MRI), various approaches have been developed, making it possible to identify morphometric and functional changes non-invasively in the human brain circuits .As functional alteration tends to be influenced and constrained by the large-scale anatomical structure of the cortex , morphomEarlier studies using VBM explored the volume and density of cortical or subcortical structures in depressed PD (dPD) patients. Gyrification, the process by which the morphological surface on brain undergoes changes to create sulcal and gyral regions , is beliTherefore, in this study, we used LGI to investigate the pattern of cortical gyrification among PD patients with and without depression, as well as the matched healthy controls, and evaluate the associations between LGI values from significant areas and depressive symptom scores. To further elucidate the effect of the severity of depression on cortical folding patterns in PD, we additionally analyzed the differences in LGI between ndPD and dPD subgroups divided with disease severity. The identification of specific cortical morphological differences between dPD and ndPD patients can shed new light on the neurobiological determinants of depression in PD, with clinical relevant implications for the diagnosis and management of PD-related depression.2.2.1.Participants involved in this research were recruited from the 2nd Xiangya Hospital, Central South University. All the PD patients were diagnosed according to the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson’s disease (2015)  by two eWe sought to recruit 30 non-depressed PD (ndPD), 30 mild-depressed PD (mi-dPD), 30 moderate-depressed PD (mo-dPD) and 30 severe-depressed PD (se-dPD) patients. With this sample size, with power of 0.8, and an alpha level of 0.05, we estimated to be able to detect effects at the level of effect size (ES) 0.65. Of the invited 120 early-stage PD patients, 9 were excluded due to potential cognitive impairment, 2 were excluded because of history of antidepressant medication, 8 due to incomplete clinical and questionnaire data, 5 due to unsatisfied imaging quality, 7 due to significant brain lesions in MRI , and 3 due to error during data preprocessing. Therefore, altogether 86 PD  patients and 43 healthy controls matched by age and sex were recruited.2.2.All scans were conducted on a 3-Tesla Siemens scanner . Axial T2-weighted images were firstly obtained to exclude any dormant brain lesions. High-resolution 3D T1-weighted structural images was acquired using magnetization-prepared rapid gradient-echo sequence, with scan parameters as follows: repetition time = 1900 ms, echo time = 2.01 ms, slice number = 176, no gap, slice thickness = 1.0 mm, voxel size 1.0 × 1.0 × 1.0 mm, flip angle = 9°, field of view = 256 mm, matrix size = 256 × 256.2.3.The 3D T1-weighted images were preprocessed using FreeSurfer 5.3.02.4.χ2 test. Relationships between average lGI values from significant regions and BDI scores within dPD patients were analyzed using Pearson’s correlation. p < 0.05 was considered significant.Statistical Package for the Social Sciences (SPSS) version 25 was applied to perform Statistical analyses of demographic data and correlation analyses. One-way ANOVA was used to compare age, years of education, duration and MMSE, UPDRS III, BDI scores. Hoehn & Yahr and CDR were assessed using Kruskal–Wallis test. Gender, onset side of PD symptoms and the use of anti-Parkinson drugs among groups were analyzed using p < 0.05, and Monte Carlo simulation was used for multiple-comparison correction. Average LGI values within significant clusters of the dPD patients were then extracted to perform correlation analysis with BDI scores. To further investigate the influence of the severity of depression on cortical folding patterns in PD, the differences in LGI between ndPD and dPD subgroups were additionally analyzed via QDEC with the same procedures.To perform the vertex-by-vertex comparisons of the whole-brain LGI in Query Design Estimate Contrast (QDEC), the LGI values were projected on an average template for each subject and all of the individual reconstructed cortical surfaces were aligned to the template ,b. Regio3.3.1.p < 0.001). Detailed demographics and clinical parameters of participants are summarized in There were no significant group differences in age, gender, years of education, MMSE score, CDR score, and total intracranial volume among dPD, ndPD, and HC, as well as dPD subgroups . Specifically, the course and onset side of PD, H-Y classification, UPDRS III scores, and the distribution of the use of anti-Parkinson drugs between dPD and ndPD groups were also well-matched. As predicted, groups were significantly different in BDI scores with higher mean BDI scores in the dPD group  and an additional cluster mapped onto the right paracentral gyrus ; Table 33.2.3.r = −0.337, p = 0.009; the right cluster: r = −0.286, p = 0.028, The dPD group exhibited significantly reduced LGI relative to the ndPD group within two clusters. One cluster had a peak vertex mapped onto the left inferior parietal lobe comprising portions of the superior-parietal lobe, the other had a peak vertex located within the right posterior cingulate gyrus comprising portions of the right caudal anterior cingulate gyrus, superior-frontal gyrus and paracentral lobule ; Table 3To further elucidate the effect of the severity of depression on cortical folding patterns in PD, the comparisons between dPD subgroups and ndPD were conducted. Compared to ndPD, no significant differences of LGI was found in any brain areas in mi-dPD; mo-dPD showed reduced LGI in one cluster which had a peak vertex in the right posterior cingulate gyrus involving superior-frontal gyrus and paracentral lobule; while se-dPD exhibited more extensive reduction of LGI involving the left parietal, bilateral parahippocampal, cingulate gyrus, fusiform gyrus, lingual gyrus and the right superior-frontal, paracentral lobule (peak localized in the left parietal, the left lingual and the right parahippocampal region respectively, 4.In the present study, we investigated the differences in LGI between PD patients with- and without depression compared with matched controls, as well as between ndPD and dPD subgroups divided with disease severity. Three main findings emerged. Firstly, compared to ndPD, the dPD patients exhibited decreased LGI in the left parietal, the right superior-frontal, the posterior portion of cingulate and paracentral regions, and the LGI values within these areas negatively correlated with BDI scores within dPD group. Secondly, reduced gyrification was observed in mo-dPD and involving a larger region in se-dPD patients, but not in mi-dPD patients. Thirdly, both dPD and ndPD were characterized by a pattern of hypo-gyrifification in bilateral occipital regions involving potions of inferior temperal and fusiform cortex when compared to healthy controls. To our knowledge, this is the first study to explore the pattern of cortical gyrification in PD patients with- and without depression.Although data on cortical gyrification in dPD patients remains lack, several possible explanations for these results could be speculated. In general, there are mainly two competing mechanical models for convolution formation during human brain development, i.e., differential growth theory  and axonWhile according to the tension-based theory of cortical morphogenesis, it is the mechanical tension along the axons in white matter that drives cortices fold in characteristic species-specific patterns . In othede novo depression have reported cortical gyrification abnormalities across multiple brain regions, including the left lingual gyrus, right posterior superior temporal sulcus (de novo depression. Nevertheless, in the subsequent analyses between dPD subgroups and ndPD, while the mi-dPD showed no area with LGI reduction, the mo-dPD showed reduced LGI in the right posterior cingulate gyrus, superior-frontal gyrus and paracentral lobule. And the se-dPD exhibited more extensive reduction of LGI involving the parahippocampal, cingulate gyrus, fusiform gyrus, lingual gyrus, which largely overlapped with those reported in a previous VBM study exhibiting negative correlation between cortical volume and the severity of depression in dPD patients (de novo depression (de novo depression (Previous studies on patients with l sulcus , precunel sulcus . These apatients . These apression . These rpression . Future Notably, mi-dPD patients showed no significant differences of LGI relative to ndPD, which, from the perspective of tension-based theory of cortical morphogenesis, was well in line with our previous DTI study detecting no white matter damage in the early stage of dPD . This reAnother finding of this study was that compared with HC, both dPD and ndPD showed reduced gyrification in bilateral occipital regions covering potions of inferior temperal and fusiform cortex, which were rarely overlapped with those observed in dPD relative to ndPD. These results indicated that PD-related gyrification changes mainly involved the temporal-occipital regions, whereas depression in PD were associated with different patterns of gyrification change. Functional abnormalities and cortical morphological changes in temporal-occipital regions, which are known to be involved in high-order sensory processing, have been frequently reported in patients with PD . These a5.Some limitations of this study should be taken into account when interpreting these results. First, more than a half PD patients in the present study had received anti-Parkinson medications. Although all participants did not take medicine at least 12 h prior to psychiatric assessment and MRI scanning, and the distribution of the use of anti-Parkinson drugs between dPD and ndPD groups showed no significant differences, It is hard to say the long-term influence of anti-Parkinson medications could completely be eliminated. Future studies with more detailed information on medications including their daily dose, frequency and how long they have been used, as well as with drug-naïve participants are warranted. Second, the sample size of this study, especially for the dPD subgroup analyses, was relatively small. Further work with a larger sample is needed to replicate our results. Third, as mentioned above, there was no subjects with primary depression. Future studies including age-matched subjects with primary depression may better locate the cortical gyrification alterations relating to depression in patients with PD. Last but not the least, although the effect of antidepressants have been reported to be associated with changes in different areas of the depression-related neural network in PD , whether6.In conclusion, the present study demonstrated that cortical gyrification is decreased within specific brain regions among PD patients with versus without depression, and those changes were associated with the severity of depression.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by The Medical Research Ethical Committee of the 2nd Xiangya Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.CT contributed to the conception and design of the study. SC, QL, MW, CS, FZ, YL, JY, YT, and XL contributed to the data collection. QS contributed to the data analysis and writing the manuscript. HL contributed to the data collection and manuscript revision. JL contributed to the English language revision. All authors contributed to the article and approved the submitted version.


Similar trends were observed in cholecystectomy  and several other surgeries; however, the results were inconsistent across all analyses. Surgeries with higher percentages of PCA administration had lower median worst-pain scores. In conclusion, age may affect postoperative pain intensity after specific surgeries; however, a comprehensive understanding of the complex interplay between age, surgical intervention, and pain intensity is required. Pain management strategies should consider various factors, including age-related variations.Age-related differences in pain perception have been reported in various contexts; however, their impact on postoperative pain intensity remains poorly understood, especially across different surgical procedures. Data from five hospitals were retrospectively analyzed, encompassing patients who underwent 10 distinct surgical procedures. Numeric rating scale scores were used to assess the worst postoperative pain intensity during the 24 h after surgery. The multivariate linear regression model analyzed the relationship between age and pain intensity. Subgroup analyses were performed according to sex and patient-controlled analgesia (PCA). This study included 41,187 patients. Among the surgeries studied, lumbar spine fusion (β = −0.155,  Pain is a common and complex experience following surgical procedures that varies in intensity and duration across individuals and surgical interventions . HoweverAmong the various factors that can influence postoperative pain perception, age has been identified as a significant predictor ,11,12. HThis study investigated the association between age and pain intensity experienced on the first day after surgery in 10 distinct surgical procedures. The 10 surgeries under examination included arthroscopic rotator cuff repair (ARCR), cesarean section (C/sec), cholecystectomy, hip hemiarthroplasty, laparoscopic herniorrhaphy, open hernia repair, hysterectomy, lumbar spine fusion, total hip arthroplasty (THA), and total knee arthroplasty (TKA). By identifying the potential associations between age and pain intensity in various surgical contexts in five South Korean hospitals, we aimed to clarify age-related differences in postoperative pain perception, paving the way for tailored pain management strategies based on patient age and specific surgical procedures. The surgical types were determined based on previous studies; we extended our analysis to expand the scope of surgeries, encompassing obstetric and gynecologic surgeries—including cesarean sections and hysterectomies—and herniorrhaphies, a surgical procedure commonly performed on elderly patients.The Clinical Research Ethics Committee of Chuncheon Sacred Heart Hospital, Hallym University, approved this retrospective cohort study. The need for informed consent was waived due to the study’s retrospective design. All data were collected from five hospitals at Hallym Medical Center through electronic medical records. Our dataset included patients’ baseline characteristics and records of anesthesia, surgery, laboratory examination, and prescription between 1 January 2013, and 30 June 2023.This study included adult patients aged ≥ 18 who underwent one of the 10 surgical procedures between 1 January 2013, and 30 June 2023. The 10 surgical procedures were as follows: ARCR, C/sec, laparoscopic cholecystectomy, hip hemiarthroplasty, laparoscopic inguinal herniorrhaphy, open inguinal herniorrhaphy, hysterectomy, lumbar spine fusion, THA, and TKA. Surgery types were classified according to the Health Insurance Charge Code of the Republic of Korea . LaparosThis study excluded patients with cooperative surgery, missing data, or multiple surgeries.The exposure was the age (years) of the patients. The primary outcome was the worst pain intensity during the 24 h after surgery. Pain intensity was determined using a numeric rating scale (NRS) ranging from 0 (least) to 10 (worst). Secondary outcomes were the dose of opioids used during the postoperative 24 h. Opioids included morphine, oxycodone, meperidine, nalbuphine, tramadol, transdermal fentanyl patch, transdermal buprenorphine patch, fentanyl, and alfentanil. Because several types of opioids were included, the conversion dose was calculated based on morphine. The ratio of the conversion dose is presented in The covariates included patient characteristics, such as body mass index, comorbidities , history of alcohol consumption, smoking, and medication , and perioperative factors, such as physical status, emergency, anesthesia, surgery time, fluid balance, intraoperative monitoring , and patient-controlled analgesia .Continuous data were expressed as medians and interquartile ranges, and categorical data were expressed as frequencies and percentages. We used a locally estimated scatterplot smoothing line to fit a smooth curve through the scatterplot of age and NRS. Visualizing the relationship between age and NRS as an optimal-fit curve makes it easier for readers to understand.2 between age and NRS score was also calculated. For the subgroup analysis, we analyzed the adjusted association between age and worst pain 24 h postoperatively depending on sex and patient-controlled analgesia (PCA) administration.Considering the covariates, we analyzed the adjusted association between age and worst pain at 24 h postoperatively using linear regression. The partial Rp-value ≤ 0.005 was considered statistically significant. SPSS version 26.0  was used for all analyses, and graphs were drawn using R version 4.2.3 .Using Bonferroni correction, a This study enrolled 47,694 patients aged ≥ 18 who underwent 10 types of surgical procedures between January 2013 and June 2023. A total of 6507 patients were excluded, and 41,187 patients were included in this study . The numThe median worst pain intensity according to surgery ranged from 3 to 5 on the NRS. Surgeries with a median NRS score of ≥4 included ARCR, cholecystectomy, laparoscopic herniorrhaphy, open herniorrhaphy, lumbar spine fusion, and TKA.The median opioid dose administered during surgery ranged from 0 to 28.8 mg, depending on the surgery. In herniorrhaphy, ≥75% of the patients did not use opioids. Details of pain intensity and opioid dose administered during the 24 h after surgery are summarized in The association between the worst pain score during the 24 h after surgery and age is summarized in However, for seven types of surgery—those other than C/s, laparoscopic herniorrhaphy, and open herniorrhaphy—the worst pain scores decreased significantly with age when other factors were adjusted. Details of the association between age and worst pain during the 24 h after surgery are summarized in Considering the surgical characteristics, C/sec and hysterectomy were excluded from the analysis based on sex. The worst pain scores for cholecystectomy and lumbar spine fusion decreased significantly in males and females. Details of the association between age and worst pain according to sex during the 24 h after surgery are summarized in The number of patients who received PCA was 29,388. The percentage of patients who received PCA in ARCR, C/sec, hip hemiarthroplasty, hysterectomy, lumbar spine fusion, TKA, and THA was over 80%; however, that of herniorrhaphy was 10–20%. Except for ARCA and hysterectomy, the worst pain score significantly decreased with age in patients who received PCA. Details of the association between age and the worst pain during the 24 h after surgery in patients who received PCA are summarized in Locally estimated scatterplot smoothing lines show an age-related decrease in the administered dose of opioids during the 24 h after surgery in several surgeries, such as hip hemiarthroplasty, hysterectomy, lumbar spine fusion, THA, and TKA. The association between the administered dose of opioids during the 24 h after surgery and age is summarized in However, for six types of surgery, including ARCR, cholecystectomy, hip hemiarthroplasty, lumbar spine fusion, THA, and TKA, the administered dose of opioids was significantly reduced with age when other factors were adjusted. Details of the association between age and the administered dose of opioids during the 24 h after surgery are summarized in This study investigated the relationship between age and the worst postoperative pain during the 24 h after surgery in 10 surgical procedures. The worst pain associated with cholecystectomy and lumbar spine fusion decreased consistently and significantly with increasing age in all analyses, including the subgroup analysis. These were also included in six surgeries , which decreased the administered dose of opioids with age. However, considering a 2.4 unit reduction in the NRS is required for clinically meaningful pain relief in moderate or severe pain , only luJacqueline et al. reported an association between postoperative pain and age using an international database of hip replacement, knee replacement, spinal fusion, and laparoscopic surgery . Their sHowever, two studies reported an association between age and postoperative pain in patients using analgesic methods. Koh JC et al. investigated postoperative pain in young (age 20–39 years) and older adult (age ≥ 70 years) patients with patient-controlled epidural analgesia application . AlthougIn our study, we found that the median NRS worst pain score was the same in all patients and in patients who received PCA in seven surgeries that had a high percentage of PCA administration, such as ARCR, C/sec, hip hemiarthroplasty, hysterectomy, lumbar spine fusion, THA, and TKA. In contrast, in surgeries with a low percentage of PCA administration, such as cholecystectomy and herniorrhaphy, the median NRS worst pain score in patients who received PCA was lower than that in all patients. These results were consistent with the order of the administered median doses of opioids according to surgery. According to the administered opioid dose, the top seven surgeries were those that had the same median NRS for patients with and without PCA, while the bottom three surgeries were those that had different median NRS for patients with and without PCA. However, to clarify the association between opioids and the worst pain, further studies that consider the adverse effects of high doses of opioids are needed.The effects of aging on pain intensity should be considered based on several factors. Aging is associated with anatomical and neurochemical changes  affectinThe relationship observed between age and postoperative pain intensity in various surgical procedures should be considered the potential role of pharmacokinetics, especially in the context of opioids. Opioids are commonly used analgesics for postoperative pain management, and their pharmacokinetic profiles can vary with age, which could potentially impact pain outcomes in the elderly . ElderlyThe strength of this study is that it focused on 10 types of surgeries, which may represent the various spectra of surgical procedures, and investigated patients using pain control modalities, such as PCA. However, this study has some limitations:The present study used the NRS to assess pain intensity. Although the NRS is a commonly used tool, it is subjective and may not capture the full complexity of pain experiences. Nonetheless, it provides a structured format, has good sensitivity, and generates data that can be statistically analyzed for audit purposes compared to the VAS, which may reduce variability in interpretation ,30,31.This study focused on postoperative pain within 24 h after surgery. Pain experiences might change over an extended period, and considering pain trajectories beyond the first 24 h could provide additional insights.This study acknowledges that various pain control modalities may have been used and that some data may be heterogeneous, except for PCA, which could have influenced pain intensity. Recently, multimodal analgesic methods are used, even in minor surgeries such as laparoscopic cholecystectomy and inguinal hernia repair ,30. SpecWhile our intention was to assemble a diverse dataset to bolster the generalizability of our results, this study may be susceptible to potential biases stemming from variations in hospital protocols, patient populations, and data-collection methodologies. Moreover, these variations may potentially influence the observed outcomes.In conclusion, this study provided valuable insights into the relationship between patient age and postoperative pain during various surgical procedures. Although age influences postoperative pain intensity in some surgeries, the findings are inconsistent across all procedures. They can differ according to the type of surgery and PCA administration. These findings suggest that the impact of pain control modalities emphasizes the importance of personalized pain management approaches. Future research should address the limitations of this study and explore additional factors that might influence postoperative pain to enable better pain management practices and improve patient outcomes.