Patients and Methods. This was a cohort study of 309 patients with knee OA. Patients with mild-to-moderate disease were treated weekly with IAIs of 2 mL of polymerized-collagen for six weeks (n = 309). Follow-up was for 6–60 months. The primary endpoints included the following determinations: (1) therapeutic effect; (2) survival from total knee replacement surgery (TKR); (3) Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and pain . Clinical improvement was defined as a decrease in pain exceeding 20 mm on the VAS and the achievement of at least 20% improvement from baseline with respect to the WOMAC score. Radiographic analysis was performed at baseline and 60 months. The joint space width in the medial, lateral, and patellofemoral compartments was calculated.  Polymerized-type I collagen (polymerized-collagen) is a downregulator of inflammation and a tissue regenerator. The aim was to evaluate the effect of intra-articular injections (IAIs) of polymerized-collagen among patients with symptomatic knee osteoarthritis (OA) in delaying or preventing joint replacement surgery. p < 0.05). Kaplan–Meier survival analysis of the therapeutic effect demonstrated 98.8% survival at 60 months with TKR as the endpoint. There was no significant reduction in joint space in any compartment based on the analyzed radiographs. No serious adverse events were recorded.  Patients who received IAIs of polymerized-collagen had a statistically significant improvement in the primary criteria ( Polymerized-collagen increased the time to TKR by at least 60 months, modifying the disease course, improving functional disability, and decreasing pain. The progreement . The radPatients treated with polymerized-type I collagen who received oral or parenteral corticosteroids or IA injection of steroids, glucosamine/chondroitin sulphate products, or any hyaluronic substance during the follow-up were considered as treatment failures. Patients who underwent TKR, arthroscopy, high tibial osteotomy (HTO), bone-patellar tendon-bone (B-PT-B) reconstruction, or anterior cruciate ligament (ACL) reconstruction were also considered as failures.The protocol was approved by the National Commission for Scientific Research (IMSS Ref No. 09-B5-61-2800/201700/1336). The study was conducted in accordance with the principles of good clinical practice and the revised Declaration of Helsinki, 1989. All the participants provided written informed consent.p values ≤0.05 were considered significant. Statistical analysis was performed using SPSS v.21 . For our survival approach, we estimated the unadjusted survival from TKR, arthroscopic surgery, or osteotomy by the Kaplan–Meier method and curves in SAS v.9.4  analysis. Multiple regression analysis was performed to assess associations between baseline characteristics and clinical outcomes. AS v.9.4 . We thenAS v.9.4 . We asseAt the beginning of the study, the national program for deferral of total knee replacement surgery included 335 patients. We excluded 26 patients as follows: 13 patients younger than 45 years and 13 patients with Kellgren-Lawrence (KL) grade IV.n = 160, 52%), followed by KG III . The demographic and clinical characteristics of the patients are presented in Sixty-seven percent of all patients were women. The mean age at the time of intervention was 64.0 ± 8.7 years. Most of the patients had Kellgren-Lawrence (KL) grade II  patients withdrew from the study .The WOMAC pain subscale score, WOMAC disability subscale score, WOMAC stiffness subscale score, patient pain on the VAS, and pain evaluated by a physician decreased significantly from baseline to 60 months .At 60 months, 295 (95.5%) patients who received the intervention responded to treatment, and none underwent TKR due to the persistence of symptoms. Five (1.6%) patients underwent arthroscopic surgery; 7 (2.3%) patients underwent HTO; and 2 (0.6%) patients underwent ACL reconstruction .p < 0.05) between baseline and the posttreatment period  and their assessments of therapy response . The Likt period . The patt period .p < 0.014)  . However< 0.014) .Throughout the five-year study period, there were no records of serious adverse reactions or long-term complications related to the IAIs of polymerized-type I collagen except for injection site pain lasting <24 h in all patients.Patients received stable doses of NSAIDs during the administration of polymerized-type I collagen. Thus, during first week of treatment phase, all patients received 1600 mg per day of ibuprofen. Then, during the follow-up, NSAIDs were taken as needed. Patients took on average 1-2 tablets per month of ibuprofen. None of the patients received corticosteroids, glucosamine/chondroitin sulphate products, or viscosupplementation during the study period.1.25 2.38 4.52, p < 0.0001). Also, overweight, and obese in dividuals had a higher risk compared to normal weighted individuals  . However, the changes over time of our symptom assessments, WOMAC and 100 mm VAS, were not predictors of failure. Arthroscopy had the most considerable freedom from outcome compared to HTO and ACL reconstruction  . At basetruction .OA of the knee is a common cause of chronic joint pain. It affects 35% of individuals >65 years and is the leading cause of disability in this group of patients. Several therapeutic approaches have been used, including medication  and a core treatment program consisting of exercise, education, dietary advice, and biomechanical interventions, as well as surgery as the last resort .unpublished data].Total knee replacement is an effective treatment for end-stage knee OA. However, this option is only suitable for a subset of patients with controlled comorbidities, patients who are older than 40 years, and patients who can afford the intervention . NeverthHerein, we evaluated the clinical benefit of intra-articular polymerized-type I collagen and found that the weekly application of six injections decreased pain as well as the need for TKR and arthroscopy at the five-year follow-up.There are at least two previous clinical trials that have evaluated the effect of collagen in OA treatment. One of them has investigated a medical device, MD-Knee , containing collagen of porcine origin of molecular weight equal to 300,000 dalton, produced through a process of tangential filtration. It is a pure product, contaminant-free, with standardized chemical and physical characteristics. The purpose of an in situ introduction of collagen is to provide an effective bioscaffold. On the other hand, its degradation in the constituent amino acids constitutes a nutritional support for tissues of the other joint structures. MD-Knee preparation is equally effective in knee OA symptoms over six months after a five-week injection course as the HA formulation (SUPARTZ®) . MoreoveNonetheless, our patients showed clinical improvement according to the WOMAC and VAS scores at all the follow-up visits. Indeed, polymerized-type I collagen also had a clinical benefit in the group with severe knee OA, defined as patients with a WOMAC subscale of functional disability score ≥20 and EVA ≥50.According to a meta-analysis of 74 randomized clinical trials of IA hyaluronic acid products vs. placebo in knee OA, saline solution had a placebo effect characterized by an approximately 30% reduction in pain that persisted for at least 3 months, while hyaluronic acid improved pain by 40–50% . In the The other main outcome of our study was the need for TKR or arthroscopy. We described a 98.8% covariate-adjusted knee survival rate at 60 months (characterized by the absence of TKR or arthroscopy). In comparison, a study that evaluated the IAI effect of a high-molecular-weight hyaluronic preparation in knee OA reported a 67% knee survival rate (absence of TKR) at 60 months . Our resRegarding the radiological results, significant progress was observed when they were evaluated for KL grading. Most of the patients advanced from stage II to III, but not from III to IV. Nonetheless, reduction in radiographic joint space width is recognized as a standard for demonstrating structural benefits in knee OA .In the present study, polymerized-type I collagen prevented any significant change in joint space narrowing in the medial, lateral, and patellofemoral compartments at five years of follow-up. This suggests that the patients had no radiological progression, implying preservation of the hyaline cartilage.In addition, it is important to highlight the low incidence of local and systemic AEs of the drug. This result is in agreement with the low incidence of AEs attributable to IA therapies reported in clinical trials in knee OA, with the main AEs being postinjection pain and swelling, as in our study . MoreoveThe main limitation of our study was our open design. It is well known that a placebo is effective in the treatment of OA, especially with respect to pain, stiffness, and self-reported function , 40–43. Polymerized-type I collagen has an excellent long-term clinical outcome and a safe profile. The obtained data show that polymerized-type I collagen improves functional disability, decreases pain, and increases the time of surgical deferral of TKR, suggesting that it could slow or halt the radiographic evolution of the disease. It is a nonsurgical treatment option that certainly deserves future research.


Transitional drainage, which is followed by cholecystectomy plays a key role in the management of acute cholecystitis, especially in high-risk surgical patients. Endoscopic naso-gallbladder drainage (ENGBD) is an alternative to percutaneous transhepatic gallbladder drainage (PTGBD) for patients who need temporary drainage. There is a lack of prospective comparison on the relevant outcomes of the two drainage methods during the period of drainage, especially the subsequent cholecystectomy.This is a randomized controlled two-arm non-blind single center trial. Patients with acute cholecystitis undergo emergent or early cholecystectomy and need drainage will be randomly assigned to group PTGBD or ENGBD. Pain score is defined as the primary endpoint, whereas several secondary endpoints, such as the rates of technical success, clinical remission, open conversion of cholecystectomy will be determined to elucidate more detailed differences between two groups. The general feasibility, safety, and quality checks required for high-quality evidence will be adhered to.This study would provide the first type A evidence concerning the comparison of ENGBD versus PTGBD in surgically high-risk patients with acute cholecystitis, it will be the first trial designed to determine the impact of two drainage methods on not only peri-drainage but also peri-LC.NCT03701464. Registered on October 10, 2018. According to Tokyo Guidelines 2018(TG18) flowchart, percutaneous transhepatic gallbladder drainage (PTGBD) should be considered as the first-line alternative to surgical intervention in high-risk patients, especially in some Grade II (moderate) and most of Grade III (severe) AC by the TG18 severity grading. Nevertheless, it may be limited in patients with thrombocytopenia, coagulopathy, large ascitic fluid, and Chilaiditi syndrome.,6 In this circumstance, endoscopic gallbladder drainage (EGBD) had also been made another alternative management in high-volume institutes by skilled endoscopists by TG18 management strategies for gallbladder drainage. EGBD, including endoscopic transpapillary gallbladder drainage (ETGBD) by using endoscopic naso-gallbladder drainage (ENGBD) or endoscopic gallbladder stent (EGBS) and endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), is an effective method for acute cholecystitis both technically and clinically and seems to be safer than traditional PTGBD by a systematic review.Laparoscopic cholecystectomy (LC) was the fundus-first approach for acute cholecystitis (AC). As the global population ages, not only the incidence of AC increases because of the strong relation between AC and age by previous studies, so far, there is no prospective comparison of ENGBD or EGBS with PTGBD, especially in their impacts while LC. Temporary or permanent drainage is essential for AC patients at high risk of surgery. In this study, we regard drainage as a temporary bridge to cholecystectomy in patients at high risk of early LC, yet stents were not expected to fall off during the waiting window, we chose this untouched territory comparing the ENGBD and PTGBD.Despite a prospective study comparing EUS-GBD and PTGBD and a randomized, controlled trial had confirmed that ENGBD and EGBS all appear to be suitable for the drainage which is also associated with an overall adverse events rate as high as 14%, including bile leak peritonitis, cholecystitis, bleeding, subcapsular hematoma, pneumothorax, catheter misplacement, and inadvertent removal. Moreover, it is contraindicated in patients with large peritoneal ascites, coagulopathy, thrombocytopenia, and Chilaiditi syndrome. For these reasons, less-invasive forms of ENGBD that are more efficient, more safe and less painful have been developed. It was first proposed in 1984, but reported in 1990, the technical success, clinical success, post-procedure adverse events were 88.9%, 81.5%, 9.3%, respectively, according to the data provided by the only two randomized controlled studies,12 in comparing ENGBD and EGBS. Despite such promising achievement from previous studies, the benefits of ENGBD and PTGBD on major clinical outcomes have never been compared prospectively. In particular, the effects of the two drainage method on LC remains uncertain and not only an extensive evaluation but also a retrospective study pointed out that ENGBD was more conducive to the smooth implementation of LC.PTGBD has a technical success rate of nearly 97%, clinical response rates range from 56% to 100%,22.1The primary objective of the study is to determine the clinical pain remission of ENGBD versus PTGBD in patients requiring temporary gallbladder drainage, our hypothesis is that in comparison with standard PTGBD, ENGBD could not only relieve the pain symptoms associated with acute cholecystitis itself, but also relatively alleviate the severe pain caused by drainage.2.2The study will also compare ENGBD and PTGBD on clinical outcomes of drainage and the difficulties of cholecystectomy in surgically high-risk patients with acute cholecystitis, especially drainage success rate, clinical remission, and adverse events. Also, their impacts on cholecystectomy will be focused and targeted, including difficulty grading of cholecystectomy, cholecystectomy duration, pathology, and so on.2.3The trial is an investigator-initiated, parallel group, single-center, randomized controlled, with the allocation ration of 1:1, non-blind trial; however, the statistician would not know the grouping.2.4This manuscript written adheres to SPIRIT 2013 Statement.2.5The trial would be set at an university affiliated tertiary-care A hospital center, which performs approximately more than 2000 Endoscopic Retrograde Cholangiopancreatography (ERCP) procedures per year. The outline of trial procedures is presented in Figure 2.62.6.1Patients that were not considered suitable for early or urgent cholecystectomy because of high-surgical risk, in which case biliary drainage followed by delayed LC is recommended by the TG18 flowchart: Grade II (moderate) AC, antibiotics and general supportive care fail to control inflammation; Grade III (severe) AC, after antibiotics and general organ support, negative predictive factors present including jaundice (TBIL ≥2), neurological dysfunction, respiratory dysfunction, or no negative predictive factors present but American Society of Anesthesiologists physical status classification (ASA-PS) is 3 or greater or Charlson comorbidity index (CCI) is 4 or greater.2.6.22), consent refusal, coagulation dysfunction (INR > 1.5) and low-peripheral blood platelet count (<50 × 109/L), using anticoagulation or antiplatelet drugs; bile duct stones; prior surgery of Bismuth II, Roux-en-Y and choledochojejunostomy, preoperative coexistent diseases: acute pancreatitis, GI tract hemorrhage or perforation, severe liver disease , any malignant diseases.Exclusion of patients who meet one or more of the following criteria: age <18 or >90 years, pregnant or breastfeeding, severe obesity  or to the reference group (PTGBD). Of course, risks and benefits associated with surgery would be routinely communicated and agreed in writing.The experimental group patients are sedated by intravenous administration of sufentanil and propofol, then selective bile duct cannulation, a 0.025- or 0.035-inch guidewire is advanced into the cystic duct and subsequently into the gallbladder, withdraw the catheter, a 5Fr naso-gallbladder catheter is inserted into the gallbladder along the guidewire. PTGBD is guided by ultrasound, an 18-gauge needle is inserted into the gallbladder, a 0.035-inch guidewire is coiled into the gallbladder and a 9Fr dilator expands the skin, then an 8Fr 20 cm catheter is placed.When ENGBD was technically unsuccessful or clinically ineffective, endoscopic nasobiliary drainage (ENBD), PTGBD and EUS-GBD were used as alternative procedures. The patients of inclusion would be given appropriate and quality treatment at anytime, in order to reduce waiting and improve adherence. Properly trained volunteers would accompany patients on key treatments, such as ERCP and PTGBD, extubation, LC, etc. This not only improves adherence, because of the convenience to patients, but also monitors adherence to a certain extent.All patients of inclusion would be assessed by the attending physician in accordance with recent guidelines for AC management, including sufficient infusion, maintenance of electrolyte balance, antibacterial agents, the monitoring of respiratory and hemodynamics, correction of acidosis and complications.–17 figure out the short interval increases intraoperative difficulty, we require all patients to undergo cholecystectomy 3 months after drainage, so that edema and inflammation around the gallbladder subsided completely.In particular, there is no strict recommendation for extubation time, ENGBD group would extubate when the bile in the naso-gallbladder tube becomes clear, which is approximately 4 days after the drainage based on our experience. PTGBD group extubate after more than 2 weeks due to fistula formation. Also, no consensus has been reached about the optimal timing of LC after drainage. Because most studies2.82.8.1The primary outcome is the pain score, defined as pain experienced during mobilization from the supine to the standing position. Using the visual-analogue scale, pain score would be obtained within 2 hours before drainage and at post-drainage 24, 48, and 72 hours in conscious and communicating patients by a specially trained nurse, who devoted herself to the objectivity and authenticity of the scores. The details of assessment are as follows: draw a 10-cm line on a piece of paper, mark one end of the line with the number 0, indicating no pain; the other end with 10, indicating the most severe pain; the middle part indicates different degrees of pain. While assessing the pain of patients, make sure the patient could not see the numbers on the paper and let them mark the position according to their feelings about the pain. Then the nurse would get a score based on the mark. Pain scores reflect directly the degree of pain, the remission of pain not only relieves the pain symptoms associated with acute cholecystitis itself, but also relatively alleviates the severe pain caused by tube.In order to avoid the effects of anesthesia, we chose to evaluate the pain 24 hours after drainage. Especially, all pain assessments should be performed without the administration of pain killers or after using an analgesics for 6 hours. All modifications in pain management are recorded. Our team routinely prepares a multimodal approach to pain management, which is applied mainly based on nonsteroidal anti-inflammatory drugs and other adjuvant drugs, but tries to avoid applying it.2.8.2Table 2.9Please see Table 2.10 using the method provided by Luo et al and Wan et al, the median post-procedure pain score in the PTGBD group was 5.4 ± 3.1. And the mean visual analog score of post-procedure pain in the ENGBD group was 1.3 by Itoi et al. Using a theoretical sample size for two-sample design, nine participants are needed in each group with 80% power and a 5% significance level. Allowing for a 10% loss to follow-up, we plan to recruit 22 patients (11 in each group).The sample size calculation is based on the primary outcome-the pain score after drainage. According to the research by Jang et al,2.11The recruitment would last 20 months, which began in June 2018. This duration was estimated based on the number of admissions for surgical high-risk AC patients at the team in previous 2 years. To achieve adequate participant enrollment, relevant work on the study would be performed around the clock, including nights and weekends as routine clinical practice.2.12The randomization numbers were generated by statistician using computer program with 1:1 allocation, stored and encoded 20 sealed, opaque envelopes independently. When a participant meets inclusion and inclusion criteria, two volunteers first record the name and the code of the next unopened envelope, then open the envelope and sign their names. At last, the treatment assignment would be sent to the attending physicians, which could get only one allocation at a time after all pre-drainage preparations were completed, including the evaluation of patients and informed consent of participants.2.13This is an open-label, unblinded trial for patients and physicians because of the nature of the intervention (position and shape of drainage tube). However, the investigator of collecting secondary outcomes, the assessor of clinical and biological data in charge of statistical analyses and outcome assessment will be masked as to the subjects assigned group.2.142.14.1All data are prospectively collected and managed by the well-trained research volunteers. white blood cell (WBC) count, electrolytes, total bilirubin, C-reactive protein (CRP), and so on. This would systematically reflect the characteristics of participants.The baseline data would be collected and registered on inclusion: age, sex, body mass index (BMI), body temperature, interval between onset of AC and drainage, comorbidities and coexisting conditions, american society of anesthesiologists (ASA) grade, charlson comorbidity index (CCI), AC grade based on TG 18 severity grading,The peri-drainage data would be obtained from 2 hours before drainage to one week after ENGBD or PTGBD, such as drainage success, clinical remission, adverse events, pain scores within 2 hours before drainage and at post-drainage 24 h, 48 h, 72 h, etc.The following data are collected and registered on peri-LC: gallbladder wall thickness changes (pre-drainage to pre-LC), duration and hemorrhage of LC, gallbladder integrity, drainage tube, hospitalization , surgical site infection, severe adhesion, pathology, and LC-related complications.Results that are negative or undetected or measured as 0 should have corresponding symbolic representation and can not be vacant, in order to distinguish from missing values. The treatment of outliers should be judged from both medical and statistical aspects by the statistician during blind examination.Images and biological samples including venous blood and bile will be collected for probably ancillary and long-term research. Also, all patients will be followed up 6 months after cholecystectomy.The volunteers of data acquisition have rich clinical experience and rigorous working attitude, and received training and guidance. Data storage would be carried out by two independent investigators to ensure reliability and validity.We would also pay attention to and collect the information of the participants who discontinue or deviate before cholecystectomy and the follow-up are completed. To promote participants’ retention and enthusiasm, we would establish workflow manuals contact patients regularly, communicate properly and take effective care of their health.2.14.2P values of <.05 were considered to represent statistical significance. Categorical variables would be reported as counts and percentages. The mean and standard deviation or median with interquartile ranges (IQR) were used to describe continuous variable data, as appropriate.A predefined statistical analysis plan will be followed. All statistical analyses were conducted with IBM SPSS (version 21.0). The primary analysis is a comparison between ENGBD and PTGBD for the pain remission based on an intention-to-treat principle. A multilevel, random-slope model would be fitted to the data with time points nested in patients to allow for clustering of data within each patient. This model adjusted for the fixed effects of treatment group, time , and treatment × time interaction. An unstructured covariance pattern was selected for the repeated measurements as the least restrictive structure, which resulted in better model fit based on log-likelihood values than more constrained patterns. Estimates of the difference in pain scores between treatment groups were assessed overall and at individual time points.t test is used, if the normal distribution and homogeneous total variance are satisfying, otherwise, Wilcoxon test is used.The secondary analysis is a comparison between ENGBD and PTGBD for the rates of technical and clinical success, adverse events, and changes in the gallbladder wall thickness . Also, the outcomes during cholecystectomy including time duration, open conversion would also be analyzed. The Chi-square test or Fisher exact test was used for dichotomous variables, and Wilcoxon test was used for rank data. For quantitative data, two-tailed Student A blinded adjudication committee will assess the occurrence of the primary and secondary endpoints after the last patient has completed follow-up.2.15Setting up a data monitoring committee and interim safety analysis are unnecessary because of the high security and short cycle of this trial.2.16All adverse events thought to be related to the trial would be recorded rigorously and carefully. Any unexpected major serious complications suspected to be associated with ENGBD must be reported to interviewer and attending physicians, the trial may be temporarily stopped, and effective treatment measures in the first place will be taken by attending physicians.2.17A auditing committee consisting of an endoscopist, a surgeon and a sonographer, would monitor the trial at least once every 3 months. They remain independent from investigators and audit the frequency, procedures, and safety of the trial.2.18Any changes to eligibility criteria, outcomes, and analyses would obtain approval from the ethics committee and the clinical trial.2.19Data would be handled in a confidential way. During the whole experiment, sensitive information such as the patient name, identity card number would not be exposed by coding.2.20All investigators would have access to the final trial data set after the end of the study.2.21Data analysis, interpretation, and findings would be presented at academic conference and published in peer-reviewed journals. After the end of the trial, the interviewer will complete the writing and submit the manuscript via open access as soon as possible. Every participant would get the results and conclusions by mail.3To our knowledge, the study would be the first randomized controlled study powered to investigate the effect of ENGBD and PTGBD on peri-drainage and peri-LC in poor surgical AC population. Moderate and severe AC are usually associated with increased morbidity and mortality if rushed cholecystectomy is performed, it is becoming increasingly difficult to ignore the optimal management of AC, which includes transitional and permanent drainage, especially when it comes to critically ill patients with multiple comorbidities. Part of the reason may be that ENGBD has to precisely over-select into the difficult visualizing, long, narrow, tortuous cystic ducts, which is a challenge because the ducts could be blocked by stones. The weighted pooled rates for technical success of ENGBD is 81% according to a proportion meta-analysis. However, this technique uses standard off-the-shelf ERCP accessories and can be performed in patients who are coagulopathic or using antiplatelet or anticoagulant agents, and it has certain advantages including better drainage effect which can be observed directly, convenient removal of drainage tube, no establishment of abnormal anatomic fistula, and so on. Thus, it may be regarded as a bridging therapy for acute cholecystitis followed by interval surgical cholecystectomy. Unfortunately, the impact of ENGBD on LC is rarely reported.Only one small retrospective discovery of limited quality compared the ENGBD and PTGBD in AC patients to date. However, it has a high risk of conversion to an open procedure during cholecystectomy by a multicenter analysis.Compared to direct surgery, PTGBD shortens the operative duration of LC in patients with moderate to severe AC.As a large surgical endoscopy center that completes more than 2000 ERCPs per year, our team not only has a rich experience in cholecystectomy, but also masters excellently the endoscopic minimally invasive technique, we are confident to complete this major impact study. The trial has the potential to optimize drainage management with direct and realistic benefits for critical AC patients. It is worth mentioning that we would also pay attention to the effects of the two drainage methods on the cholecystectomy. If the study finds out that ENGBD may contribute to late cholecystectomy, it will be an excellent alternative or a powerful complement to PTGBD.4The current study protocol is version 3.0 . The trial opened to recruitment on October 10, 2018. Maybe we would complete the recruitment on October 10, 2020.The authors would like to thank Dr Hao Xu from our medical center for giving us assistance during the therapeutic process.All authors approved the final manuscript. PLM and PY make the same contribution to this work. PLM: protocol development, drafting of this manuscript, critical revision of the manuscript for significant intellectual content. PY: Taking responsibility in execution of the trails and patient follow-up. BB, YYL: providing personnel, environmental support and tools and instruments that are vital for the project. HPW, JY: taking responsibility in statistical analysis, logical interpretation and presentation of the results. TYL, YL: reviewing the article before submission not only for spelling and grammar but also for its intellectual content. WBM, XL: constructing an idea or hypothesis for manuscript, planning methodology to reach the conclusion, and providing financial support.Peilei Mu: 0000-0003-3513-9513Ping Yue: 0000-0001-8736-949XBing Bai: 0000-0001-8672-8569Yanyan Lin: 0000-0001-7417-0190Jinduo Zhang: 0000-0002-3425-9614Haiping Wang: 0000-0002-7771-5077Ying Liu: 0000-0002-0997-4480Jia Yao: 0000-0002-0811-8287Wenbo Meng: 0000-0002-9355-0225Xun Li: 0000-0003-3787-1558


Pain, agitation-sedation and delirium management are crucial elements in the care of critically ill patients. In the present study, we aimed to present the current practice of pain, agitation-sedation and delirium assessments in Chinese intensive care units (ICUs) and investigate the gap between physicians’ perception and actual clinical performance.We sent invitations to the 33 members of the Neuro-Critical Care Committee affiliated with the Chinese Association of Critical Care Physicians. Finally, 24 ICUs  from 20 hospitals participated in this one-day point prevalence study combined with an on-site questionnaire survey. We enrolled adult ICU admitted patients with a length of stay ≥24 h, who were divided into the brain-injured group or non-brain-injured group. The hospital records and nursing records during the 24-h period prior to enrollment were reviewed. Actual evaluations of pain, agitation-sedation and delirium were documented. We invited physicians on-duty during the 24 h prior to the patients’ enrollment to complete a survey questionnaire, which contained attitude for importance of pain, agitation-sedation and delirium assessments.p = 0.003 and < 0.001). Delirium assessment was only performed in three patients . In questionnaires collected from 91 physicians, 70.3% (95% CI: 60.8–79.9%) and 82.4% (95% CI: 74.4–90.4%) reported routine use of pain and agitation-sedation scale assessments, respectively. More than half of the physicians  reported daily screening for delirium using an assessment scale.We enrolled 387 patients including 261 (67.4%) brain-injured and 126 (32.6%) non-brain-injured patients. There were 19.9%  and 25.6% (95% CI: 21.2–29.9%) patients receiving the pain and agitation-sedation scale assessment, respectively. The rates of these two types of assessments were significantly lower in brain-injured patients than non-brain-injured patients (The actual prevalence of pain, agitation-sedation and delirium assessment, especially delirium screening, was suboptimal in Chinese ICUs. There is a gap between physicians’ perceptions and actual clinical practice in pain, agitation-sedation and delirium assessments. Our results will prompt further quality improvement projects to optimize the practice of pain, agitation-sedation and delirium management in China.NCT03975751. Retrospectively registered on 2 June 2019.ClinicalTrials.gov, identifier The online version contains supplementary material available at 10.1186/s12871-021-01286-w. Pain, agitation-sedation and delirium (PAD) management is one of the key elements in the care of critically ill patients. To date, several guidelines and consensus statements have recommended that the comprehensive evaluation of PAD is the first step in optimizing analgesia and sedation in the intensive care unit (ICU) –3. HowevCritically brain-injured patients pose particular challenges in PAD management , 10. AltIn this study in Chinese ICUs, we primarily aimed to present the current practice regarding PAD assessments, which was compared with the physicians’ perception of the practice obtained from an on-site questionnaire survey. We also deliberately focused on PAD management in ICU-admitted brain-injured patients.The study design was a cross-sectional one-day point prevalence investigation combined with an on-site questionnaire survey. The IRB of Beijing Tiantan Hospital approved the study protocol (KY2017–062-02), which was registered at ClinicalTrials.gov (NCT03975751). The study was conducted in accordance with the declaration of Helsinki (1964). Written informed consent was obtained from each patient or their next of kin.We sent invitations to the 33 members of the Neuro-Critical Care Committee affiliated with the Chinese Association of Critical Care Physicians  by emailAll adult patients admitted to the participating ICUs during the on-site investigation were enrolled in the present study. The exclusion criteria included age under 18 years, less than 24 h of ICU stay before the screening, and taking part in other studies.The patients were predefined as belonging to the brain-injured group when their primary diagnoses were traumatic brain injury, stroke , hypoxic-ischemic encephalopathy, elective craniotomy for brain tumor, intracranial infection, idiopathic epilepsy, and cranial venous sinus thrombosis . OtherwiA uniform case report form was designed to collect the data  and Acute Physiology and Chronic Health Evaluation II scores at admission to the ICU. Nursing records during the 24-h period prior to enrolment were reviewed, and data were collected, including sequential organ failure assessment (SOFA) score, the presence of artificial airways , the use of mechanical ventilation , the presence of arterial lines and central venous catheters, the presence of any types of drainage tubes , the use of intracranial pressure monitoring, the performance of body temperature control , the presence of physical restraints, the PAD assessment , the use of analgesics, sedatives, anti-delirium drugs and neuromuscular blocking agents . The total daily dose of opioids was converted to the equianalgesic dose of fentanyl as previously reported ) than that in the brain-injured group  , pain assessment was performed more often  but agitation-sedation assessment was performed less often  in patients admitted to neuro-ICUs compared to those admitted to other types of ICUs  and 178 (68.2%) admitted to neuro-ICUs and other types of ICUs, respectively. Although the overall rate of assessment of pain and agitation-sedation did not differ between patients admitted to neuro-ICUs and other types of ICUs , 29.7% (95% CI: 25.1–34.3%) and 18.3% (95% CI: 14.5–22.2%), respectively. The three types of agents were administered less frequently in brain-injured patients than in non-brain-injured patients  using the CAM-ICU; the patients were two brain-injured patients and one non-brain-injured patient. Anti-delirium agents were used in six patients (three in the brain-injured group and three in the non-brain-injured group), with four administered haloperidol and two administered olanzapine. No patient received neuromuscular blocking agents during the 24 h prior to enrolment.n = 61) than in brain-injured patients (n = 77), but no significant differences in the doses of other sedatives and opioids were found between the two groups , oAmong the 91 physicians taking part in the survey, 63  reported that there was a written analgesia and sedation protocol in their units. There were 64  and 75  physicians who reported the routine use of pain and agitation-sedation scale assessment, respectively  physicians reported very frequent/frequent combined use of analgesia and sedation.We found that the point prevalence of PAD assessment was suboptimal, especially for delirium screening, in Chinese ICUs. A significant gap existed between the actual practice and the physicians’ perception of the practice. To the best of our knowledge, this is the first study reporting the real practice of PAD management in Chinese ICUs.In accordance with the results of previous studies , 6, we aEarly quality improvement studies have shown that the routine incorporation of pain and agitation-sedation assessments into clinical practice can reduce the incidence of pain and agitation, reduce the duration of mechanical ventilation and rate of nosocomial infections, and decrease the need for analgesics and sedatives , 28. RecAlthough evidence has shown that pain and sedation assessments are feasible and reliable in the majority of brain-injured patients , 13, barDiagnosis of delirium in brain-injured patients with coma is controversial. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition , the disIn our patients without brain injury, the rates of administration of opioids (40.8%), sedatives 41.8%) and the combination of the two types of agents 31.7%) were comparable to those reported by Richards-Belle et al. in the United Kingdom  [.8% and t1.7% wereThere are limitations in the present study. First, the limitations inherent in point prevalence studies and questionnaire surveys could not be avoided in the present study. Because the questionnaires used in survey studies on PAD management were relatively confirmative –7, we diIn conclusion, in critically ill patients admitted to the Chinese ICUs, we found that the actual PAD assessment rate was suboptimal, especially with regard to the delirium screening. A gap existed between physician perception and actual practice in clinical performance. Our results highlight the need for prompt quality improvement and the optimization of practices of PAD management in ICUs in China. A standard PAD management protocol should be established for critically brain-injured patients.Additional file 1. Case report form for cross-sectional investigation.Additional file 2. Predefined survey questionnaire for on-site survey.Additional file 3: Figure S1. Distribution of 20 recruited hospitals.Additional file 4. Analyses of the questionnaire surveys.


There is a large incidence of shoulder instability among active young athletes and military personnel. Shoulder stabilization surgery is the commonly employed intervention for treating individuals with instability. Following surgery, a substantial proportion of individuals experience acute post-operative pain, which is usually managed with opioid pain medications. Unfortunately, the extended use of opioid medications can have adverse effects that impair function and reduce military operational readiness, but there are currently few alternatives. However, battlefield acupuncture (BFA) is a minimally invasive therapy demonstrating promise as a non-pharmaceutical intervention for managing acute post-operative pain.This is a parallel, two-arm, single-blind randomized clinical trial. The two independent variables are intervention  and time . The primary dependent variables are worst and average pain as measured on the visual analog scale. Secondary outcomes include medication usage, Profile of Mood States, and Global Rating of Change.The magnitude of the effect of BFA is uncertain; current studies report confidence intervals of between-group differences that include minimal clinically important differences between intervention and control groups. The results of this study may help determine if BFA is an effective adjunct to physical therapy in reducing pain and opioid usage in acute pain conditions.NCT04094246. Registered on 16 September 2019.ClinicalTrials.gov  Shoulder and glenohumeral instability are serious problems for athletes and military personnel –6. In geManagement of shoulder dislocations usually includes shoulder stabilization surgery, which is considered the “gold standard” for treatment of shoulder dislocation in young, active patients , 9–11. TPhysical therapy interventions focus on reducing pain and physical impairment associated with shoulder surgery. Standard care for patients post-shoulder surgery consists of two phases: (1) early rehabilitation from 24 h to 2 weeks post-surgery and (2) mid-term rehabilitation from 2 to 6 weeks post-surgery. Early rehabilitation after shoulder stabilization surgery focuses on pain control, protection of the surgical repair, prevention of a “stiff” shoulder, and regaining scapular control –15. WithOpioid prescription is the widely employed method to manage post-operative pain in both Civilian and Military Health Systems. In representative civilian populations, 26% of patients undergoing arthroscopic shoulder procedures received at least one refill of their opioid prescription following surgery compared to 12% and 13% of patients following hip and knee procedures, respectively . The VetBattlefield acupuncture (BFA), an auricular acupuncture protocol developed to treat acute and chronic pain in austere environments , may proBFA has been taught and adopted throughout all branches of the Department of Defense (DoD) over the past two decades to provide alternatives to side effect laden prescription medications . DespiteBFA is an integrative pain treatment method that may be effective in reducing pain and opioid use post-surgery. The purpose of this study is to determine differences in pain, mood, self-reported improvement, and medication use during and after a standard physical therapy rehabilitation protocol supplemented with BFA, compared to a standard physical therapy rehabilitation protocol alone, for patients following shoulder stabilization surgery. The primary objective is to assess the effect of BFA on post-surgical pain (average and worst pain at 48 h and 72 h post-surgery). We hypothesize standard rehabilitation supplemented with BFA will produce greater reductions in pain compared to standard rehabilitation alone at 48 h and 72 h post-surgery.Additional objectives are to assess the effect of BFA on: (1) medication use, (2) mood, and (3) self-reported improvement throughout the 4-week post-operative rehabilitation period, and (4) pain at 1 week and 4 weeks post-surgery. It is hypothesized that participants receiving standard rehabilitation supplemented with BFA will have greater reductions in medication use and improvements in patient’s self-reported mood and improvement across the 4-week post-operative follow-up period. Further, participants receiving standard rehabilitation with BFA will have lower pain levels at 1 and 4 weeks post-surgery compared to those receiving standard rehabilitation only.This study is a parallel, two-arm single-blind randomized clinical trial. All participants will complete five study sessions following surgery: 24 h, 48 h, 72 h, 1 week, and 4 weeks post-surgery Fig.  28]. Re. Re28]. Participants will be recruited from the population of patients presenting to the Arvin Cadet Physical Therapy Clinic and the Keller Army Community Hospital (KACH) Physical Therapy and Orthopedic Clinics prior to and status-post shoulder stabilization surgery. A total of 105 male and female Department of Defense (DoD) beneficiaries, ages 17–55 will be recruited for the study. A 15% drop-out rate is anticipated, which will result in at least 90 patients completing the study, with 45 patients per treatment group. On average KACH orthopedic surgeons perform eight shoulder stabilization surgeries monthly, suggesting the recruitment goal is feasible.DoD beneficiaries age 18 to 55 years old (17 if cadet)Prior to or within 24 h post shoulder stabilization surgerySelf-reported pain rating of at least 2 out of 10 on a Numerical Pain Rating Scale (NPRS)Inclusion criteria:Self-reported pregnancyHistory of bloodborne pathogens, infectious disease, or active infectionHistory of metal allergyHistory of bleeding disorders or currently taking anti-coagulant medicationsParticipants not fluent in EnglishExclusion criteria:Participants will be screened prior to consent as part of routine clinical care by the investigative team during the first post-operative visit, 24 h after surgery. Those meeting criteria for inclusion will be informed as to the need and purpose of the research and invited to participate. Study participants will complete informed consent followed by a baseline examination . ConsentParticipants and the treating physical therapists will not be blinded to group assignment. Verification of the medication log by the outcome assessor may be another source of bias. Outcome assessors who record pain, self-report function, and mood surveys, perform data reduction, and perform data analysis will be blinded to the participants’ treatment group. Participants frequently require clarification of outcome measure instructions during completion of data collection forms and may require additional assistance if the surgery is performed on their dominant extremity. Participants will interact with the outcome assessor and complete data collection forms behind a closed curtain, where the outcome assessor is not able to see the patient. Non-standard blinding techniques are often implemented in trials assessing nonpharmacological treatments and may minimize either conscious or unconscious researcher recording and reporting bias during completion and verification of the data collection forms .Both groups will receive standard post-surgical physical therapy according to guidelines developed at our institution , and ear cleansing with an alcohol swab), auricular acupuncture using the five points specified within the BFA protocol will be administered. Each ear will potentially be punctured with ASP needles at five sequential points: cingulate gyrus, thalamus, omega 2, point zero, and Shen-Men Fig. . The acuThere is no standard time for the ASP needles to remain in the participant’s ears, but they may remain up to 3–5 days as they naturally work their way out of the skin. Participants will be instructed on how to properly care for and remove the ASP needles should they become irritating. There are no documented cases of loss of treatment effect should participants remove ASP needles prematurely to their natural falling out. All participants in the study intervention group will receive BFA treatment at the initial (24-h) time point. Repeat treatment intervention may be provided during the 48-h, 72-h, and 1-week follow-up visits, but will not coincide with standard physical therapy rehabilitation sessions. The decision whether BFA intervention will be provided during the follow-up visits of the intervention group participants will be left to the discretion of the treating physical therapist and preference of the patient. Treating physical therapists will take into account the patient’s current pain level and prior response to BFA. Additionally, for each participant, the number of BFA interventions executed, the number of ASP needles inserted at each intervention, and the location of each needle’s placement will be recorded for descriptive analyses. If ASP needles remain in place at follow-up visits and the patient requests additional treatment, additional ASP needles will be placed adjacent to locations used previously.All BFA treatments will be performed by investigators trained and certified on the standard BFA protocol developed by Dr. Niemtzow . ParticiDemographic characteristics will be recorded and include sex, age, ethnicity, military demographics, height, weight, and surgical history. The primary outcome measure will be pain  at 24 h, 48 h, 72 h, 1 week, and 4 weeks after surgery. Two previous studies suggest that the greatest effect of BFA on pain occurs at 1 week or less , 34. SecThe VAS assesses the perception of pain intensity by asking the patient to mark their level of pain along a 100-mm line, where the left limit indicates no pain and the right limit indicates the worst pain imaginable , 36. TheThe POMS is a 40-item questionnaire designed to measure the transient emotional states of tension-anxiety, depression-dejection, fatigue-inertia, vigor-activity, confusion-bewilderment, and anger-hostility in sports and other settings .The GROC is a 15-point self-report Likert scale  of patient-perceived status since the onset of treatment . The GROAt each visit, the physical therapist will assess the surgical site and neurological status of the patient. The area of treatment will be examined for those patients who have received BFA. Any side effects or adverse events will be recorded in the patient’s electronic medical record and either treated or referred to an appropriate medical provider for treatment. Serious adverse events will be reported to the IRB in accordance with the approved study protocol. At the conclusion of the study, each patient’s medical record will be screened for any adverse events.α = 0.05, β = 0.80, and an effect size of 0.6 (change in VAS worst pain between 24 h and 1 week post-surgery), resulting in a required sample of 90 participants. The effect size was determined through examination of data from a previous published study at the same institution [An a priori power analysis was performed using G*Power, version 3.1.9.2  with titution . To accot test, and time using paired t tests. Alpha for planned pairwise comparisons will be corrected using the Sidak’s correction to control for family-wise type I error. The Cohen d coefficient will be used to assess the effect size between pairwise comparisons. Prior to performance of the ANOVAs, all outcome measures will be assessed for normality. The appropriate non-parametric statistical tests will be used for any non-normality distributed outcomes.Descriptive statistics, including measures of central tendency and dispersion, will be calculated for demographic data. Frequency distributions will be estimated for categorical data. Four separate 2-by-5 mixed-model analyses of variance (ANOVA) with group as the between-subjects factor  and time as the repeated measure within-subjects factor  to determine the effect of BFA on pain, medication use, self-reported improvement (GROC), and mood (POMS) over the 4-week post-operative period. Alpha will be set at 0.05 for all omnibus comparisons, which are the group*time interaction, the main effect for group (fixed factor), and the main effect for time (repeated measure). Planned pairwise comparisons will be performed to examine significant main effects for group using independent When post-intervention data points are missing, data will be replaced using multiple imputation for participants who received their allocated intervention . All staThe purpose of this study is to determine differences in pain, mood, self-reported improvement, and medication use during and after a standard physical therapy rehabilitation protocol supplemented with BFA, compared to a standard physical therapy rehabilitation protocol alone, for patients following shoulder stabilization surgery. BFA may be an effective adjunct to physical therapy to reduce pain and opioid utilization in patients with acute pain , 27, 34.This study is not without limitations and design constraints. The primary limitation is physical therapists and patients are not blinded to treatment groups. Many non-physiologic factors, including placebo effects, may contribute to treatment response in patients who have received BFA. We elected to forgo a sham treatment group due to the lack of feasibility in maintaining a realistic sham treatment at our institution. The most recent study of BFA that utilized a sham intervention applied the treatment while the patient was still under anesthesia (Crawford 2019). BFA represents a low-risk and low-cost alternative method of pain control when compared to opioid medications, making the potential for a placebo contribution to the response to treatment more acceptable , 45. BliThis study was approved by the RHC-A IRB; protocol ID number 19KACH0003, initially approved 3 September 2019, modification approved 28 October 2019. Recruitment began 25 September 2019 and will be tentatively completed in December 2022.Additional file 1.SPIRIT 2013 ChecklistAdditional file 2. Shoulder Stabilization Rehabilitation GuidelinesAdditional file 3. Battlefield Acupuncture Intervention


Pain remains a prevalent symptom for rheumatoid arthritis (RA) patients despite a wide therapeutic choice. The objective of this study was to provide a multidimensional evaluation of pain.A total of 295 RA patients from 7 French rheumatology centres were enrolled in a cross‐sectional study. Patients completed a chronic pain assessment questionnaire approved by the French National Authority for Health, the health assessment questionnaire (HAQ) as well as depression and anxiety scales . Disease activity (DAS28) and ESR were recorded. A multivariate descriptive analysis was undertaken using principal component analysis (PCA).38.4% of patients had a pain score > 40 mm/100, although 83% were on biological treatment and 38.7% were in remission based on the RA activity score. The PCA analysis found four axes representing 70% of total variance. The axes, per cent of variance and variables represented were as follows: (a) axis 1, 41% variance, anxiety and depression scores, sensory and affective qualifier score, HAQ and pain impact on daily life; (b) axis 2, 13% variance, disease activity score (DAS28) and pain relief with current treatment; (c) axis 3, 9% of variance, RA duration and radiographic score and (d) axis 4, 6% of variance, DAS28 and ESR. Moderate to severe pain was significantly associated with axes 1 and 2.Despite a high proportion of patients on biological treatments, 38.4% of patients continue to experience moderate to severe pain. Pain is associated with the RA activity score, but also with the depression and anxiety scores.Substantial proportion of rheumatoid arthritis (RA) patients still experiences relevant pain, although more than 80% on biological treatment. Pain is primarily associated with anxiety and depression scores and with disease activity score. These findings highlight the need to assess patients’ mental well‐being alongside. Clinical measures of disease activity to better manage pain and guide treatment decisions. Inflammation and joint destruction are traditionally considered to cause nociceptive pain, but the intensity of the pain does not always correlate with the disease activity score (DAS) and structural damages. In recent years, there have been many improvements in RA treatment with the emergence of biological Disease‐Modifying Anti‐Rheumatic Drugs (bDMARDs) frequently associated with synthetic DMARDS (sDMARDs) (e.g. methotrexate). Fewer patients have severe inflammatory and destructive disease. Nevertheless, across multiple areas of health measures, pain relief remains a priority for patients  have an emerging role in pain regulation  Carry out an assessment of pain and of its various components in RA patients managed in a hospital setting with current treatments and without fibromyalgia, (b) Assess the links between different RA characteristics, emotional state, functional state and pain and (c) Compare the effects of different DMARDS on pain.2This is a cross‐sectional, multicenter, descriptive observational study conducted in seven French rheumatology centres (NCT01706029).2.1Patients willing to participate in the study were recruited in the course of in‐ or outpatient care between October 2012 and December 2014. The study was conducted following approval of a French regional Ethics Committee and all patients gave their written informed consent prior to their inclusion in the study.To be eligible for the study, patients had to have established RA according to the 1987 ARA criteria , progressive cancer or lymphoproliferative disease, severe psychiatric conditions and dementia, acute infectious diseases or being less than 18 years of age.Patients with fibromyalgia (with the 1999 ACR criteria) were excluded to not interfere with pain and psychological assessments.2.2https://has‐sante.fr/upload/docs/application/pdf/douleur1.pdf), a questionnaire containing elements of the Brief Pain Inventory  of 100 mm or a numeric scale (NS) from 0 to 10 (if VAS was not comprehensible) to assess the pain currently experienced, the average pain intensity experienced over the last 8 days (VAS8d) and the most intense pain experienced over the last 8 days.Different pain qualifiers (short‐form Mc Gill Pain questionnaire) to measure pain experienced , with a scale for each ranging from 0 (absent), through 1 (weak), 2 (moderate) and 3 (strong) to 4 (extremely strong). The scores have been expressed as percentages of the total score for each of the two categories.The Hospital Anxiety and Depression Scale (HAD) .A scale for assessing the interference of pain in daily life including 6 areas , each with a scale of 0 to 10.Evaluation of pain relief with current treatment The main outcome was the multidimensional assessment of pain carried out using a chronic pain assessment questionnaire for adults, as approved by the French National Authority for Health (HAS)  (scores range from 0 to 3).Short‐form of Beck depression Inventory (BDI)   with a STAI‐state score (STAI‐A) and a STAI‐trait score (STAI‐B) (scores range from 0 to 80 for each)   and treatment histories for sDMARDs and bDMARDs.The secondary outcomes were as follows:2.3® 9 software  and R v3.3.2 . The STROBE recommendations were followed  of the Limoges University Hospital using SASA descriptive analysis of the data was performed first in the total sample then in subgroups: (a) patients with VAS8d < 40 mm versus ≥40 to separate patients with moderate and severe pain from those with only mild pain  was computed on all explanatory highly correlated quantitative variables with VAS8d  as an illustrative variable. Two complementary analyses were also computed with (a) "the most intense pain experienced in the previous 8 days"  and (b) "current pain"  as illustrative variables.T‐test was also performed by modality of the illustrative variable studied to determine whether the coordinates of the individuals on the axis varied significantly from the average coordinates.A one‐way analysis of variance was performed for each new axis to compare the coordinates of the individuals on this axis differed depending on the illustrative variable studied . For the following variables: current pain VAS, Last 8 days average pain VAS and Worse pain VAS, if some data were missing, they were replaced by the associated pain numeric scale (0 to 10) multiplied by 10 to have a score on 100.3A total of 299 RA patients were eligible; 295 were included and completed the study, 3 patients did not meet the inclusion criteria and 1 patient withdrew consent. Seventy‐two patients were not eligible because they fulfilled the 1999 ACR fibromyalgia criteria.3.1Patient demographics and RA characteristics are shown in Table 3.2In terms of pain management, satisfaction was generally good, as shown in Figure However, a high percentage of patients (38.4%) had a VAS8d ≥ 40 mm/100, while 13.7% had a VAS8d ≥ 70 mm/100 Figure . The meaAmong terms used by patients to describe their pain, emotional terms were more commonly cited than sensory qualifiers (24.4% ± 25.0 as against 19.4% ± 17.0 respectively). HADS scores were suggestive of clinically important anxiety or depression , emphasized by the more accurate Beck scale (moderate or severe depression in 34.4% of cases) and STAI scores . Among our RA population, 21 patients (7.1%) had an history of depression and 16  were on antidepressants. In terms of the impact of pain on daily life, the most significant was the impact on working life, followed by the effects of pain on sleep and mood.3.33.3.18d ≥ 40 mm/100), the depression and anxiety scores, HAQ score, sensory and emotional pain qualifier scores, impact on daily life score and DAS28 score were significantly higher than in patients with a VAS < 40 mm. There was no difference between the two groups in terms of immunological status, duration of the RA or structural damage.As shown in Table 3.3.2Patients treated with sDMARDs only, those treated with bDMARDs only and those receiving a combination of both treatments did not differ in terms of quantitative and qualitative pain parameters or in relation to the impact of pain on daily life (Data S1). The results were identical with the analysis of the biological DMARDs subgroups  (Data S1).3.48d (<40 and ≥40 mm/100) serving as an illustrative variable. A total of 197 patients were included in the PCA analyses, these patients had non‐missing data concerning the variables included in the analysis. Four axes were retained, they represent a total variance of 70%  , the depression scores , the sensory and emotional qualifier scores, the HAQ score and the various scores for the impact of the pain on daily life. This axis, therefore, represented the emotional aspect of the pain and its impact. A high value on this axis corresponded to a high values of the corresponding variables.R2 = 32%, p < 0.0001) As compared to mean patient coordinates, patients in the VAS8d ≥ 40 group had significantly higher coordinates (p < 0.0001), while patients in the VAS8d < 40 group had significantly lower coordinates (p < 0.0001)  showed that the pain level was associated with this axis . As compared to mean patients’ coordinates, patients in the VAS8d ≥ 40 group had significantly higher coordinates (p < 0.0001) and the patients in the VAS8d < 40 group had significantly lower coordinates (p < 0.0001).The analysis of the individuals’ coordinates on axis 2 in relation to the pain level  showed that the pain level correlated with this axis .The variables contributing to axis 3 were the RA duration and the SENS radiographic score. The pain level was not associated with this axis .Axis 4 was mostly represented by the ESR and the DAS28. A high value on this axis corresponded to a high DAS28 and ESR value. The pain level was not associated with this axis  , which represent axis 3.Nieuwenhuis, de Wit, Boonen, and van der Helm‐van Mil  assessedMcWilliams et al. identified subgroups of patients for which there was concordant or discordant data between patient‐reported symptoms and inflammation criteria (worse PROMs despite less markedly elevated inflammation or less severe PROMs despite elevated inflammation) (McWilliams, Ferguson, Young, Kiely, & Walsh, There are some limitations, our study is cross‐sectional and does not allow us to assess fluctuations in pain over time. The RA patients were included in various French hospitals with a high prevalence of biologic treatments. This, therefore, limits the extent to which our results can be generalized. We have not assessed cognitive aspects of pain such as “coping” or “catastrophism”. PCA analysis was only performed with two thirds of patients because of missing data. The absence of relation between the duration of the illness, structural injuries and pain could be linked to a lack of statistical power. Others mechanisms may contribute to residual pain. Fibromyalgia has a higher prevalence in RA compared to general population. We used the ACR 1990 criteria to exclude fibromyalgia in our population, but a misclassification of putative associated fibromyalgia cannot be excluded. The second hypothesis is central sensitization. Indeed, joints affected by active synovitis are more sensitive to pain due to peripheral sensitization induced by local inflammation. Increased and sustained nociceptive input from joints, blunting of normal pain modulation and neuroinflammation with activation of microglia by cytokines and chemokines can trigger dysregulation of central nervous system named central sensitization (McWilliams & Walsh, However, we were committed to carry out a multidimensional assessment combining different quantitative and qualitative aspects, including the psychological component, and the effect on functional ability and behaviour in daily life. Moreover, the use of a descriptive statistical approach including PCA allowed us to clarify the information obtained during assessments by identifying the variables that were correlated, and by the combination of the variables into four synthetic axes.The results of this study should have an impact on patient's daily care. More than a third of RA patients suffer from moderate to severe pain despite a high proportion of patients on biological treatment. For those patients still suffering from pain, given the strong association of pain and depression/anxiety showed in the present study, a mechanistic multidimensional analysis of the pain could avoid inappropriate therapeutic escalation of DMARDs and should offer a more tailored care. The link between anxiety/depression and persistent pain suggests a broader approach to manage these patients, in particular, include a systematic evaluation of such symptoms in the core set of rheumatologic tools. In the future, it would be interesting to develop a simplified questionnaire in order to assess various aspects of the pain in RA and to provide direction for the clinician.None.PVS and PB designed the study protocol and collected the data. PVS, SP, APT, ABL, MS, CR, RMJ, SP and PB collected the clinical data. PVS and APT wrote the manuscript. All authors discussed the results, revised the manuscript critically for important content and approved the final version.French regional Ethics Committee, Comité de protection des personnes du Sud‐Ouest et Outre‐mer 4, N° CPP12‐0.007/2012‐A00058‐35.The study complies with the Declaration of Helsinki.Data S1Click here for additional data file.


Abdominal surgery is common and is associated with severe postoperative pain. The transverse abdominal plane (TAP) block is considered an effective means for pain control in such cases. The quadratus lumborum (QL) block is another option for the management of postoperative pain. The aim of this study was to conduct a meta-analysis and thereby evaluate the efficacy and safety of QL blocks and TAP blocks for pain management after abdominal surgery.We comprehensively searched PubMed, EMBASE, EBSCO, the Cochrane Library, Web of Science and CNKI for randomized controlled trials (RCTs) that compared QL blocks and TAP blocks for pain management in patients undergoing abdominal surgery. All of the data were screened and evaluated by two researchers. RevMan5.3 was adopted for the meta-analysis.p < .001), 4 h ,6 h ,12 h  and 24 h ; postoperative morphine consumption at 24 h ; and duration of postoperative analgesia . There was no statistically significant difference between the two groups with regard to the incidence of postoperative nausea and vomiting (PONV) .A total of 8 RCTs involving 564 patients were included. The meta-analysis showed statistically significant differences between the two groups with respect to postoperative pain scores at 2 h (standardized mean difference [Std.MD] = − 1.76; 95% confidence interval [CI] = − 2.63 to − 0.89; The QL block provides better pain management with less opioid consumption than the TAP block after abdominal surgery. In addition, there are no differences between the TAP block and QL block with respect to PONV. There are many kinds of abdominal surgeries, including but not limited to colorectal resection, appendectomy, cesarean section, hysterectomy, and laparoscopic cholecystectomy . PostopeAs effective constituents of multimode analgesia, quadratus lumborum (QL) block and transversus abdominis plane (TAP) block are mainly used for postoperative analgesia in abdominal surgery. At present, there have been meta-analyses –9 comparCompared with TAP blocks, the QL block, which is a regional variation of the TAP block, has been suggested to be a more reliable approach for pain after abdominal surgery. QL blocks result in more extensive sensory blocks than TAP blocks .Some studies –14 have Therefore, the purpose of this study was to evaluate, in the form of a meta-analysis, whether QL blocks or TAP blocks are superior for postoperative pain management and reduce the incidence of adverse reactions after abdominal surgery.The study was a meta-analysis, and ethics approval was not needed. This review and meta-analysis was reported on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).We searched the following databases (the time limit was from the establishment of the database to September 2019): PubMed, EMBASE, EBSCO, the Cochrane Library, Web of Science and CNKI. We identified randomized controlled trials (RCTs) comparing the use of QL blocks and TAP blocks for analgesia after abdominal surgery. The reference lists within these publications were also investigated to identify other qualified trials not found in the initial database search. No limitations were set with regard to the language of publication. The search terms included “quadratus lumborum block”, “QL block”, “transversus abdominis plane block”, “TAP block”, “abdominal surgery”, “abdominal wall”, “abdominal muscles”, “pain management”, “postoperative pain control”, and “postoperative pain management”.The inclusion criteria were as follow: (1) population: patients undergoing abdominal surgery; (2) study design: RCTs; (3) intervention: QL block; (4) comparison: TAP block; (5) primary outcomes: postoperative pain scores; and (6) secondary outcomes: postoperative opioid consumption, PONV incidence and postoperative analgesia duration. Two reviewers searched for and selected studies according to the abovementioned strategy. The specific process was as follows: (1) retrieved references were deduplicated using Endnote software; (2) screening was initially performed by reading the titles and abstracts; (3) the full texts of the initially identified articles were read, eligible studies were selected and the risk of bias was assessed for each included article; (4) the third researcher made the final decision in any cases of disagreement with respect to the inclusion of studies.Two investigators extracted the data from each included study, including basic information , primary outcomes (pain scores) and secondary outcomes . All opioids were converted into equianalgesic doses of IV morphine for analysis (IV morphine 10 mg = IVfentanyl 100 μg = IVsufentanil 10 μg) . Pain scThe methodological quality of each RCT was evaluated by two investigators, who used the Cochrane Handbook, and the third researcher made the final decision in any case of disagreement. The following aspects were assessed: random sequence generation, allocation scheme concealment, blinding, accuracy of data results, freedom from selective reporting and other biases. The quality of the outcomes in the meta-analysis was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Table .Table 12 was < 0.5 or p was > 0.1, the level of heterogeneity was low, and a fixed-effects model was applied. Otherwise, a random-effects model was used to analyze the sources of heterogeneity. Continuous outcomes are represented as the standardized mean difference (Std.MD) with the associated 95% confidence interval (CI). Dichotomous outcomes are represented as the relative risk (RR) with the associated 95% CI. Due to the limited number (< 10) of included studies, publication bias was not evaluated.The statistical analysis was conducted using RevMan 5.3. We performed a heterogeneity test on the included studies and calculated the statistics. When IA total of 135 relevant studies were initially identified, and 8 studies  were eveThe Cochrane Handbook for Systematic Reviews of Interventions was used to evaluate the risk of bias of the RCTs. Five studies , 17–19 e2 = 0.83, p < .10). There was a significant difference in postoperative pain scores at 2 postoperative hours between the 2 groups . There was a significant difference in postoperative pain scores at 4 postoperative hours between the 2 groups . There was no significant difference in postoperative pain scores at 6postoperative hours between the 2 groups . There was a significant difference in postoperative pain scores at 12 postoperative hours between the 2 groups . There was a significant difference in postoperative pain scores at 24 postoperative hours between the 2 groups . There was a significant difference in morphine consumption at 24 postoperative hours between the 2 groups . There was a significant difference in postoperative analgesia duration between the 2 groups . There was no significant difference in PONV between the 2 groups  Five RCTs originated in Asia, and the patient sample of one of the RCTs was limited to children. There may be relevant differences in the analytical results of the integrated data.(2) The types of surgery varied, including cesarean sections, total abdominal hysterectomies and appendectomies. The degree of postoperative pain varies among patients undergoing different abdominal surgeries. (3) The anesthetic drugs and concentrations used in the RCTs were different. Bupivacaine was used in 4 RCTs at concentrations of 0.125, 0.2 and 0.25%. The concentrations of ropivacaine used in the other 4 RCTs were 0.25 and 0.375%. (4) Three RCTs used subarachnoid anesthesia, and five RCTs employed general anesthesia.The limitations of this meta-analysis are as follows: in the data extraction, some observation indexes in the literature were only reported as the mean and median or in the form of graphics and text; thus, these results could not be included in the analysis, which may have excluded some high-quality studies. Furthermore, there was no explicit mention of the optimal drug type and concentration for the two trunk plane blocks, which need to be further studied to arrive at a satisfactory approach. During the data collection process, the original data from requested from the author by e-mail, but no response was received. Finally, although our meta-analysis has shown that there is a statistically significant difference in postoperative pain scores between patients receiving QL blocks and TAP blocks, a difference in pain scores that is less than 2 points has limited clinical relevance. Further studies are needed to clarify the more subtle clinical differences in pain after receiving a QL block compared with a TAP block after abdominal surgery.Compared with the TAP block, the QL block provides better pain management with less opioid consumption after abdominal surgery. However, further large RCTs are needed to confirm these findings.


Scientific Reportshttps://doi.org/10.1038/s41598-020-67786-w, Published online 09 July 2020Correction to: In this Article, the legend of Figure 2a and 2b is incorrect:Anisakis-sIgE (InmunoCAP) and rAni s 1 (ELISA) results between allergic patients who suffered a mild to moderate reaction with those who experience a severe allergic reaction. (a) Values of Anisakis-sIgE . (b) Values of sIgE to rAni s 1 .”“Comparation of should read:Anisakis-sIgE (InmunoCAP) and rAni s 1 (ELISA) results between allergic patients who suffered a mild to moderate reaction with those who experience a severe allergic reaction. (a) Values of Anisakis-sIgE . (b) Values of sIgE to rAni s 1 .”“Comparation of Additionally, the Supplementary Information file that accompanies this Article contains an error in Supplementary Figure S1, where the number of total asymptomatic blood donors who underwent SPT is 20 out of 30 with a total of 12/20 positive results and not 12/30.Furthermore, the legend for Supplementary Figure S1 is incomplete,®). sIgE to rAni s 1 and rAni s 7 were analyzed by ELISA in 46 asymptomatic blood donors with Anisakis-sIgE greater than 0.35 KUA/L (n=47). A clinical follow-up were done in 31 of them and SPT were performed in 21. ¥Patients presenting allergic symptoms related to recent consumption of fish. §Patients with urticaria, not related to recent consumption of fish. ¤Patients with gastrointestinal disorders not related to recent consumption of fish. ¶Patients without symptoms related to recent consumption of fish. CRD, component resolve diagnostic test. SPT, skin prick test.”“Clinical and diagnostic test results in the Blood donors’ population. From 403 blood donors, 53 had positive levels of Anisakis-sIgE  from which 47 were asymptomatic. sIgE to rAni s 1 and rAni s 7 were analyzed by ELISA in 46 sensitized asymptomatic blood donors with Anisakis-sIgE greater than 0.35 KUA/L (n = 47). A clinical follow-up was done in 31 of them and SPT were performed in 21. ¥Patients presenting allergic symptoms related to the recent consumption of fish. §Patients with urticaria, not related to the recent consumption of fish. ¤Patients with gastrointestinal disorders not related to the recent consumption of fish. ¶Patients without symptoms related to the recent consumption of fish. CRD, component resolve diagnostic test. SPT, skin prick test.”“Clinical and diagnostic test results in the Blood donors’ population. From 403 blood donors, 53 had positive values of Anisakis-sIgE (≥ 0.35KUA/L, ImmunoCAPThe correct Figure S1 and its accompanying legend appear below as Figure


A few modes of perioperative local analgesia have been studied in order to reduce postoperative pain after laparoscopy, including preemptive local anesthetics in the trocar sites and intraperitoneal anesthetics administration at the end of the surgery. However, the evidence regarding their efficacy are conflicting. In addition, the combination of both aforementioned methods has been rarely studied. Our aim was to evaluate whether subcutaneous trocar site and/or intraperitoneal analgesia reduce pain after gynecologic operative laparoscopy. This was a single-centered, randomized, controlled, double-blinded trial. The patients were randomly assigned to one of four equally sized groups: group 1—subcutaneous and intraperitoneal analgesia; group 2—subcutaneous analgesia and intraperitoneal placebo; group 3—subcutaneous placebo and intraperitoneal analgesia; Group 4—subcutaneous and intraperitoneal placebo. The patients, the surgeons, and the pain evaluators were all blinded to the patient’s allocation. Included were patients who underwent elective operative laparoscopy. Exclusion criteria were: active infection, pregnancy, known sensitivity to Bupivacaine-Hydrochloride, chronic pelvic pain, surgeries with additional vaginal procedures, conversion to laparotomy, and malignancy. A total of 9 ml of Bupivacaine-Hydrochloride (Marcaine) 0.5%, or Sodium-Chloride 0.9%, as a placebo, were injected subcutaneously to the trocar sites (3 ml to each trocar site), prior to skin incision. In addition, 10 ml of Bupivacaine-Hydrochloride 0.5%, diluted with 40 ml of Sodium-Chloride 0.9% , or 50 ml of Sodium-Chloride 0.9%, as a placebo, were injected intraperitoneally at the end of the surgery. By utilizing the 10 cm Visual-analogue-scale (VAS) we assessed post-operative pain at rest at 3, 8, and 24 h, and during ambulation at 8 and 24 h. The study was approved by the local Institutional Review Board and has been registered at clinicaltrials.gov. We conformed to the CONSORT recommendations. Between December 2016 and July 2019, a total of 119 patients were included in the study. Demographic and interventional characteristics were similar among the groups. The level of postoperative pain, either at rest or with change of position, was not significantly different between the groups, at all-time points. Application of subcutaneous and/or intraperitoneal analgesia is not effective in reducing pain after gynecologic operative laparoscopy.https://clinicaltrials.gov.Clinical trial identification number: NCT02976571. Date of trial registration 11/29/2016. URL of the registration site:  It has been shown that nociceptive stimuli can alter the electrophysiological processes in the neurons2.This alteration results in a lower pain threshold and an increased response to pain stimuli.One of the techniques for reducing pain and opiate demand after surgery is the use of local anesthesia in surgical incisions1.By infiltrating a local anesthetic before the incision is made, these effects should in theory be avoided. This, in turn, can potentially increase mobilization and shorten hospitalization after surgery3, whereas administration of intraperitoneal anesthetics at the end of surgery was found to be effective in reducing intensity of postoperative abdominal pain5, as well as shoulder-tip pain6. However, a few studies failed to show these beneficial effects of both trocar site local anesthesia7, and the intraperitoneal anesthesia9. A recent systematic review by Long et al.10 examined the evidence regarding the practice of preemptive analgesia administration; they reported that laparoscopic incisional infiltration has a modest effect, although data regarding this intervention are inconclusive. In addition, intraperitoneal analgesia was reported to likely be beneficial for postoperative pain control10. Nevertheless, the combination of incisional site and intraperitoneal analgesia has rarely been studied, and the evidence is conflicting14.In an attempt to reduce postoperative pain following laparoscopy, a variety of methods of perioperative local analgesia have been studied. Injection of preemptive local anesthetics into the trocar sites has been shown to be beneficial in reducing postoperative pain during ambulationTherefore, our goal was to study how administration of preemptive incisional site subcutaneous (SC) anesthetics, combined with-operative intraperitoneal (IP) analgesia, affects postoperative pain levels  among patients undergoing operative gynecologic laparoscopy.During the study period, 129 patients met the inclusion criteria. Of these, five patients declined to participate, and additional four patients were excluded due to technical reasons (none of the investigating surgeons was available). After enrollment, one patient was found to have malignancy during the operation. Ultimately, 119 patients  completed full pain assessment  scores in 3, 8 and 24 h after surgery, in either univariate or multivariate analyses  given during recovery Table . Only 6 When comparing patients who were treated with and without subcutaneous anesthesia and patients with and without intra-peritoneal anesthesia, we did not detect differences in both pain assessment and analgesic prescription outcomes.We did not detect any difference among the study groups in postoperative levels of pain with change of position or at rest, or analgesic use, at any point in time, in both univariate and multivariate analyses. Also, differences were not found when comparing patients who were treated with and without subcutaneous anesthesia and patients with and without intra-peritoneal anesthesia.15 and Grube et al.16 also failed to show effectiveness of preemptive trocar-site analgesia in reducing postoperative pain. Arden et al.17 reported that intraperitoneal instillation of bupivacaine at the end of laparoscopic hysterectomy did not reduce postoperative pain, nor did it affect the utilization of opioid analgesics.Ghezzi et al.3 reported that preemptive local anesthetics injected into the trocar sites reduced postoperative pain at ambulation 5 h after surgery. Chou et al.4 showed that the combination of preoperative and postoperative intraperitoneal Bupivacaine reduced pain at 2 and 4 h postoperatively.Nevertheless, a few studies reported beneficial effect for the aforementioned interventions. Ravndal et al.18 found no beneficial effect of preemptive local anesthetic wound infiltration on postoperative pain; however, this intervention was shown to reduce postoperative analgesic consumption. Marks et al.5 found that analgesia instilled intraperitoneally significantly decreased pain during a 6-h interval after laparoscopy. Long et al.10 studied the evidence regarding the practice of preemptive analgesia in various forms. They reported modest effect of incisional infiltrations and stated that conclusions drawn by previous studies are conflicting. In addition, they found that intraperitoneal analgesia given upon completion of surgery is likely beneficial.A few systematic reviews have also addressed the role of different interventions for reducing postoperative pain. Ong et al.19. Because we combined two modalities of analgesia , we chose the lowest dose that had been shown to be efficient for each modality20. Therefore, it is possible that due to safety concerns we failed to reach the threshold for adequate postoperative pain relief. Secondly, most patients in our study underwent minor surgeries, such as diagnostic laparoscopies and salpingectomies. It is possible that if we included only major surgeries (such as hysterectomies and myomectomies), higher levels of pain would have been reported and statistically significant differences in primary and/ or secondary outcomes would have been obtained. Nevertheless, it is important to mention that 5 mg (20 ml of 0.25%) Bupivacaine instilled subcutaneously was reported to be effective in reducing postoperative pain even in diagnostic laparoscopies21. It is also possible that the immediate postoperative pain relief, was a confounding factor since it lowered the level of postoperative pain. However, as all the medications administered at recovery room have an elimination half-life (T1/2) of up to six hours, together with the fact that no difference in MME was detected between the groups, it is safe to assume that the immediate postoperative pain relief did not affect the primary outcome. Lastly, our patients possibly reported only low to medium postoperative pain because they were merely asked to move from prone to sitting position, rather than engage in more strenuous activities, such as walking in the ward.Our findings, namely the lack of effectiveness for both incisional site and intraperitoneal analgesia administration, could have a number of explanations. First, it is possible that the analgesic dosage we used is insufficient. The maximal dosage of Bupivacaine allowed for local analgesia in adults is 175 mg, since it is associated with the highest risk of cardiovascular toxicity among the various local anesthetics availableThis study has several strengths. To the best of our knowledge, this is the first study that compared 4 types of interventions—SC analgesia only, IP analgesia only, combined SC and IP analgesia, and no analgesia at all (placebo). Moreover, the randomized, double-blinded design, as well as implementing standardized intraoperative and postoperative protocols for pain relief, has minimized the risk for potential bias. Lastly, we investigated the effect of preemptive analgesia on postoperative levels of pain and utilization of medication, including the demand for opioid-based analgesics.That said, our study is not free of limitations. To begin with, we only assessed short-term outcomes, namely the first 24 h following surgery, and did not evaluate the full recovery period which culminates with the patient returning to full activity. However, as no differences were detected in the first 24 h, it is unlikely we would have found any differences in later periods. Another setback is that we did not evaluate the effect of the various interventions on the time elapsed until full mobility. Yet, it is important to emphasize that no thromboembolic events, which are a major concern in non-mobile patients, were recorded. Lastly, the surgeries included in this study vary in baseline levels of pain expected, and this variation may be a confounding factor. However, as mentioned earlier, the groups were not significantly different as for the frequency of major or minor surgeries, so it is safe to assume that this had a negligible effect on the results, if at all.In conclusion, it appears that administration of preemptive subcutaneous trocar-site analgesia with or without administration of intraperitoneal analgesia upon completion of surgery does not affect the level of postoperative pain.This was a 4-arms randomized controlled trial. Participants were recruited from the Gynecologic Department at the Edith Wolfson Medical Center, Holon, Israel, from December 1st, 2016 until July 31st, 2019. Inclusion criteria included patients with good general health (defined as American Society of Anesthesiologists grade 1–2), who were undergoing a laparoscopic surgery for benign indications. Exclusion criteria included patients who suffered from chronic pelvic pain , pregnancy, allergy to Bupivacaine hydrochloride, emergency surgeries, execution of additional vaginal procedures, and surgeries performed for the following indications: active pelvic infection, ectopic pregnancy, or malignancy. In order to eliminate possible confounders that might increase the level of postoperative pain independently, post-assignment exclusion was executed in cases of conversion to laparotomy and intraoperative diagnosis of malignancy (confirmed by frozen section pathology).This study was approved by the Wolfson medical center review board , and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov . The clinical trial was registered prior to patient enrollment.22.This manuscript adheres to the applicable CONSORT guidelinesGroup 1—SC Bupivacaine hydrochloride  0.5% and IP Bupivacaine hydrochloride 0.5%.Group 2—SC Bupivacaine hydrochloride 0.5% and IP Sodium Chloride 0.9% (NaCl).Group 3—SC NaCl 0.9% and IP Bupivacaine hydrochloride 0.5%.Group 4—SC NaCl 0.9% and IP NaCl 0.9%.This is a double-blinded study, with parallel assignments, to one of the four following groups:After providing written informed consent, patients were randomly assigned to one of the study groups.http://www.randomization.com). In order to ensure allocation concealment the random allocation sequence was kept with the lead author (OG), which was not a part of the recruiting, operating, or pain assessment team.The randomization was performed in blocks of 40, using an on-line randomization program (An assigned nurse (IW) prepared syringes prior to each surgery, outside of the operation room, according to the randomization list, and unlabeled syringes were provided to the surgeons upon commencing surgery. The content of each syringe was written in the concealed list only. Patients, surgeons, anesthesiologists, and pain assessment researchers were all blinded to patients’ allocations.Syringes were prepared according to the following instructions:The first syringe, for SC injection, contained 9 ml of Bupivacaine hydrochloride 0.5% or NaCl 0.9%, as placebo. Three ml of this solution were injected subcutaneously (exclusively beneath the skin) at each trocar site, prior to skin incision.The second syringe, for IP instillation, contained 10 ml of Bupivacaine hydrochloride 0.5% or 10 ml of NaCl 0.9%, as placebo, with an additional 40 ml of NaCl 0.9% . This solution was instilled intra-abdominally prior to abdominal closure by irrigating the diaphragm and the pelvis . All surgeons administered the solutions at the same locations and in the same manner.In order to study the short-term and long-term effects of intervention, postoperative pain at rest was evaluated at 3, 8, and 24 h after surgery. According to our protocol, patient ambulation starts 8 h following surgery; therefore, postoperative pain with change of position was evaluated at 8 and 24 h after surgery.23. Therefore, we used a 10-cm VAS to scale the level of pain. For assessing pain at rest, prone patients were asked to grade the level of pain in the abdomen and at the tip of the shoulder on a scale of 0 (defined as no pain) to 10 (defined as the worst pain ever experienced). For assessing pain with change of position, patients were asked to grade their pain using the same scale, while shifting from lying in bed to sitting in a chair. A member of the surgical team who was not involved in the index surgical case administered the VAS scale.Prior studies have utilized the VAS for evaluating similar outcomesWe conducted a preoperative fasting of 6 h for solids and liquids, and formulated a standardized protocol for preoperative management, anesthesia, and analgesia.All patients received general anesthetic induction and maintenance. Patients were premedicated with 2 mg intravenous (IV) Midazolam . General anesthesia was induced with 2 mg/kg IV Propofol , 2 mg/kg IV Meperidine , and 0.6 mg/kg IV Rocuronium Bromide . General anesthesia was maintained with an infusion of 50–150 mg/kg/min IV Propofol, combined with inhaled Sevoflurane  and oxygen. Under general anesthesia with endotracheal intubation, the patient was positioned properly and draped. Antibiotics and thrombophylaxis were given when indicated.First-line: 1 g IV Paracetamol, up to 4 times per day upon demand.Second-line: 1 g oral Dipyrone (not available in the USA), up to 4 times per day upon demand.Third-line: Opioid-based medication, either 2–3 mg IV Morphine  or 20–30 mg IV Meperidine.In the recovery ward, pain medication was provided by the attending nurses upon demand, according to the following regime:First-line: 1 g IV Paracetamol, up to 4 times per day upon demand.Second-line: 1 g oral Dipyrone, up to 4 times per day upon demand.Third-line: 75 mg Intramuscular Diclofenac Sodium  75 mg, up to 3 times per day upon demand.Fourth-line: 100 mg IV Tramadol Hydrochloride , up to 3 times per day upon demand, usually along with 10 mg IV Metoclopramide .Upon transfer to the postoperative ward, a uniform, standardized, postoperative pain-relief regime was applied for all patients, consisting of:All procedures were performed by one of three senior surgeons in our department. Three trocars were placed in all laparoscopies—umbilical (5-mm), another 5-mm trocar, positioned at the left lower abdomen, and an additional 10-mm trocar placed in the supra-pubic area. Both SC and IP solution administration was performed in the same manner by all surgeons, as described above. At the end of each surgery, the fascia was closed using absorbable suture , and the skin was closed using skin glue .All but 8 patients were discharged on postoperative day 1, according to our departmental protocol. The latter requested later discharge and therefore discharged on postoperative day 2–3. The patients were instructed to use non-opioid, over-the-counter analgesics  at home, and refer to unit when these interventions were not helpful—no patient referred for this reason. All patients returned for a routine follow-up visit 2–3 weeks after surgery.21, it was estimated that each intervention  would result in a 20% reduction in the primary outcome, as compared to non-intervention (administration of SC or IP placebo). In order to attain a power of 80% and a significance level of 0.05, the total sample size required was calculated to be 25 patients for each group. We included 30 patients in each group, in order to make up for any potential loss of follow up.The primary outcome was defined as the level of abdominal pain felt with change of position  at 8 h after surgery. Based on previous studiesWe measured the levels of pain experienced at rest  at 3, 8, and 24 h after surgery. We also estimated the level of abdominal pain felt with change of position at 24 h after surgery.Post-operative analgesic treatment was also measured, both in recovery and post-operative ward.24.We estimated the amount of pain treatment given during recovery by calculating the MME given during recovery. The conversion factors for parenteral Morphine and Meperidine were 3 and 0.4 respectivelyAdditionally, we recorded prescriptions for analgesics in general and particularly opiates (Tramadol Hydrochloride) at 3, 8 and 24 h post-surgery.25.All statistical analyses were conducted using the R Statistical Software, version 3.5.2 We compared the four study groups regarding patients' and surgery characteristics using Analysis of Variance (ANOVA) for continuous variables, and the Chi-square or Fisher exact tests for categorical variables.The type of surgery was grouped into two categories: major  and minor .We compared the longitudinal outcomes (MME and discrete VAS scores) at each time point post-surgery) using ANOVA. Also, univariate mixed-effects linear models were conducted to estimate the univariate association between the study groups and those outcomes, using the surgeon's identity as a random effect.We compared categorical outcomes  using the Chi-square test. Also, we used univariate mix effects logistic models with the surgeon's identity as a random effect and calculated the univariate odds ratios for those outcomes.We performed multivariate mixed-effects linear models to assess the associations between the study groups and MME during recovery and discrete VAS scores in each time point after surgery. The models were adjusted for the number of previous operations, BMI, the patient’s age, and the length and type (major vs. minor) of surgery, and were clustered for the surgeon's identity.Multivariate mixed-effects logistic models were performed to assess the risk for the need for analgesic treatment at each time point after surgery, adjusting for the type of surgery (major vs. minor) and the MME given during recovery. Those models were also clustered for the surgeon's identity.We also conducted secondary analyses, comparing observations with and without subcutaneous and intraperitoneal anesthesia. Those analyses were also performed using both linear and logistic mixed effects models.https://www.R-project.org.R Statistical Software, version 3.5.2, URL