Prevalence and predisposing factors for the development of thoracic pain (TP) in patients with chronic interstitial lung disease (cILD) are largely unknown. Underestimation and insufficient therapy of pain can lead to worsened ventilatory function. Quantitative sensory testing is an established tool for characterization of chronic pain and its neuropathic components. We investigated frequency and intensity of TP in cILD patients and the potential association with lung function and quality of life.We prospectively investigated patients with chronic interstitial lung disease to analyze risk factors for the development of thoracic pain and quantify thoracic pain through quantitative sensory testing. In addition, we studied the relationship between pain sensitivity and lung function impairment.p = 0.02) patients with pulmonary sarcoidosis. The occurrence was mostly spontaneous and not related to thoracic surgical interventions . Patients with thoracic pain showed a significant impairment of mental well-being (p = 0.004). A higher sensitivity to pinprick stimulation during QST can be observed in patients with thoracic pain (p < 0.001). Steroid treatment was associated with lower sensitivity within thermal (p = 0.034 and p = 0.032) and pressure pain testing (p = 0.046). We observed a significant correlation between total lung capacity and thermal (p = 0.019 and p = 0.03) or pressure pain sensitivity (p = 0.006 and p = 0.024).Seventy-eight patients with chronic interstitial lung disease and 36 healthy controls (HCs) were included. Thoracic pain occurred in 38 of 78 patients (49%), most frequently in 13 of 18  DRKS00022978. The dAlthough the exact frequency is unknown, a subgroup of IPF/ILD patients develops thoracic pain (TP), sometimes migrating, sometimes localized, which is difficult to classify especially in absence of a history of thoracotomy or any other thoracic intervention, and is often not associated with cough . InadequQuantitative sensory testing (QST), developed within the framework of the German Research Network “Pain” and used worldwide since 2002 as a routine tool to assess pain , is a vaAim of this study was to systematically investigate frequency and intensity of thoracic pain in cILD patients and explore possible correlations with lung function impairment as well as deterioration of quality of life.2.2.1.The study prospectively investigated patients with cILD and a control group of healthy controls (HCs). Study participants were consecutively recruited among patients with cILD followed at the Ruhrlandklinik between April 2017 and November 2019.Inclusion criteria were an interstitial lung disease diagnosed according to American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria 2013 . PatientAs a control group, we investigated HCs with age > 18 years, no pre-existing lung diseases, no chronical pain syndromes, no pre-existing analgesic medication or neurological conditions such as polyneuropathy. Healthy controls were recruited among the employees of our institution after an accurate anamnestic screening for underlying diseases or conditions associated with chronic thoracic pain. The study was approved by the local ethics committee of the Medical Faculty of the University Duisburg-Essen (16-7028-BO), and registered in the German register of clinical studies (DRKS00022978). Written informed consent was obtained from all participants.2.2.All questionnaires were collected prior to performing QST. The Short Form 12 (SF-12) questionnaire was employed for assessing health-related QoL regarding physical and mental well-being . The pai2.3.TP was defined as persistent or intermittent pain ≥1 in the numeric rating scale (NRS), the most frequently used pain assessment scale .QST is an established psychophysical test protocol for the quantitative evaluation of somatosensory function . The tesQST was performed by two trained examiners. Participants were trained in QST procedures by performing all tests on one hand, once. Subsequently, QST measurements were performed on both sides of the thorax. Patients were instructed not to look at the test area.2.3.1.Thermal measurement was performed with a Medoc TSA 2001-II device  , 20. The2.3.2.MDT was measured with modified von Frey filaments made of optic glass fibers  that exert forces between 0.25 and 512 mN increasing by a factor of two from filament to filament , 22. The2.3.3.MPT was measured with a PinPrick-Set  that exert forces between 8 and 512 mN increasing by a factor of two from pinprick to pinprick . The con2.3.4.Using needle stimulators of different intensities, a stimulus–response curve of MPS was generated . Seven d2.3.5.2. The single stimulus and the stimulus train were rated by the patient on a numeric rating scale between 0 and 100, separately. The procedure was repeated five times. The wind-up ratio was calculated as the arithmetic mean pain rating of the five trains divided by the arithmetic mean pain rating of the five single stimuli  within an area of 1 cm stimuli .2.3.6.2 and pressure limit of 20 kg/cm2, equivalent to 2,000 kPa. The algometer was applied to the thenar of the respective test side, as testing on the chest is not possible due to the insufficiently large contact area to the muscles in the intercostal space. The application was made manually, with an increasing force of 50 kPa/s, corresponding to 0.5 kg/cm2/s. Participants were asked to indicate the onset of a burning, stinging, drilling or pulling sensation. Application of pressure was stopped on feedback and the force reached was recorded as the threshold  with a contact area of 1 cmhreshold , 26. Thehreshold .2.4.® SPIRO or Vyntus® PNEUMO and Masterscreen Body from Carefusion/Vyaire Medical. Blood gas analysis was performed with ABL from Radiometer to measure arterial oxygen tension, arterial carbon dioxide tension, arterial oxygen saturation, and alveolar-arterial oxygen tension difference. Lung function tests were performed at the time of QST.Measurements including FVC, forced expiratory volume in 1 s (FEV1), TLC and DLCO were carried out with Vyntus2.5.Variables distribution was calculated by using Kolmogorov–Smirnov test. Descriptive statistics (frequency and mean ± standard deviation) were performed. Non normally distributed variables are presented as median with interquartile range (IQR). Sample size was calculated based on a number of 360 patients with a new diagnosis of ILD per year at our institution and the fact that up to 10% of them are expected to have TP not dependent on surgical procedures (estimated population size 36). The minimum sample size of ILD patients with TP is 33 with a confidence level of 95% (95%CI) and a margin of error of 5%.U-test or Student’s t-test for continuous variables and chi-square test for categorical variables. Correlations between continuous variables were calculated by using Pearson or Spearman correlation tests. We considered p ≤ 0.05 to be statistically significant. Statistical analysis was performed with SPSS 27.0 .Comparison between cILD patients and HCs were tested using the Mann–Whitney 3.3.1.We enrolled 81 patients with cILD followed at our Institution between April 2017 and November 2019, mostly in the outpatient clinic. As a control group, 36 healthy subjects were included. Three patients were excluded from testing because QST or lung function were not completed. cILD patients and HCs differed significantly in female percentage, age and pack/years .3.2.p = 0.07; p = 0.02) than in those with other cILDs (47%), and less frequently in patients with EAA (29%) (p = 0.07). TP was spontaneous in 76% of cases, related to previous thorax interventions in 5%, and of unknown origin (not indicated by the patients) in 19% of cases.TP occurred in 38 (48.7%) of 78 examined patients with cILD . Time sip = 0.009), the intake of opioids did not differ between the groups. Furthermore, we did not detect any difference in frequency of previous interventions between TP+ and TP−  and without thoracic pain (TP−). The intake of non-opioid analgesics was higher in TP+ compared to TP− patients  but did not reach values that are indicative of neuropathic pain. The number of pain areas was significantly higher in TP+ patients (p < 0.001) ranging from 0 to 7 pain areas without differences in localization of pain.In the physical health summary scale, we did not observe any difference between TP+ and TP− patients, whereas mental health score was significantly more impaired in TP+ compared to TP− patients  and DMA (p = 0.012) on the left body side reflecting a higher sensitivity to pinprick stimulation. Measurements of CDT, WDT, CPT, HPT, MDT, WUR, and PPT did not differ between TP+ and TP− patients (TP+ patients had higher MPS compared to TP− on both body sides and a significant difference in MPT (patients .p = 0.034) and left side  of the body, while CPT was only significant on the right side  and PPT only significant on the left side .Patients under corticosteroid treatment had lower sensitivity within thermal testing and pressure pain testing compared to patients without steroids. Differences in HPT were significant on the right side , independent from the presence or absence of TP  and PPT  on both sides of the body, meaning that the higher are the values of TLC, the better was cold sensitivity and the lower was the pressure pain sensitivity  and PPT on the right side of the body in cILD patients was found ; p = 0.002 (left)], MPS , DMA  and PPT  on both body sides and in HPT (p = 0.045) only on the left body side (p = 0.025 (right); p = 0.005 (left)] and MPT  on both sides and in CDT (p = 0.005), CPT (p = 0.009) and MPS (p = 0.017) on the left side of the body (Significant differences between cILD patients with thoracic pain (TP+) and HCs could be observed in CDT [ody side . TP+ patthe body . TP− pat4.This is the first study specifically investigating thoracic pain in patients with chronic interstitial lung disease. Thoracic pain occurred in 48.7% of patients with chronic interstitial lung disease, most frequently in those with pulmonary sarcoidosis. Moreover, we found an association of thoracic pain with lung function and quality of life. Pain intensity did not differ between patients with pulmonary sarcoidosis and the other patients with chronic interstitial lung disease.Thoracic pain seems to be an underestimated symptom in patients with chronic interstitial lung disease and, in general, knowledge on thoracic pain in patients with interstitial lung disease is scarce. A recent study reported that the prevalence of pain in ILD patients was 62% compared to 25% in healthy controls, with thoracic pain being the most frequent form (46%), followed by joint and limb pain . In thatIn our study, pain usually occurred spontaneously, and appeared to be related to the disease itself rather than to previous interventions. It is likely that this kind of pain is associated with the fibrotic involvement and consequent thickening of the pleura, especially in idiopathic pulmonary fibrosis, where the fibrotic changes are predominantly localized in the subpleural area. In patients with pulmonary sarcoidosis, on the other side, thoracic pain may be related to an involvement of small nerve fibers. It has been reported that small fiber neuropathy occurs in 30%–50% of sarcoidosis patients, with pain and paresthesia being the most common symptoms , 29. FurWith regard to pain characterization, significant signals in specific tests among the whole quantitative sensory testing were observed in cILD patients. Comparing cILD patients with thoracic pain and healthy controls, the observed significant differences in cold detection threshold, heat pain threshold, dynamic mechanical allodynia and pressure pain threshold mean a lower sensitivity to thermal testing and increased sensibility to pressure at the thenar. In addition, the lower values in cold detection threshold and cold pain threshold, and higher values in heat pain threshold in patients without thoracic pain compared to healthy controls underline the lower sensitivity to thermal stimuli of cILD patients. In contrast, patients without thoracic pain point out higher values in mechanical pain threshold as well as lower values in numeric rating scale in mechanical pain sensitivity compared to healthy controls, which discloses a lower sensitivity against pinprick stimulation and contrasts with the higher sensitivity to pinpricks in patients with thoracic pain. In summary, thoracic pain in ILD compared to healthy controls seems to be characterized by decreased perception and pain sensitivity in response to thermal stimuli. Moreover, patients with thoracic pain compared to healthy controls showed an increased sensitivity to pinprick stimuli and pressure pain.We observed that subjects under long-term corticosteroid treatment had a lower sensitivity to temperature and pressure during quantitative sensory testing. This may be explained by the analgesic effect of corticosteroids as described in previous studies .Similarly to the study by Shen et al. , we did The positive correlation between total lung capacity and pressure pain threshold indicates that higher pressure on the thenar is necessary to trigger a painful sensation in patients with better values in total lung capacity. This means that patients with more pronounced restriction have a hypersensitivity to pressure at the thenar. In patients with sarcoidosis, the hypersensitivity at the thenar could possibly be explained by a generalized sensitivity to pain in other parts of the body associated with a chronic pain syndrome or small fiber neuropathy .Thoracic pain seems to cause a limitation of mental well-being in patients with thoracic pain. An association between pain in patients with ILD and impaired quality of life was observed by Shen et al. . Our stuThis study has several limitations. First, the sample size of the present study does not allow to perform subgroup analyses or prediction model to investigate risk factors for thoracic pain. Second, we did not include patients with lung diseases other than ILDs as a control group. This may lead to overestimation of thoracic pain as symptom in ILD, as the prevalence of pain in patients with chronic obstructive pulmonary disease is reported with 32%–60% . MoreoveThis study was performed to investigate prevalence and risk factors of thoracic pain in patients with chronic interstitial lung disease. Thoracic pain mostly occurs spontaneous as a frequent symptom in chronic interstitial lung disease patients, especially in pulmonary sarcoidosis. Timely identification of thoracic pain may allow starting symptomatic treatment at early stage, before impairment in quality of life occurs.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of the Medical Faculty of the University Duisburg-Essen. The patients/participants provided their written informed consent to participate in this study.MS and FB are responsible for all content of the manuscript, contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. SK contributed substantially to the study design and the writing of the manuscript. JF-B contributed substantially to the data analysis and the writing of the manuscript. GW contributed substantially to the study design, data analysis, and the writing of the manuscript. UC contributed substantially to the data interpretation and the writing of the manuscript. All authors contributed to the article and approved the submitted version.This study received funding from Boehringer-Ingelheim Pharma GmbH & Co. KG. The funder was not involved in the study design, collection, analysis, interpretation of data, and the writing of this article or the decision to submit it for publication.FB and UC received speaker and advisor honoraria, travel and research grants from Boehringer Ingelheim Pharma, not related to this study.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interestThe handling editor PS declared a past co-authorship with the author FB.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chondromalacia patellae (CP) is a common and main cause of knee pain, the prevalence of the disease in the general population is as high as 36.2%, especially in middle-aged patients aged between 30 and 40 years (up to 50%). The use of manual therapy (MT) to dredge the meridians and muscles around the knee joint and stimulate the relevant acupoints can play vital roles in relieving pain and improving function. The purpose of this study is to assess the effectiveness, safety and further comprehensively, completely and multi-dimensionally explain the mechanism and treatment advantages of MT for CP.A prospective randomized controlled clinical trial design was used to study the efficacy and safety of MT in the treatment of CP. One hundred and twenty cases of CP patients will be recruited and randomly divided into experimental group and control group according to 1:1. The control group: sodium hyaluronate; experimental group: MT added on the basis of the control group. Both groups will receive standard treatment for 4 weeks and followed up for 3 months. And at the same time, pay attention to its efficacy and safety indicators. Observation indicators include: the visual analogue scale pain score; the Western Ontario and McMaster Universities Arthritis Index scores; the Lysholm scores, and Bristol scores, adverse reactions, etc. Data analysis was performed using SPSS 25.0 software.This study will precisely evaluate the effectiveness and safety of MT in the treatment of CP. The results of this experiment will provide more reliable clinical basis for the selection of MT for patients with CP. It is a degenerative disease of patellar cartilage, which is a common and main cause of knee pain. Most patients with this disease have different degrees of poor patellofemoral joint force line and (or) abnormal patellar motion track, making the lateral patella perennial high pressure, which can lead to the secretion of pain-causing inflammatory factors such as interleukin-6, causing pain and subsequent patellofemoral articular cartilage softening until gradual denudation. The prevalence of the disease in the general population is as high as 36.2%, especially in middle-aged patients aged between 30 and 40 years (up to 50%). The prevalence rate in women is higher, about twice that in men. This disease often occurs after strenuous exercise, which can lead to soft legs, joint swelling and pain, restricted movement and other symptoms. The pain is obvious after going upstairs and downstairs, climbing, squatting, kneeling and even sitting for a long time, which seriously affects the quality of life.,4 Hence, CP has become a major global public health problem, and the effective treatment is of great significance.Chondromalacia patellae (CP), also known as patellofemoral pain syndrome, anterior knee pain syndrome, patellofemoral joint syndrome, etc., was first proposed by Aleman.,6 The consensus released by the International Patellofemoral Research Center in 2018 believes that the key treatment of CP is exercise therapy and physical intervention, and its management should include an individual, multi-modes exercise and treatment method. Among all the treatment methods, manual therapy (MT) has occupied a certain advantage in clinical application due to its simple operation, obvious effect, small side effects, high safety and good economic effect.CP is generally treated conservatively in the early stage of the disease, while surgical treatment is suitable for advanced patients. Through methods including cartilage transplantation and total knee replacement, the normal tissue structure around the patella can be restored and reconstructed, and finally the purpose of treating the disease can be achieved.–11 The use of traditional Chinese medicine massage to dredge the meridians and muscles around the knee joint and stimulate the relevant acupoints can also play vital roles in relieving pain and improving function.Based on modern western medical theory, MT techniques include joint mobilization, manual stretching and trigger point dry needle. Many studies have found that joint mobilization is effective in pain reduction, while the most effective joint mobilization is aim at the knee joint complex directly rather than at the lumbar-pelvic region or other surrounding joints, although lumbar-pelvic manipulation can also improve patients’ pain and function.In recent years, studies on the effect of MT for CP have increased at home and abroad, but its clinical efficacy is still unclear. Therefore, the purpose of our study is to precisely evaluate the advantages and disadvantages of MT in the treatment of CP in this randomized controlled trial.This is a prospective randomized controlled clinical trial studying the effects of MT on CP. This protocol follows the latest Consolidated Standards of Reporting Trials 2017) . Before randomization, all patients needed to sign an informed consent form, and only patients who sign informed consent will be enrolled in the study. During the test, they are free to choose whether to continue the test at any time.Those who meet the diagnostic criteria of CP; age: ≥18 and ≤65 years old, regardless of gender; within 3 months before enrollment, they did not receive joint cavity injection treatment and did not take any drugs to treat CP; those who have certain communication and understanding ability, and can express their own will correctly; no other soft tissue and bone diseases of the knee joint; those who voluntarily accept corresponding treatment and can cooperate; no other serious nervous or mental diseases; and those who have signed the informed consent.Patients who suffer from acute systemic illness or acute swelling; patients who have severe impairment of limb function; patients with severe heart, lung, liver and kidney dysfunction; patients with local skin infection or ulceration; patients combined with severe mental illness; patients who are allergic to the drugs used in this study; and patients who are unable to understand the study protocol or unwilling after explanation.Patients with serious adverse events or serious complications, which is not suitable for the next step; patients with poor compliance, affecting the judgment of efficacy and safety; the disease progresses during the treatment process, and the treatment plan needs to be changed; and for any reason, the subject asked to withdraw from the trial.According to the preliminary clinical trial, the total effective rate of MT combined with sodium hyaluronate was 93.4%, and that of sodium hyaluronate was 66.6%. Use PASS15.0 to estimate the sample size, adopt a superiority design, in which α = 0.05, β = 0.2, test power = 0.8, number of cases in experimental group: number of cases in control group = 1:1, boundary value = –0.4. According to the software calculation, the total sample size of the 2 groups was 110 cases. Taking into account the clinical shedding rate of about 10%, a total of 120 cases will be finally included. The included patients will be numbered according to the order of treatment and divided into the treatment group and the control group by completely random method, with 60 cases in each group.This study will select patients who meet the study criteria by recruiting them at the hospital. A randomized controlled study will be conducted, in which sodium hyaluronate will be used in the control group and the experimental group will include MT exercise on the basis of the control group. If necessary, the attending doctor may adjust the treatment according to the patient’s condition, and all interventions will be recorded in detail for final outcome analysis. Efficacy assessors are not aware of the study plan, and data statisticians are not involved in study design and implementation. The health of each patient will be assessed before and after the treatment, including observational indicators, and all patients will be followed up by telephone.Patients will be placed in the sitting or supine position, and the knee joint will be kept bent 70° to 90°, sterilized strictly, with sterile towel laid and aseptic operation performed. The lower lateral or inner side of the patella will be used as the conventional puncture point, and the knee joint cavity will be punctured through a 5 mL syringe. If there is joint effusion, it will be drained first, and then 25 mg sodium hyaluronate will be injected ; if not, 25 mg sodium hyaluronate can be directly injected into the joint cavity. After injection, help the patient to move the knee joint so that sodium hyaluronate can be evenly coated on the internal surface of the joint. One time/week, 4 times as a course of treatment. Health education should be carried out for patients to avoid acute jumping, walking up and down stairs, climbing mountains and other activities that damage joints, and remind them to pay attention to the warmth of joints as well. Pay attention to communicate with patients, be aware of their psychological and emotional changes, avoid or relieve anxiety, depression, and other adverse emotions of the elderly patients.The treatment group will be given MT on the basis of conventional treatment. Manual therapy is jointly completed by 2 experienced doctors, it lasts for about 20 minutes per time, once a day, and lasts for 4 weeks in total.Improvement in joint pain and function is the main observation item, and which is respectively assessed by the visual analogue scale pain score or a comprehensive evaluation commonly using the Western Ontario and McMaster Universities Arthritis Index scores, Lysholm scores, or Bristol scores.Main efficacy indicators: total effective rate: /total number of people × 100%. Clinical control: pain and other symptoms disappear, joint activity is normal, integral reduction ≥ 95%; significantly effective: pain and other symptoms disappear, joint activity is not limited, 70% ≤ integral reduction < 95%; effective: pain and other symptoms basically disappear, joint activity is slightly limited, 30% ≤ integral reduction < 70%; and ineffective: no significant improvement in symptoms such as pain and joint activity, integral reduction < 30%.Including the number of patients who experience any uncomfortable symptoms during treatment .Data will be collected according to the evaluation criteria before and 4 weeks after the treatment, and each patient was followed up by telephone for 3 months after the end of treatment. It was impossible to collect follow-up information and record the reasons for loss to follow-up. Access to the database is limited to the researchers in this research group.Throughout the trial, each participant will be monitored for safety. All adverse event occurrences will be referred to the office of the Clinical Research Ethics Committee, which will review the events and determine causal relationship.t test will be used between groups and paired-sample t test will be used within groups; if not, non-parametric test will be used and the results will be expressed in quartiles; the count data were tested by chi-square. The incidence of adverse events is compared by chi-square test. P < .05 is statistically significant.In this study, SPSS25.0 statistical analysis software  will be used for data analysis. If the measurement data meet the normal distribution, independent-sample ,13 Moreover, doctors and patients concern constantly about the potential adverse effects of these operation.CP is one of the common diseases of knee joint. Pain and dysfunction caused by CP severely decreases the quality of life of patients. Currently, the diagnostic standard of CP has not yet formed a unified consensus. There is no effective cure for the treatment of CP, and the effects of surgical treatment which are widely used in clinic, such as cartilage transplantation and total knee replacement, is not superior o non-surgical treatment.At present, MT is one widely used conservative treatment for patients with CP. Manipulative therapy can promote blood circulation and accelerate metabolism, mainly through the following mechanisms to achieve the purpose of treatment: increase the local nutrient supply, and strengthen the “pumping effect” of cartilage tissue itself, which is conducive to the self-repair of the articular cartilage. Eliminate local intra osseous venous stasis, reduce intra ossseous hypertension, and promote absorption of local inflammatory tissue. Exogenous cold pathogen is one of the causes of CP, manipulative treatment can generate heat and disperse cold, and promote local Qi and blood circulation. Promote the mechanical balance of the knee joint, release the adhesion, and improve the stability and functional state of the knee joint.As far as we know, there has been no standard large-sample clinical study on MT in the treatment of CP, although increasing studies have found that MT has a statistically significant effect on alleviating symptoms of CP with a well-established safety profile. We intend to evaluate its efficacy and safety in a prospective randomized controlled study.Conceptualization: Yan Cai, Ying Deng.Data curation: Yan Cai, Yanxing Guo.Formal analysis: Yan Cai, Yuxing Guo.Software: Yan Cai, Yuxing Guo.Writing – original draft: Liang Ou, Yanxing Guo.Writing – review & editing: Yan Cai, Ying Deng.


The analgesic effect of acupuncture is widely recognized, but the mechanical characteristics of acupuncture for pain relief, compared to non‐steroidal anti‐inflammatory (NSAIDs) and placebo medication, remain unknown.To compare the modulation effects of acupuncture treatment with NSAIDs and placebo medication on descending pain modulation system (DPMS) in knee osteoarthritis (KOA) patients.This study recruited 180 KOA patients with knee pain and 41 healthy controls (HCs). Individuals with KOA knee pain were divided randomly into groups of verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), and waiting list (WT), with 36 patients in each group. VA and SA groups included ten sessions of puncturing acupoints or puncturing non‐acupoints acupuncture treatment for two successive weeks. Celecoxib capsules were continuously given orally to patients in the SC group at a dosage of 200 mg daily for 2 weeks. In the PB group, patients received a placebo capsule once a day for 2 weeks at the same dosage as celecoxib capsules. In the WL group, patients did not receive any treatment. Patients underwent a resting‐state BOLD‐fMRI scan pre‐ and post‐receiving the therapy, whereas HCs only underwent a baseline scan. Seed  based resting‐state functional connectivity (rs‐FC) was applied in the data analysis.All groups demonstrated improved knee pain scores relative to the initial state. There was no statistical difference between the VA and SA groups in all clinical outcomes, and vlPAG rs‐FC alterations. KOA knee pain individuals reported higher vlPAG rs‐FC in the bilateral thalamus than HCs. KOA knee pain patients in the acupuncture group  exhibited increased vlPAG rs‐FC with the right dorsolateral prefrontal cortex (DLPFC) and the right angular, which is associated with knee pain improvement. In contrast with the SC and PB group, the AG exhibited significantly increased vlPAG rs‐FC with the right DLPFC and angular. Contrary to the WT group, the AG showed greater vlPAG rs‐FC with the right DLPFC and precuneus.Acupuncture treatment, celecoxib, and placebo medication have different modulation effects on vlPAG DPMS in KOA knee pain patients. Acupuncture could modulate vlPAG rs‐FC with brain regions associated with cognitive control, attention, and reappraisal for knee pain relief in KOA patients, compared with celecoxib and placebo medication. Acupuncture treatment, celecoxib, and placebo medication have different modulation effects on ventrolateral periaqueductal gray (vlPAG) descending pain modulation system (DPMS) in knee osteoarthritis (KOA) knee pain patients. Acupuncture could modulate vlPAG resting‐state functional connectivity (rs‐FC) with brain regions associated with cognitive control, attention, and reappraisal for knee pain relief in KOA patients, compared with celecoxib and placebo medication. Therefore, understanding the source and mechanism of pain is essential for treatment development. Local indicators of the knee joint and changes in the central nervous system (CNS) play a role in the development of knee pain. Biomechanical variables The first line recommended medication for treating knee pain caused by KOA in medical practice is NSAIDs medications.Assessing the physical functioning of DPMS in a non‐invasive manner continues to be difficult. The resting‐state functional magnetic resonance imaging (fMRI) technique allows for the identification of correlations between remote brain regions  through their highly correlated low‐frequency spontaneous fluctuations non‐invasively.Furthermore, prior research demonstrated that central sensitization and increased vlPAG activity in osteoarthritis patients are associated with skin irritation in pain areas.In this current work, a comparison of the vlPAG rs‐FC was made between individuals who experienced KOA knee pain and the healthy controls (HCs) matched with them. Furthermore, the mechanism by which the vlPAG rs‐FC could be modulated by different longitudinal interventions, including verum acupuncture, sham acupuncture, celecoxib, placebo medication, and a waiting list, was investigated. Additionally, the possible different vlPAG rs‐FC modulation effects between verum acupuncture and sham acupuncture/celecoxib treatment/placebo medication/waiting list control were compared. We hypothesized that different interventions have different modulation effects on vlPAG DPMS in KOA knee pain patients, and acupuncture could modulate the pain perception by DPMS, allowing psychological factors such as cognitive control, attention, and reappraisal to influence the pain experiences. It is hoped that this study could enhance the understanding of the mechanical characteristics of acupuncture for KOA pain relief compared with NSAIDs and placebo medication.2In this study, the clinical and fMRI datasets of KOA knee pain patients were collected from two simultaneous trials.2.1Knee osteoarthritis knee pain patients and HCs were involved in this study. The diagnostic criteria for KOA were derived from the American College of Rheumatology (ACR) criteria and published in their adjusted form in 1991.The matched HCs were enrolled. The inclusion criteria were that all HCs: (1) were aged from 40–60 years and were right‐handed, (2) were free from any pain conditions, (3) had no history of mental or CNS illness, (4) had no history of any systemic illness, like diabetes or hypertension, and (5) provided written permissions to conduct the study. HCs met the exclusion criteria if they: (1) were women who were either pregnant or nursing, (2) were alcohol or drug abusers, or (3) had contraindications to MRI scan.2.2In this trial, the patients experiencing knee pain due to KOA were observed for 4 weeks, of which the first 2 weeks of run‐in period checked whether KOA patients were eligible and still willing to participate. There were five patient groups and an HCs group, with 36 participants in each group. The patients were randomly assigned to verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), and waiting list (WL) control groups. The celecoxib and placebo groups were masked (double‐blinded) to treatment, and the subjects of verum acupuncture and sham acupuncture were kept single‐blinded. Two MRI scans were done on KOA knee pain patients before and after treatments, whereas HCs received one scan.2.3Ten sessions of acupuncture stimulating medication were given to the VA and SA over two successive weeks, each session lasting for 30 min. In the SC group, celecoxib capsules  were orally given to patients for 2 weeks of 200 mg. In the PB group, patients received a placebo capsule once a day for 2 weeks at the same dosage as celecoxib capsules. In the WL group, patients did not receive any treatment, but they were informed that after 2 weeks, they would receive ten sessions of acupuncture or 2 weeks of celecoxib for free.The details of acupoint and non‐acupoint selections in the VA and SA group can be seen in this previously published protocol.Two trained and licensed acupuncturists conducted all acupuncture treatments. All acupoints and non‐acupoints on both sides of the body were pierced using small needles made of disposable stainless‐steel measuring 0.25 mm to 40 mm in length . When inserting the needles, the penetrating depth was kept between 0.5 cun and 1.5 cun. The locations in the VA and SA groups were gently manipulated to induce a specific acupuncture sensation (deqi).All patients refrained from taking their usual medicines intended to treat KOA during the trial. Ibuprofen, in the form of sustained‐release capsules containing 300 mg, was authorized for use as the rescue therapy in cases of severe pain.2.4This research focused on the vlPAG rs‐FC as its primary endpoint. The clinical assessments were: (1) visual analog scale (VAS), with 0 signifying no pain and 10 signifying the worst pain imaginable,2.52, voxel size 1 × 1 × 1 mm3 and scanning duration = 4 min). BOLD resting state functional pictures were acquired using echo‐planar imaging . During the resting state fMRI scan, all subjects were asked to remain conscious, hold their heads steady, close their eyes, and plug their ears.Sessions of fMRI scanning were conducted at the University of Electronic Science and Technology of China's MRI Center. FMRI brain images were acquired on a 3.0 Tesla system  with an 8‐channel head coil. Before the functional run, T1 MRI images were acquired in three dimensions . Frequency was represented as a percentage (%).All statistical evaluations were performed using SPSS 25.0 . Normality distribution of the data was assessed, using the visual inspection of histograms and Shapiro–Wilk test. Data that did not follow a normal/Gaussian distribution were analyzed by using non‐parametric test. We used the following statistical statistical tests: chi‐squared test, Mann–Whitney 2.7.2http://www.fil.ion.ucl.ac.uk/spm) and MATLAB R2013b . The initial ten‐time points were omitted during pre‐processing for signal stability and subject adaptability. The fMRI images were corrected for slice timing, head motion, segmented, and six head‐movement variables. The white matter signal and cerebrospinal fluid (CSF) signal were regressed. The functional volumes were normalized to the Montreal Neurological Institute (MNI) template space by co‐registering functional pictures with high‐resolution T1‐weighted anatomical images. Subjects were excluded if either translation or rotation of the head motion exceeded ±2 mm or ±2° at any angle. To further limit the detrimental impact of head movement, the volumes with FD >0.5 mm, the one time‐point preceding and two‐time points following the ‘poor’ time points, were eliminated from the data.Functional BOLD information was pre‐processed using DPARSFA A priori vlPAG seed with the following peak coordinates: 4, −26, −14, and a 3 mm radius was utilized. This seed was already utilized in earlier investigations.t‐test. Pre‐ and post‐treatment values for each group were compared using paired t‐tests. Next, factorial design modules were utilized to assess alterations in rs‐FC (post‐treatment minus pre‐treatment) between the verum acupuncture and sham acupuncture groups, acupuncture (verum + sham) and celecoxib groups, acupuncture and placebo medication groups, as well as acupuncture and waiting list groups. Covariables included gender, age, and body mass index (BMI) at baseline. As previous studies mentioned, variables that were percentage transformed could mitigate potential scaling problems.http://www.fil.ion.ucl.ac.uk/spm/software/spm12) was used to analyze functional connectivity in the rest status. All analyses utilized a threshold of voxelwise p < 0.005 (uncorrected) and cluster‐level p < 0.05 .From the vlPAG seed, the averaged time course was derived, and a voxel‐wise correlation analysis was performed. By applying the regression coefficient between all brain voxels and the time sequence of each seed, contrast pictures for each individual were created. Furthermore, the correlation coefficient map's normality was enhanced by applying Fisher's r‐to‐z transform. The baseline vlPAG rs‐FC of KOA knee pain patients and healthy controls were compared by employing a two‐sample 3Knee osteoarthritis knee pain patients 180 were recruited, and 31 patients did not complete the study or had excessive head movement. This trial included 41 HCs of the matched age and gender; however, five HCs could not enroll in the MRI scan because of schedule issues. Therefore, 149 KOA knee pain patients and 36 matched HCs were involved in the final analyses Figure .3.1p > 0.05). The VA, SA, SC, PB, and WL groups showed no significant variation in terms of gender, age, BMI, disease duration, VAS, SF‐MPQ, WOMAC, and SF‐12 (p > 0.05) (Table p > 0.05)  Table .3.2p < 0.05; Table U test showed the changes in VAS, SF‐MPQ, and WOMAC were statistically different between the SC and PB groups   Figure .3.3.2After longitudinal VA treatment, KOA knee pain subjects had increased vlPAG rs‐FC with the right dorsolateral prefrontal cortex (DLPFC), and bilateral angular Figure , Table 4z value was obtained for the rs‐FC in the right DLPFC/angular/precuneus site. It was discovered that the proportion alterations of rs‐FC between vlPAG and DLPFC/angular/precuneus were positively correlated with the matched SF‐MPQ percentage alterations in the acupuncture group .3.5All 180 patients were monitored for safety and tolerability. One patient in the VA group discontinued the study due to a fractured upper limb unrelated to the treatment. Four patients in SA and four patients in VA groups developed mild bruising around the acupoints/non‐acupoints, all of which were back to normal after 2 weeks of follow‐up. One patient discontinued celecoxib during the intervention period due to intolerable gastric discomfort, and no further gastric discomfort occurred after 2 weeks of follow‐up.4This study explored the vlPAG rs‐FC alternations and the modulation effects of verum, sham acupuncture, celecoxib, placebo, and waiting list treatment in KOA knee pain patients. The clinical and vlPAG rs‐FC results showed no significant difference between VA and SA groups. Acupuncture (VA + SA) and celecoxib groups had similar clinical effects on pain relief in KOA knee pain patients. Furthermore, the acupuncture group showed a significantly increased vlPAG rs‐FC with the right DLPFC and right angular, compared with celecoxib treatment, placebo, and waiting list groups. Interestingly, these vlPAG rs‐FC changes were correlated with a decreasing KOA pain intensity in the acupuncture group. To our knowledge, this is an initial study exploring the mechanical characteristics of acupuncture on DPMS compared with NSAIDs and placebo medications for KOA knee pain relief.4.1This study found that verum acupuncture (puncturing acupoints) and sham acupuncture (puncturing non‐acupoints) were all equally effective for KOA knee pain relief and had similar effects on vlPAG rs‐FC, which is similar to the findings from previously published literature on RCTs and meta‐analyses. Some research reported no advantage of puncturing acupoints over non‐acupoints for treating knee pain,4.2This study found no clinical therapeutic efficacy difference in knee pain relief between acupuncture treatment and celecoxib, which further validated the analgesic effect of acupuncture. Celecoxib is the most widely used NSAIDs for the medication of KOA.The neuroimaging results showed that KOA knee pain patients had increased vlPAG rs‐FC with bilateral thalamus compared with HCs. Neuroanatomical studies have found that the thalamus has neural fiber connections with PAG through the thalamus‐PAG pathway,Nevertheless, this study found that celecoxib did not affect vlPAG rs‐FC in KOA patients. It is believed that celecoxib might take action for KOA knee pain relief mainly through the local anti‐inflammatory and analgesic mechanism in the knee joint, with limited involvement of vlPAG DPMS at the supraspinal level. Unlike celecoxib, acupuncture could modulate vlPAG rs‐FC with the right DLPFC and angular for knee pain relief in KOA patients. Research has shown that the DLPFC is directly connected to PAG through DLPFC‐thalamus‐PAG/DLPFC‐ACC‐thalamus‐PAG pathway,4.3This study found that acupuncture treatment had a better therapeutic effect than placebo medication in knee pain relief for KOA patients. The neuroimaging results showed that the AG exhibited increased vlPAG rs‐FC with the bilateral DLPFC and the right angular compared with the PB group. The acupuncture effect has long been considered a magic placebo in western countries. Although several studies indicate that acupuncture is not a placebo,Studies have shown that endogenous opioid and non‐opioid mechanisms  may mediate placebo analgesia.This research had the following drawbacks: (1) each group's sample size was relatively small, preventing us from comparing clinical outcome variations across the different groups; (2) the inflammation and pain‐related variables in the knee joint were not observed and investigated, preventing a comprehensive analysis of acupuncture and celecoxib mechanism for KOA knee pain; (3) the course of acupuncture and celecoxib treatment for KOA patients was relatively too short, which might have influenced the clinical and neuroimaging results; (4) there may have been a risk of bias between the two concurrent trials in this study; (5) neither KOA patients in the celecoxib nor placebo groups received nocebo‐related psychological assessments in this study, which might have a potential impact on the clinical and fMRI results in this study; (6) this study only observed DPMS from the perspective of resting‐state functional connectivity in KOA knee pain patients, and structural connectivity as a topic worth studying in the future; and (7) the fMRI data with cardiac‐gating was not obtained5Acupuncture treatment, celecoxib, and placebo medication have different modulation effects on vlPAG DPMS in KOA knee pain patients. Acupuncture could modulate vlPAG rs‐FC with brain regions associated with cognitive control, attention, and reappraisal for knee pain relief in KOA patients, compared with celecoxib and placebo medication.ZL and FL are the corresponding authors. JZ and FZ contributed equally to this article. Study protocol and design: FL, ZL and FZ; acquisition of data: SC, XD, XZ, CT, WH, YC, NJ, NS, YZ, XL and SH; analysis and interpretation of data: JZ, ZL, WY and RS; drafting of the manuscript: JZ and FZ; proofread and revise the manuscript: ZL, FL, and MW. All authors reviewed the manuscript.This study was supported by funds from the National Natural Science Foundation of China , Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No.ZYYCXTD‐D‐202003), and Postdoctoral Science Foundation .None of the authors have any conflict of interest.Table S1.Click here for additional data file.Table S2.Click here for additional data file.


The national “Internet +” policies and the emergence of internet hospitals have created a new direction for the management of pain outside of the hospital. Nevertheless, there are no consolidated studies conducted by pain physicians on the current state of internet hospital–based online medical services used by patients with pain outside of a hospital setting.In this retrospective study, we aimed to examine the status of the use of internet hospitals by patients who experience pain. Moreover, we identified the factors that influenced patients' decisions to make an online visit through the internet hospital.Detailed information was collected online and offline from outpatients with pain at the information technology center of West China Hospital of Sichuan University from February 2020 to April 2022. Binary logistic regression analysis was conducted to identify the determinants that influenced patients' decisions to make an online visit to the internet hospital.P=.045) and middle-aged  patients, employed patients , nonlocal patients , and the ordinary staff  were more likely to have the intention to choose online visits through the internet hospitals.Over a 2-year period, 85,266 pain-related clinic visits were recorded. Ultimately, 39,260 patients were enrolled for the analysis, with 12.9%  having online visits. Both online and offline clinics had a greater number of visits by women than men. The average age of patients attending the online clinic was 46.85 (SD 16.56) years, whereas the average age of patients attending the offline clinic was 51.48 (SD 16.12) years. The majority of online clinic visitors  were employed, and one of the most common occupations was farming . In addition, 51.8% (2635/5088) of patients who participated in the online clinics lived outside the hospital vicinity. Young (odds ratio [OR] 1.35, 95% CI 1.01-1.81; Internet hospitals are flourishing as a more efficient and promising method of pain management and follow-up for patients with pain outside the hospital. People with pain who are young, working, and not in the vicinity of hospitals are more likely to visit internet hospitals. One of the most common reasons for seeking medical care is pain, which can be classified as acute pain or chronic pain. Chronic pain is defined as pain that lasts or recurs for more than 3 months. Over 30% of the world's population experiences chronic pain , and in With the development of the internet and electronic devices, mobile medicine and telemedicine have emerged. Mobile medical apps for chronic pain management and follow-up are also available on the market. A number of studies  suggest Mobile medicine and telemedicine are the main components of internet health care. Internet hospitals currently exist only in China, and there is no such thing as internet hospitals abroad ,7. TelemInternet hospitals are a new business model derived from the “Internet +” medical care in China, which is an extension of telemedicine and traditional physical hospitals. Using the medical resources of the physical hospital and internet technology, internet hospitals provide closed-loop online and offline as well as front-end and back-end medical services . In geneThere have not been any major studies on the use of internet hospitals for out-of-hospital pain management. The aim of this retrospective study was to examine the status of the use of internet hospitals among patients with pain and identify the factors influencing patients’ decisions to seek an online visit through internet hospitals. This study also provides scientific evidence for promoting the use of internet hospitals for pain management.This is a retrospective study that included all patients who attended the pain Clinic of West China Hospital of Sichuan University between February 2020 and April 2022. The independent variables were the patient's sex, age, working status, occupation, and residence; the dependent variable was whether the patient visited the internet hospital. Both the dependent variables and the independent variable were obtained through the information technology center of West China Hospital of Sichuan University. For analysis, data relating to patients’ age, sex, disease diagnosis, comorbidities, occupation, and place of residence were organized in Microsoft Excel 2016. However, due to incomplete information on disease diagnosis and comorbidities, these 2 variables were not compared between online and offline groups and were not included in the binary logistic regression. The age groups were as follows: younger than 18 years for the underage group, 18 to 44 years of age for the young group, 45 to 64 years of age for the middle-aged group, and 65 years and older for the older group. Regarding employment status, patients in the employed group consisted of those employed by the national civil service, professional and technical staff, general personnel, workers, as well as farmers and freelancers; patients in the unemployed group consisted of those who were not currently employed.t test was applied for continuous variables. Binary logistic regression analysis was used to identify the factors that affected patients’ intentions to choose online visits through the internet hospital. Variables with statistical differences between the 2 groups in the bivariate analysis were included in the logistic regression model. The final set of covariables included age, employee status, occupation, and place of residence; the dependent variable was whether or not to visit an internet hospital.To analyze the data, IBM SPSS Statistics 27 was used. The mean, SD, and percentages were used to describe the demographic characteristics of the final sample. For differences between online and offline groups, the chi-square test was used for categorical variables and the independent samples 2-tailed This study was approved by the ethics committee on the biomedical research of West China Hospital of Sichuan University under the approval number 2022 Review (467); it was also registered on the Chinese Clinical Trial Registry (ChiCTR2200059152). This study did not require informed consent, and the study data were anonymous. There was no compensation provided to the participants.From February 2020 to April 2022, a total of 85,266 outpatient visits to pain clinics were retrieved. Of these, 7875 outpatient visits with incomplete information were excluded from this study, resulting in 77,391 outpatient visits, including 7821 online visits and 69,570 offline visits. We then screened out repeat visits so that only 1 piece of information was retained for each patient. A total of 39,260 patient records were retrieved, 5088 (12.9%) for the online clinic and 34,172 (87.0%) for the offline clinic .From February 2020 to April 2022, a total of 5088 patients with pain opted to conduct online visits at West China Internet Hospital. This represented 12.9% of all pain-related outpatient visits. The study results indicate that there were differences in age, working status, occupation type, and place of residence between the online and offline visit patients. Therefore, we performed a binary logistic regression analysis to determine the factors that influenced patients to choose online clinics through internet hospitals. This is a retrospective study that explored the current status of the use of internet hospitals for outpatients with pain in a tertiary hospital and the factors influencing their decision to choose online treatment. According to our study results, 12.9%  of patients chose to use the internet hospitals for out-of-hospital pain management, and patients who were young, middle-aged, employed, and nonlocal, and those who worked as ordinary staff were more inclined to choose internet hospitals.In China, patients with pain rarely receive the full range of standardized pain management because they lose contact with their physicians when they leave the hospital setting, compounded by the uneven distribution of medical resources and the impact of COVID-19. There are pain management apps designed for patients experiencing various types of pain, such as cancer pain, low back pain, and post–knee replacement pain -18. HoweThis study, for the first time, examined the current status of the use of internet hospitals by patients with pain. Currently, the number of online clinic visits is much lower than that of offline clinic visits, but internet hospitals are in a phase of rapid and steady growth. The reasons why people prefer to use offline clinics may be that they are currently more accustomed to offline, face-to-face visits and have less trust in online forms of consultation; some people are not even aware of the existence of online clinics. In both online and offline clinics, female patients outnumbered male patients, which is consistent with a higher prevalence of chronic pain among women ,21. HowePatients may choose online visits based on their working status and occupation types. In our study, we discovered that patients who were working were more likely to use online clinics. This may be because patients who are working are very busy and using the internet hospital can save them time; on the other hand, people who are working are more likely to be tired and experience pain. At the same time, we found that workers and farmers were less likely than civil servants to choose online outpatient services, while ordinary staff were more likely to choose online outpatient services. This phenomenon might be influenced by differences in education levels, with workers and farmers potentially being less accustomed to smartphone use. However, workers and farmers perform heavy manual labor, and their pain may be greater. In addition, we found that patients with pain who were not in proximity to physical hospitals were more likely to use the online services of internet hospitals, suggesting that internet hospitals can overcome geographical restrictions and be more convenient for patients. In particular, the internet hospital plus drug delivery service can fulfill the medication requirements of patients in remote areas with minor diseases, thereby reducing the pressure of physical hospital visits . In addiOur results showed that patient age, proximity to physical hospitals, employment status , and occupation types influenced patients’ choices to use internet hospitals. Therefore, it is better to initially promote pain management through internet hospitals among young people, employed individuals, and those residing in nonlocal areas and then expand it to other patient groups.Since the outbreak of COVID-19, there has been a massive boost in the number of internet health care visits, with 60%-95% of out-of-hospital patients reportedly switching from offline to online medical care in countries such as Italy, the United States, and India . The furThere are several disadvantages associated with patients seeking pain relief through internet hospitals. First, the disease diagnosis made online may be inaccurate because of the inability to perform a physical examination, laboratory tests, and imaging tests during online treatment through internet hospitals . Second,Although the COVID-19 lockdown has now been lifted, it is undeniable that internet hospitals have played an important role in the epidemic in China. Epidemic prevention and control is only one of the objectives of internet hospitals, and in the future, internet hospitals will serve more chronic diseases, such as chronic pain discussed in this study.In the future, internet hospital and pain follow-up apps can be combined to provide more diversified and comprehensive services to patients with chronic pain on the internet hospital platform. In addition, the establishment of an electronic patient health information database is more conducive for doctors to understand patients’ condition and make a more accurate diagnosis. With the development of artificial intelligence, patients with chronic pain can use wearable devices to evaluate their health status at home , gradualThis study has several limitations. First, we did not collect a great deal of information about the patients, such as their educational level, the length of their illness, or any other factors that may have affected their decision to use an internet hospital. In the collected data, the two possible influencing factors of disease diagnosis and comorbidities were not statistically analyzed due to the irregular and incomplete completion of information by patients. Additionally, this was a single-center study and used only 1 representative tertiary hospital in Southwest China as an example, which may not reflect the situation in other regions. Last, it is still unclear whether internet hospital–based out-of-hospital pain management is effective for patients with chronic pain.Currently, out-of-hospital pain management through the internet is becoming increasingly popular, especially in the postepidemic era. Although it is still in the exploration, improvement, and practice stages, additional research is needed to verify its effectiveness in pain management and promote its further development and improvement.


IntroductionPain management in patients with chronic kidney disease is challenging. Due to impaired kidney function, analgesic options are limited. Postoperative analgesia in transplant recipients is further complicated by their vulnerability to infections, titrated fluid management and optimal haemodynamics to maintain graft function. Erector spinae plane (ESP) blocks have been used successfully in a variety of surgeries. This study is a quality improvement project aiming to assess the efficacy of continuous erector spinae plane catheter analgesia in the postoperative management of kidney transplant recipients.MethodsWe conducted an initial audit over a period of three months. All patients who underwent kidney transplantation under general anaesthesia with erector spinae plane catheters were included. Erector spinae plane catheters were secured prior to induction, and continuous local anaesthetic infusion was maintained postoperatively. Pain scores using the numerical rating scale (NRS) were recorded at intervals in the first 24 hours postoperatively, and supplementary analgesics given were noted. Following satisfactory results from the initial audit, we implemented erector spinae plane catheters as part of multimodal analgesia in transplant patients in our centre. We re-audited all transplants done over the next year to reassess the quality of postoperative analgesia.ResultsFive patients were audited during the initial audit. The average NRS score ranged from 0 at rest to a maximum of 5 during mobilisation. All patients were given only paracetamol to supplement analgesia, and none required opioids. During the re-audit, data was collected on postoperative pain management in 13 subsequent transplants conducted over the next year. The NRS scores ranged from 0 at rest to 6 on mobilisation. Two patients required boluses of fentanyl 25 mcg via the catheter, and the rest reported satisfactory analgesia with paracetamol as needed.ConclusionThis quality improvement project changed our centre’s practice in managing postoperative pain in kidney transplantations. We switched from securing epidural catheters to erector spinae plane catheters due to better safety profile, minimal use of opioids and lesser adverse effects. We shall continue to re-audit our practices for the best outcomes. Erector spinae plane (ESP) block is evolving as a popular technique for perioperative analgesia in recent years. Initial reports of its successful use in thoracic surgeries and neuropathic pain led to its use in various abdominal procedures including hepatectomy, nephrectomy and percutaneous nephrolithotomy . As per Five patients with end-stage kidney disease who underwent live-related donor kidney transplantation in our centre, between May and September 2021, were included in the initial audit. The re-audit was done in the year that followed between October 2021 and September 2022, and thirteen patients were included. The patients were explained in detail about the technique of the insertion of an ESP catheter, the benefits and associated complications. A written informed consent was obtained.The ESP catheters were placed preoperatively in the operating room before the induction of general anaesthesia. Standard patient monitoring as per the American Society of Anesthesiologists, including electrocardiogram (ECG), pulse oximetry and noninvasive blood pressure monitors, was connected. Oxygen was administered via nasal prongs. The patients were positioned prone and sedated with intravenous (IV) midazolam 1 mg and IV fentanyl 1 mcg/kg. After sterile skin preparation, a curvilinear ultrasound probe was placed in the right parasagittal plane; transverse processes at the levels of T8-T9 were identified. The erector spinae muscle superficial to it was identified. An 18G Tuohy needle was introduced in the plane with the probe, in the cephalo-caudal direction towards the transverse process. After contacting the transverse process, 20 ml of 0.375% ropivacaine with dexmedetomidine 50 mcg was injected. The correct plane was confirmed by the linear spread of the drug lifting the erector spinae muscle off the transverse processes. A 20G epidural catheter was inserted into the needle and advanced 5 cm into the space. After securing the catheter, the patient was positioned supine, and general anaesthesia was induced. Fentanyl 1 mcg/kg, propofol 1-2 mg/kg and atracurium 0.5 mg/kg were administered. Anaesthesia was maintained with oxygen, nitrous oxide and sevoflurane mixture.A modified Gibson incision was made. Fentanyl 1 mcg/kg was to be administered if patients developed tachycardia at more than 20% of baseline heart rate. However, none of the patients required additional opioids intraoperatively. At the end of the surgery, as abdominal closure began, IV paracetamol 1 g was administered, and ESP catheter infusion was initiated with 0.125% bupivacaine at 12 ml/hour. The patients were then extubated immediately after surgery and transferred to the high-dependency unit.The pain was assessed using the numerical rating scale (NRS). The patient picks a number between 0 and 10, with 0 being ‘no pain’ and 10 being ‘the worst pain imaginable’. NRS scores were recorded at one, four, eight, 12, 18 and 24 hours postoperatively by a trained staff nurse. If patients scored more than 3 on NRS, IV paracetamol 1 g was administered, and the pain was reassessed after 30 minutes. On reassessment 30 minutes later, if the pain persisted (NRS of >3), IV tramadol 50 mg was to be given. During the re-audit, the rescue analgesic was changed to fentanyl 25 mcg given via the catheter with the ongoing local anaesthetic infusion , which are commonly used as part of multimodal analgesia in other patient populations, are contraindicated here. NSAIDS are associated with acute kidney injury and the progression of chronic kidney disease . EpiduraIn the background of restricted fluid management, immunosuppression and deranged platelet function, there is a higher risk of complications of epidural analgesia, which include hypotension, epidural abscess or haematomas. The literature on the use of epidurals in kidney transplants is conflicting, with some associating improved graft function  and someThe existing literature has emphasised the need to minimise the perioperative use of opioids in kidney transplants . The enhNewer regional techniques such as quadratus lumborum and ESP blocks are being explored for effective analgesia, although technical expertise is required . ESP anaOur study, being a clinical audit, is limited by a small sample size. Further prospective studies are required to validate the efficacy of erector spinae catheters in kidney transplants. We also need to re-audit our practices regularly to ensure continued good outcomes and assess other parameters such as time to recovery or discharge and overall patient satisfaction scores.Multimodal analgesic regimens with minimal opioids may prove beneficial for early mobilisation, recovery and discharge in kidney transplants. The advancement of newer interfascial plane blocks has reduced the use of neuraxial techniques and opioids. In our study, we report the good efficacy of continuous ESP catheter analgesia.ESP analgesia, being effective and having a good safety profile, is an appealing modality and warrants further investigation into expanding its utility in renal transplantation and other surgeries. Randomised controlled trials on the effectiveness and adverse events, in comparison with epidural analgesia and other modalities, are required.


Spinal metastasis pain includes both inflammatory and neuropathic pain, and opioids, which have only a μ-opioid receptor-stimulating effect, are generally less effective in neuropathic pain. However, no previous study has been conducted for the comparisons of the efficacy of opioids in treating spinal metastasis pain.To compare the efficacy of tapentadol and methadone with other opioids for back pain caused by a metastatic spinal tumor.Retrospective cohort study.A total of 274 patients were enrolled, who started a tapentadol extended-release tablet, methadone tablet, hydromorphone extended-release tablet, oxycodone extended-release tablet, or transdermal fentanyl patch for cancer pain due to spinal metastasis in Japan from January 1, 2013 to October 31, 2021.The primary endpoint, the difference in the numerical rating scale (NRS) scores before and seven days after each opioid administration, was compared among the five groups.In patients with numbness, a decrease of the NRS score on day seven compared with before starting each opioid was significantly higher in the tapentadol group than those in the hydromorphone, oxycodone, and fentanyl groups and comparable to that in the methadone group. In patients without numbness, no significant differences were observed in decreases of the NRS scores on day seven among the five groups.Tapentadol and methadone may be more effective than hydromorphone, oxycodone, and fentanyl for cancer pain due to spinal metastasis with numbness. Periosteum being a densely innervated tissue, activation of periosteal sensory nerves by mechanical stretching of the periosteum results in more intense pain. Thus, bone metastasis pain includes both inflammatory and neuropathic pain.8 Moreover, in the presynaptic neurons of the spinal dorsal horn, which bear approximately 75% of the spinal μ-opioid receptors, the expression of these receptors is reduced following nerve injury.9 Therefore, opioids are generally less effective in neuropathic pain than in inflammatory pain.11 A previous study reported that treating bone metastasis pain with increasing opioid doses did not provide adequate analgesia in some patients.12Release of inflammatory substances such as endothelin, prostaglandins, and nerve growth factor from stromal/tumor cells induces sensitization and sensory nerves' excitation, causing nociceptive pain.14Only half of the patients with bone metastasis pain experienced temporary pain relief from conventional medications, indicating the need for better analgesics.d-aspartate (NMDA) receptor antagonist effects. These multiaction opioids can effectively treat bone metastasis pain, including neuropathic pain.16 However, no previous study has been conducted to compare the efficacy of opioids in treating bone metastasis pain.Unlike other opioids, tapentadol has μ-opioid receptor-stimulating and noradrenaline reuptake inhibitory effects, whereas methadone has μ-opioid receptor-stimulating and N-methyl-17This study aimed to gain insight into the optimal opioid selection for cancer pain due to spinal metastasis by comparing the efficacy and tolerability of tapentadol and methadone with other opioids for back pain caused by spinal metastasis, which are most frequent in bone metastases.The following data were collected from medical records: age, sex, body mass index, Eastern Cooperative Oncology Group performance status, Barthel Index, primary cancer site, pretreatment opioids and their morphine-equivalent daily dose (MEDD), the presence of pathological fracture at the spinal metastasis site, numbness, irradiation history for relieving spinal metastasis pain, concomitant medications, and laboratory values at the start of each opioid administration. The MEDD of pretreatment opioids was calculated using an equianalgesic dose table proposed by the National Comprehensive Cancer Network. The presence or absence of numbness was determined according to the medical records by physicians at the start of treatment with each opioid. Adverse events were evaluated according to the patients' complaints and medical records by physicians, nurses, and pharmacists.4 Therefore, this study investigated the worst pain in the past 24 hours included as an item in the Brief Pain Inventory Short Form . This study also investigated usage count of opioid rescue doses before and after each opioid administration because the use of opioid rescue doses can affect changes in pain intensity.Pain intensity, as reported by the patients, was based on the numerical rating scale (NRS) and obtained before and after each opioid administration . Bone metastasis pain is generally incidental and induced after movement.The rate of improvement in the following movements within seven days after starting each opioid was investigated according to the patients' complaints and medical records by physicians, nurses, pharmacists, physiotherapists, and occupational therapists: walking without support, walking with support , stair climbing, standing up, maintaining steady upright standing, maintaining sitting without support, rising from a bed, repositioning without support, sleeping well at night, taking a bath without support, taking a bath with support, shopping in the hospital setting, and discharging from the hospital or going out for several hours. Walking with and without support was considered to improve when walking speed and distance increased after starting each opioid. Stair climbing, standing up, rising from a bed, and repositioning without support were considered to improve when the frequency and speed of each movement increased after starting each opioid. Maintaining steady upright standing and maintaining sitting without support were considered to improve when the time to hold each posture increased after starting each opioid.Sleeping well at night was considered to improve when patients determined that their nighttime sleep improved after starting each opioid among patients who had nocturnal awakenings due to pain. Taking a bath without support, taking a bath with support, shopping in the hospital setting, and discharging from the hospital or going out for several hours were considered to improve when patients performed each event after starting each opioid among patients who wanted but were unable to perform each event due to pain.This study enrolled Japanese inpatients who started a tapentadol extended-release tablet, methadone tablet, hydromorphone extended-release tablet, oxycodone extended-release tablet, or transdermal fentanyl patch for cancer pain due to spinal metastasis in Japan from January 1, 2013 to October 31, 2021. Spinal metastasis was determined by the physicians using magnetic resonance imaging. Since using other analgesics or bone-modifying agents (BMAs) may influence the efficacy of opioids for pain caused by spinal metastasis, 2, 3, 4, 4, and 8 patients, who started using other analgesics or BMAs within 7 days before initiating opioid therapy or within 14 days after initiating tapentadol, methadone, hydromorphone, oxycodone, and fentanyl, respectively, were excluded.8 Therefore, this study compared the differences in the NRS scores, the differences in the usage counts of opioid rescue doses, the improvement rates for each movement, and the discontinuation rate among tapentadol, methadone, hydromorphone, oxycodone, and fentanyl groups after dividing patients according to the presence or absence of numbness, a typical symptom of neuropathic pain.18The primary endpoint was the difference in the NRS scores before and seven days after each opioid administration. The secondary endpoints were the differences in the NRS scores before and 3, 5, and 14 days after each opioid administration; the differences in the usage counts of opioid rescue doses before and 3, 5, 7, and 14 days after each opioid administration; the improvement rates for each movement within 7 days after starting each opioid; and the discontinuation rate of each opioid due to adverse events within 14 days after starting each opioid. Bone metastasis pain includes inflammatory and neuropathic pain.The differences in the NRS scores and the usage counts of opioid rescue doses were analyzed using Dunnett's test. A chi-square for independence test was conducted to compare the improvement rates for each movement and the discontinuation rate of each opioid due to adverse events among the five groups.t-test referencing the sample size calculation in a previous study comparing the efficacy of opioids for cancer pain.19 Assuming a statistical probability at a 5% level with a power of 0.80, the minimum sample size was 15. All statistical analyses were performed using BellCurve for Excel ; p-values of <0.05 were considered statistically significant.The required sample size was determined to detect an effect size of 0.80 in the NRS scores on days 0 and 7 using a sample size calculator for a paired This study was conducted in accordance with the ethical principles for medical research outlined in the Declaration of Helsinki (1964) and approved by the Ethics Review Board of the Osaka University Graduate School of Pharmaceutical Sciences . Written consent for publication of this study was obtained from all patients.p <0.001). No significant differences were observed for the other baseline characteristics among the five groups. The data of 52, 53, 60, 51, and 55 patients were included in the tapentadol, methadone, hydromorphone, oxycodone, and fentanyl groups, respectively. p = 0.96) and those without numbness (p = 0.99). In all groups, the NRS scores decreased until day 14. The changes in the worst pain scores (NRS) in the past 24 hours before and after each opioid administration in patients with and without numbness are shown in p = 0.99) and those without numbness (p = 0.97). In all groups, the usage counts of opioid rescue doses decreased until day 14. The changes in the usage counts of opioid rescue doses before and after each opioid administration in patients with and without numbness are displayed in After day three, no significant differences in decreases in the usage counts of opioid rescue doses were observed among the five groups of patients with numbness. However, in patients without numbness, no significant differences in decreases in the usage counts of opioid rescue doses were observed among the five groups on all evaluation days. In patients with and without numbness, no significant differences in the MEDD of opioid rescue doses were observed among all groups at baseline and after administering each opioid.No patient discontinued tapentadol due to adverse events within 14 days after starting tapentadol. One patient (1.9%) discontinued methadone due to nausea. Five patients (8.1%) and two patients (3.2%) discontinued hydromorphone due to nausea and daytime sleepiness, respectively. Three patients (5.9%), three patients (5.9%), and one patient (2.0%) discontinued oxycodone due to constipation, nausea, and delirium, respectively. Two patients (3.6%), two patients (3.6%), and one patient (1.8%) discontinued fentanyl due to daytime sleepiness, pruritus, and nausea, respectively.To our knowledge, this is the first study to compare the effects of opioids on cancer pain due to spinal metastasis. In patients with numbness, both a decrease of the NRS scores on day seven compared with baseline and the improvement rate for all movements within seven days after starting the administration were higher in the tapentadol group than those in the hydromorphone, oxycodone, and fentanyl groups and comparable to those in the methadone group. These results suggest that tapentadol and methadone may be more effective than hydromorphone, oxycodone, and fentanyl for cancer pain due to spinal metastasis with numbness.20 Namely, the baseline pain sensitivity is only a little influenced by the noradrenergic system, whereas under neuropathic pain, the central and peripheral noradrenergic systems are subject to plastic changes that mitigate against antinociceptive efficacy.21 Tapentadol with noradrenaline reuptake inhibition increases noradrenaline in the spinal cord and activates descending inhibitory pain pathways.22 Interestingly, experimental and clinical evidence indicates that the noradrenaline reuptake inhibition component of tapentadol may become predominant compared with μ-opioid receptor-stimulating component in neuropathic conditions.22 In this study, among patients with numbness, a decrease of the NRS scores before and after starting the administration was significantly greater in patients administered tapentadol than hydromorphone, oxycodone, and fentanyl groups, which have only a μ-opioid receptor-stimulating effect and made the NRS scores little reduced. Thus, tapentadol may be suitable for spinal metastasis pain, especially neuropathic pain.Recently, it has become clear that the noradrenaline pathway is important in preventing the progression of neuropathic pain. This endogenous descending pain modulating system plays a key role in shaping the spatial and temporal expressions of the neuropathic pain phenotype following nerve injury.23 NMDA receptor antagonists have been reported effective for such neuropathic pain,24 and the results of this study were consistent with these previous studies. In the methadone group of this study, the MEDD of pretreatment opioids was significantly higher than in the other groups. Therefore, some of the NRS reduction in the methadone group might be due to its effect on opioid-induced hyperalgesia through NMDA antagonism.Moreover, methadone with NMDA receptor antagonism also showed a significantly higher analgesic effect for cancer pain due to spinal metastasis with numbness in this study than hydromorphone, oxycodone, and fentanyl. Glutamate released from cancer cells that give rise to bone cancer excites and induces skeletal and cutaneous hyperalgesia and mechanical sensitization by potentially activating peripherally expressed NMDA receptors.25 Additionally, being bedridden for a long time due to pain increases the risk of deep venous thrombosis, bedsores, and delirium due to hypercalcemia.26 Therefore, this study clarified the efficacy of tapentadol and methadone for spinal metastasis pain could be clinically significant for pain management and in preventing complications associated with these prolonged rests. The ADL level reportedly affects the availability of discharge in patients with spinal bone metastases.27In patients with numbness, the improvement rates for each movement within seven days after starting the administration were larger in the tapentadol and methadone groups than those in the hydromorphone, oxycodone, and fentanyl groups in this study. Bone metastasis pain is commonly induced after movement, and a previous study suggested that skeletal-related events such as bone metastasis exerted a serious impact on QOL and ADL in the patients.In this study, the improvement rates for discharge from the hospital or going out for several hours in the tapentadol and methadone groups, which had higher improvement rates for all movements, were also significantly higher than those in the hydromorphone, oxycodone, and fentanyl groups. This study is also significant for discharge support because discharge from the hospital and going out for several hours are important options for cancer patients and can be goals for patients and their families, especially at the end of life.15 Approximately 70% of patients in this study also had numbness, a typical neuropathic pain symptom. Both decreases of the NRS scores and improvement rates for all movements were higher in the tapentadol and methadone group than those in the hydromorphone, oxycodone, and fentanyl groups in patients with numbness, although no statistically significant differences were observed in decreases of the NRS scores and improvement rates for any movements among the five groups in patients without numbness. Therefore, numbness can be a prime indicator in selecting the optimal therapeutic medication for managing spinal metastasis pain.In a previous study of patients with bone lesions related to multiple myeloma, >70% of patients were reported to have neuropathic pain components.In patients without numbness, the use of opioid rescue doses decreased to <1 time/day within 14 days in all groups. In patients with numbness, the use of opioid rescue doses decreased in all groups, and those in the tapentadol and methadone group tended to be larger than those in the other three groups, like decreases in the NRS scores. This result suggested that the differences in decreases of the NRS scores among the five groups could be due to the analgesic effects of the opioids rather than the analgesic effects of the opioid rescue doses. Moreover, tapentadol was shown to have fewer rescue opioid doses in the first one to two days after initiation. This could be related to the shorter half-life of tapentadol; therefore, it might reach a steady state earlier than other opioids.28 Tapentadol was associated with significantly lower incidences of constipation and vomiting and significant improvements in QOL measures compared with oxycodone/naloxone.29 Therefore, tapentadol is a viable treatment option even in patients at high risk of adverse events, such as the elderly.Regarding tolerability, no patient discontinued tapentadol due to adverse events; among the five groups, the discontinuation rate due to adverse events was the lowest in the tapentadol group. Gastrointestinal adverse events are well tolerated because tapentadol has a low affinity for the μ-opioid receptor.This study had several limitations. First, this was a retrospective study. Although no significant differences were observed in the baseline patient characteristics other than MEDD of pretreatment opioids , confounTapentadol and methadone may be more effective than hydromorphone, oxycodone, and fentanyl for cancer pain due to spinal metastasis with numbness. As spinal metastasis pain significantly affects the ADL of patients, this study clarifying the optimal opioids for cancer pain due to spinal metastasis for the first time is clinically meaningful in pain and ADL improvement.


Records of 118 DEXA patients were analyzed (DEXA dose ranged from 0.05 to 0.12 mg/kg). Intraoperative IV DEXA was associated with a significant reduction of the pain felt when PNB wore off as well as to a significant reduction of RP incidence  with no effect related to the dose administered (p = 0.053). Our results support the administration of intraoperative DEXA as a preventive measure to reduce the occurrence of RP.Rebound pain (RP) remains a challenge in ambulatory surgery, characterized by severe pain upon resolution of a peripheral nerve block (PNB). Intravenous (IV) administration of Dexamethasone (DEXA) potentiates PNB analgesic effect and reduces RP incidence although preventive effective dose remains undetermined. This retrospective analysis evaluates the preventive effect of IV DEXA on RP in outpatients undergoing upper limb surgery under axillary block. DEXA was divided into high (HD > 0.1 mg/kg) or low (LD < 0.1 mg/kg) doses. RP was defined as severe pain (NRS ≥ 7/10) within 24 h of PNB resolution. DEXA HD and LD patients were matched with control patients without DEXA ( Regional anesthesia offers several advantages in ambulatory setting, including high-quality perioperative analgesia and faster discharge from the hospital.Peripheral nerve blocks (PNBs) using different techniques  are exteFor the aforementioned reasons, the prevention of RP occurrence has become a priority, particularly in ambulatory surgery setting. Several risk factors have been found to be associated with the phenomenon such as younger age, female gender, high catastrophizing mind set, bone surgery and the absence of perioperative administration of dexamethasone ,6. DexamThe main objective of this retrospective study was to assess the occurrence of RP when perioperative IV DEXA was administered at analgesic . It is a retrospective analysis of data collected prospectively in the context of Quality Reporting in the Out-Patients Unit. The data were collected over a period of 1 year, between January 2021 and February 2022, from patients’ files and perioperative questionnaire-based sources.Ambulatory adult patients (18 to 80 years old) who underwent elective upper limb surgery (elbow and below) under axillary plexus block between January 2021 and February 2022 were included . Only paAll the patients benefited from the same perioperative analgesic protocol using multimodal analgesia. Patients who had contra-indication to the analgesics used in the perioperative multimodal analgesic protocol  were not included in the analysis. Patients who received IV DEXA were matched with patients of the control group regarding age, sex and type of surgery (bone or soft tissues surgery) .To improve the management of postoperative pain by better focusing on patients at risk of developing severe acute postoperative pain when back home, a set of preoperative questionnaires is commonly proposed to the patients to all the ambulatory patients including those undergoing regional anesthesia for ambulatory orthopedic surgery. All the questionnaires are completed on a voluntary basis.All the patients included in the study had complete perioperative records. Preoperative data collected on day 0 included preoperative pain at rest, pain on movement and pain overnight at the surgical site, using a numerical rating scale (NRS) from 0 to 10 (where 0 = no pain and 10 = worst pain). Preoperative medications, including pain relievers, were also noted. Patients also completed a pre-operative questionnaire that had been developed in 2019 as part of a previous prospective study . The anePatients were therefore asked to answer a series of preoperative questions such as the French version of the Pain Catastrophizing Scale (PCS) questionnaire, which assess negative thoughts related to pain  on a scale from 0 to 52 . PatientThe French version of the Central Sensitization Inventory (CSI) was used to measure the main somatic and emotional complaints associated with central sensitization. A validated short-form was used as CSI-9  to distinguish patients presenting with a preoperative positive central sensitization . FinallyBefore the surgical incision, the effectiveness of the sensory blockade of the axillary plexus was evaluated by a cold test (ether test) in the different territories. Only patients who presented with fully effective axillary PNB were considered for inclusion in the study . For varThe definition of RP was the same we used in our previous study , i.e., tThe sample size was calculated based on the incidence of rebound pain. The presence of RP was defined as pain intensity score > 7  reported by the patient after axillary plexus block resolution . Based on = 55) included in a previous randomized controlled trial [For analysis of retrospective data, the intravenous DEXA dose was separated into high  or low  doses. DEXA HD and LD patients were compared to control patients  was also be used to test the predictive value of intravenous DEXA prevention on the development of RP.Statistical analysis was performed with SigmaStat 3.5 . Results were expressed as proportions, mean ± standard deviation or median value (interquartile range) as specified. According to a Kolmogorov–Smirnov normality test, parametric data between the groups were compared by an unpaired Student t-test and nonparametric data by Mann–Whitney and Kruskal–Wallis Rank Sum tests. Categorical data were compared using the chi-squared test and Fisher exact test using a two-tailed probability. A Between January 2021 and January 2022, 210 patients underwent elective upper limb surgery under axillary plexus block, and intraoperative IV DEXA administration was noticed in 133 of these patients. A total of 118 patients were included in the retrospective analysis (n = 55) [p = 0.002) (As reported in n = 55) . Intraop= 0.002) . The totn = 64) and a low-dose DEXA group  as described in Thereafter, for statistical analysis, patients who received IV DEXA were divided into a high-dose DEXA group , a positive correlation was noted between the intensity of RP and the intensity of preoperative pain  as well as for the level of preoperative catastrophizing score . Important factors associated with the presence of RP  were entered in a Backward Stepwise Regression model including the intraoperative administration of DEXA independently of the dose used. In the final model, bone surgery (p < 0.001), high catastrophizing (p < 0.001) and the absence of intraoperative DEXA (p = 0.027) were predictive of RP occurrence when the axillary PNB wore off.When considering the full population of patients (p = 0.002). This finding is in agreement with previous reports [The present results support the intraoperative use of intravenous DEXA (dose 0.05–0.12 mg/kg) for the prevention of rebound pain after upper limb surgery under axillary plexus block. Regardless the dose of IV DEXA administered, our study showed a significant decrease in RP occurrence . Similarly, if we compare RP incidence in our DEXA-HD group (20%) with that in Holmberg’s study (9%), there is no statistically significant difference (p = 0.33) [According to the aforementioned findings, a dose-related preventive effect of IV DEXA on RP might be questioned. However, if we compare the incidence of RP in our DEXA-LD (<0.1 mg/kg) with that of RP in Holmberg’s study (0.23 mg/kg), the difference is not statistically significant  , no sign = 0.33) . These rProlonged nerve block, hence a smoother recovery of nociceptive sensations, has been proposed as a mechanism to reduce RP . At the Two studies in healthy volunteers ,24 usingBone surgery leads to the local release of pro-inflammatory cytokines, such as interleukin 6 (IL-6), which activate and sensitize sensory nerves, leading to an amplified pain signal . More, tThere are some limitations of this study. First, its retrospective nature involving a single center. Additionally, data regarding DEXA administration and data regarding the control group were collected in different cohorts. Second, the follow-up of DEXA patients was limited to the first 24 h, which could have contributed to the loss of additional data. In the literature, late RP, i.e., at 36 and even 48 h, is reported. Finally, the doses of IV DEXA used were left to the discretion of the anesthesiologists in charge of the patients, which may have led to possible distribution bias due to common practices and habits.It is worth noting that no adverse effects in relation to the administration of DEXA were found in the patients’ files. The relatively low doses of DEXA used in our study may actually have contributed to the absence of glycemic disorders in the patients . SimilarIn conclusion, our results support the administration of intraoperative IV DEXA as a preventive measure to reduce the occurrence of RP.To our knowledge, this study is the first dedicated to investigating the dose-dependent effect of intraoperative DEXA  in the prevention of RP. We found a preventive effect on RP including at very low doses (<0.1 mg/kg) and independent of the PNB duration. A comparison with the existing literature may be in favor of an IV DEXA ceiling effect on RP prevention which contrasts with the IV DEXA dose-related effect on sensory block duration. Further prospective studies should confirm the present findings and investigate the mechanisms underlying the IV DEXA preventive effect on rebound pain.