Background: As length of stay after total knee arthroplasty (TKA) continues to shorten, interventions that may reduce early postoperative pain and complications must be studied. Peripheral nerve block is being explored as a potential means of improving pain management. The purpose of this study was to evaluate the impact of adductor canal block (ACB) on postoperative outcomes for patients undergoing TKA.Methods: We conducted a retrospective review of 565 patients who received unilateral TKA under spinal anesthesia with a periarticular anesthetic injection. Patients were divided by ACB status. Univariate comparisons and multivariate regression were used to compare outcomes for patients receiving ACBs vs those who did not.Results: Of the 565 patients, 167 received an ACB, and 398 did not. Patients who received an ACB were less likely to require nausea medication during the immediate postoperative period. Length of stay, narcotic consumption, rate of discharge to home, postanesthesia care unit recovery time, urinary retention, ability to complete physical therapy, and 30-day readmission rate did not differ significantly between groups. After risk adjustment, the only significant finding was decreased likelihood of nausea in patients receiving an ACB.Conclusion: ACBs appear to have little to no significant impact on early clinical outcomes in patients having TKA under spinal anesthesia with a periarticular anesthetic injection. Further study of larger patient cohorts is required to validate these findings. Approximately 60% of patients report severe pain postsurgery.2 Intense postoperative pain can hinder patient recovery and lead to numerous issues, including mobility-related complications such as decreased ability to move the knee, higher risk of deep vein thrombosis, and increased length of hospital stay.4Total knee arthroplasty (TKA) is one of the most common procedures performed throughout the world.5 Additionally, anesthesia type has been shown to influence postoperative complication rate and patient satisfaction in elective TKA.7 Although some studies have shown equivocal outcomes for both anesthesia types, spinal anesthesia has been associated with decreased risk of common surgical complications, such as surgical site infection, in both total hip arthroplasty and TKA patient populations.9 Despite the benefits of spinal anesthesia, this anesthesia route has also been associated with increased risk of venous thromboembolism.7 Because of the known impact on surgical outcomes, anesthesia type must be regarded as a possible confounding variable when analyzing the influence of other treatment factors for patients undergoing TKA.8As rapid recovery protocols evolve and length of stay continues to decrease after TKA, use of peripheral nerve blockade is being explored as a potential means of improving pain management.10 Historically, the popularity of FNB increased based on its ability to reduce postoperative pain and the need for narcotics after TKA.11 However, FNB targets the femoral nerve, affecting both the afferent and efferent nerve pathways and compromising quadriceps muscle strength, which can adversely affect patient mobilization and stabilization postsurgery, and the procedure has been associated with higher instances of complications compared to procedures not utilizing FNBs.14 ACB involves the injection of anesthetic anterolateral to the femoral artery at the mid-thigh in the musculofascial space which anesthetizes the saphenous nerve and the nerve to the vastus medialis while sparing the motor branches of the femoral nerve.15 The principal strength of this method is the ability to avoid the quadriceps weakness that is associated with FNB and thereby allow for early ambulation after surgery.16Femoral nerve block (FNB) and adductor canal block (ACB) have been investigated as regional techniques that prolong the effectiveness of anesthesia.The purpose of this study was to add to the current literature by investigating the effect ACB has on early postoperative pain and outcomes after TKA performed under spinal anesthesia with a periarticular anesthetic injection (PAI)., body mass index (BMI), and procedure performed. American Society of Anesthesiologists (ASA) physical status classification score 3 or 4 was used to quantify preoperative health status. Intraoperative administration of fentanyl, hydromorphone, tranexamic acid, and dexamethasone was also recorded for each patient.Our institutional clinical research committee deemed this study institutional review board exempt. We conducted a retrospective medical records review of all patients undergoing primary unilateral TKA by 10 board-certified surgeons at a single institution. The timeline for inclusion was February 1, 2020, to September 1, 2020. Patients undergoing bilateral TKA or revision TKA were excluded. Data were collected using an administrative database for patient demographics including age, sex, marital statusAll patients were cared for in a coordinated joint replacement center and received written education materials, preoperative medical evaluations, preoperative home exercise or outpatient physical therapy, and an education class for patients and their caregivers. Based on clinical history, patients received preemptive oral medications including celecoxib, acetaminophen, and pregabalin 2 hours before their procedure. Spinal anesthesia was paired with propofol sedation and consisted of either 12 to 15 mg of hyperbaric or isobaric bupivacaine or 50 to 70 mg of mepivacaine. Patients received intravenous opioids administered intraoperatively and in the postanesthesia care unit (PACU). All patients received a standard PAI of ropivacaine and epinephrine before closure. ACBs were completed using either ropivacaine or bupivacaine administered under ultrasound guidance. The decision to administer an ACB in the operating room prior to incision was made preoperatively in consultation with the patient and anesthesiologist. Postoperatively, all patients were treated according to a multimodal pain management protocol that, depending on patient factors, included acetaminophen, oral nonsteroidal anti-inflammatory drugs, pregabalin, ketorolac, and oral opioid medications as needed. All patients received assisted ambulation on the day of surgery when appropriate.Postoperative outcomes of interest included PACU nausea and pain, administration of nausea medication within 24 hours of surgery, ability to participate in the first postoperative physical therapy session, urinary retention, narcotic consumption, length of stay (measured in hours), discharge disposition, recovery time (measured in hours), last PACU pain score measured by the 10-point numeric rating scale, and 30-day readmission. Urinary retention was defined as any incidence of recatheterization during the patient's hospital stay. Narcotic consumption was measured as oral morphine milligram equivalents and included all narcotics received outside of the operating room.t tests, was used to determine differences between groups. Fisher exact test was performed when the assumptions of chi-square testing were not met, and the Mann-Whitney U test was used for nonparametric continuous data. Multiple logistic and linear regression was used to establish the effect of ACB on postoperative outcomes while controlling for sex, administration of fentanyl, and administration of dexamethasone. These variables were selected as possible confounding factors because they were significantly different at α<0.10 between groups in preliminary univariate analysis. The same control variables were used for all regression models. All statistical analyses were performed using RStudio, version 1.4.1717 . Statistical significance was assessed at P<0.05.Patients were grouped based on whether they received an ACB at the time of surgery. Statistical analyses were used to determine the impact of ACBs on postoperative outcomes. Univariate analysis, including chi-square tests and 2-sided independent samples P=0.015). Intraoperatively, the rates of intravenous (IV) tranexamic acid, IV or intrathecal fentanyl, and IV hydromorphone use were similar between the 2 groups (P<0.001).Of the 565 patients included in the study, 167 (29.6%) received an ACB and 398 (70.4%) did not. No significant differences in age, BMI, marital status, race, or ASA physical status classification score 3 or 4 were seen between patients in the ACB and non-ACB groups . A signi2 groups . HoweverP<0.001). However, no significant differences in PACU recovery time, last PACU pain score, first physical therapy failure rate, rate of urinary retention, oral morphine milligram equivalent, or oral morphine milligram equivalent per hour were observed between the 2 groups. Patients in the ACB group experienced a significantly shorter average length of stay than those in the non-ACB group (P=0.037). The rate of discharge to home was similar between groups. However, the rate of 30-day readmission was significantly lower among patients in the ACB group (P=0.029).As shown in P<0.001) than patients in the non-ACB group  1 discharge, while no differences in postoperative narcotic utilization were observed. Based on these findings, the authors decided to limit the use of ACB to select patients known to have preoperative pain or stiffness, given the cost of ACB and the limited clinical impact on perioperative pain control. Similarly, our results suggest limited influence of ACB on postoperative outcomes, including no influence on narcotic requirements. All ACBs in our study were performed prior to incision, while Rames et al included ACBs performed primarily in the PACU.22 Despite these methodological differences, the similar results observed in both studies call into question the routine use of ACB in patients undergoing TKA.Other studies have raised similar questions about whether the clinical impact of ACB supports the use of the treatment in patients undergoing TKA.22 Ma et al and Grosso et al identified similar trends in their evaluations of the combined effect of an ACB with an intraoperative PAI.21 Ma et al conducted a meta-analysis comparing the effects of ACB+PAI with PAI alone in patients undergoing TKA.18 The authors found that ACB+PAI was associated with longer distances walked than PAI alone on POD 1, but they found no differences in pain, narcotic consumption, length of stay, and postoperative complications between groups. Grosso et al conducted a randomized controlled trial of 155 TKA patients who had spinal anesthesia and various intraoperative pain treatments that included ACB alone, PAI alone, or ACB+PAI.21 The visual analog scale (VAS) pain score was significantly higher for patients who had ACB alone on POD 1 and POD 3 in comparison to the other 2 groups. In addition, total opioid consumption was higher, and activity level during physical therapy on POD 0 was significantly lower in the ACB alone group.In comparison to the results of our study and of Rames et al,21 These data are useful to surgeons who are hesitant to incorporate ACBs into their practice based on prior experience with FNBs that reduced patients’ ability to ambulate in the early postoperative period. A meta-analysis and systematic review comparing local infiltrative anesthesia (LIA) to LIA combined with ACB determined that ACB+LIA provides improved pain control, improved range of motion, decreased morphine use on POD 0 and 1, and lower VAS scores on POD 0 and 1.23 While our study did not address the use of ACB in isolation, the results from this meta-analysis suggest the methodology used in our study is reflective of current practice patterns.As part of our standard intraoperative protocol, all patients included in our study received PAI, therefore eliminating our ability to comment on the utility of ACB used in isolation. Similar to the conclusions of both the Grosso et al and Ma et al studies, the addition of ACB to a PAI appeared to have little effect on postoperative outcomes. However, our finding that patients receiving spinal anesthesia with an ACB were just as likely to complete their first physical therapy session, the Grosso et al observation of no difference in steps taken on POD 0 between the PAI and ACB+PAI groups, and the Ma et al finding of significantly longer distances walked on POD 1 in the ACB group provide evidence that the addition of an ACB to PAI does not appear to negatively affect early ambulation.26 Perlas et al retrospectively assessed 298 patients who underwent TKA under spinal anesthesia.24 LIA and ACB+LIA were associated with improved early ambulation and a higher rate of being discharged home compared to the previous standard FNB.24 Xing et al conducted a meta-analysis of 4 randomized controlled trials and found a correlation between ACB+PAI and reduced pain scores and opioid consumption when compared to PAI alone.26 The authors noted a lower incidence of postoperative nausea in patients who had ACB+PAI. Our findings also demonstrated a reduction in the reports of nausea in the PACU for patients who received an ACB. In contrast to the findings presented in Xing et al, ACB+PAI was not associated with improved pain scores or decreased opioid consumption in our patient population.26 While previous researchers have compared the clinical impact of ACB+PAI to PAI alone, few studies have directly compared PAI and ACB. Sardana et al conducted a meta-analysis of 6 studies and found a greater reduction in VAS pain scores and opioid consumption for patients receiving PAI compared to patients receiving an ACB.25Although multiple studies have demonstrated limited clinical impact of ACB on perioperative pain control, other studies have provided contradictory evidence that the technique is associated with improved early pain control and outcomes after TKA.27 From a cost-effectiveness standpoint, Bagaria et al evaluated the feasibility of direct ACB as part of surgeon-administered PAI as a replacement for ultrasound-guided ACB by the anesthesiologist.15 After consideration of the ability of surgeons to correctly place the analgesic in the adductor canal with direct ACB methods, the authors concluded that direct ACB is a feasible treatment that may reduce the cost of the procedure and OR time for patients undergoing TKA.Given the mixed outcomes of previous studies investigating the impact of ACB in patients undergoing TKA, the cost-effectiveness of the treatment must be evaluated against the possible clinical impact. To evaluate the potential cost impact of ACB, all aspects of the treatment must be considered, including the cost of the medication, physician fee for services rendered, and the time spent administering the block in the operating room (OR). Time optimization in the OR should be a priority, considering that the estimated OR use cost is $36 to $37 per minute.Our study has limitations. First, the retrospective observational nature of this work can result in possible selection bias. Additionally, the data included in the analysis were collected from a single institution. Because of the nature of the study, the findings of this work may not be representative of the larger patient population. Despite this limitation, the inclusion of patients who underwent surgery at a single institution does allow for standardized preoperative, perioperative, and postoperative care, which can eliminate some confounding variables that otherwise may have impacted our results. Second, patient ambulation was collected from the physical therapy note in each patient's electronic medical record. Some patients may have ambulated with staff nurses, and those ambulation sessions would not be captured in the data. Future prospective trials randomizing patients to receive spinal anesthesia with and without an ACB within rapid recovery protocols are recommended to validate these findings. Although ACB seems to have had limited clinical impact on the current study cohort, further study regarding specific patient populations who may benefit from this treatment, such as opioid non-naïve patients, is warranted.Administration of an ACB significantly reduced patient accounts of nausea in the PACU. However, all other postoperative outcomes evaluated in this study were similar regardless of whether a patient did or did not receive an ACB. Despite this minor benefit, ACB seems to be of limited use in this patient population.


Chest tube removal (CTR) can cause severe acute pain which is usually described by patients as a painful experience. This study compared the effects of cold compress, transcutaneous electrical nerve stimulation (TENS), and combined cold compress-TENS on CTR-associated pain among patients with coronary artery bypass grafting (CABG).This randomized controlled trial was conducted in 2018–2019 using a double-blind four-group design. Participants were 120 patients with CABG selected from Shafa hospital, Kerman, Iran, and randomly allocated to a cold compress, a TENS, a combined cold compress-TENS, and a placebo group (compress with room temperature) and TENS with an off TENS device. Each participant received the intervention for 15 min immediately before CTR. CTR-associated pain was assessed before, during, immediately after, and 15 min after CTR. Data were analyzed using the SPSS program (v. 22.0) at a significance level of less than 0.05.P > 0.05). The mean score of pain intensity in all groups was at its highest level during CTR and gradually decreased afterwards, but this pain intensity reduction in the compress-TENS group was significantly greater than other groups (P < 0.001).The data of 29 participants in the placebo group, 26 in the TENS group, 30 in the cold compress group, and 26 in the combined cold compress-TENS group was gathered. Baseline demographic and clinical characteristics and pain intensity scores of participants had no statistically significant differences among all four groups (Combined cold compress-TENS is more effective than separate cold compress and TENS in reducing CTR-associated pain among patients with CABG. Therefore, non-pharmacological methods such as combined cold compress-TENS are recommended for managing CTR-associated pain. Cardiovascular disease is one of the major health challenges  and a leCardiac surgery is a common treatment for cardiovascular disease , 8. EachIneffective pain management among patients with cardiac surgery can increase the risk of postoperative respiratory complications such as reduced respiratory muscle strength, reduced lung volume and capacity, reduced effectiveness of coughing, and increased risk of respiratory infections. These complications negatively affect postoperative recovery and are among the major causes of postoperative death . ContrarThere are many different pharmacological and non-pharmacological pain management methods. Pharmacological methods  are usually associated with different side effects such as dyspnea, nausea, and gastrointestinal bleeding. Therefore, non-pharmacological methods are usually preferred for pain management –18. ThesCold compress is a common non-pharmacological method for managing CTR-associated pain. It is among the oldest, easiest, and safest pain management methods . Cold coTENS is another non-pharmacological method for pain management  which haSeveral studies reported the effectiveness of cold compress in reducing CTR-associated pain , 29, 30,This randomized controlled trial was conducted in 2018–2019 using a double-blind four-group design. Participants were 120 hospitalized adult patients with CABG recruited from the cardiac surgery intensive care unit of Shafa hospital, Kerman, Iran. They were selected based on the following selection criteria: an age of 18–75 years, Iranian nationality, full consciousness, hemodynamic stability, sensitivity to cold, no use of tranquilizers or analgesics 1 h before CTR, no cigarette smoking or drug abuse, and no self-report history of Raynaud’s disease, sensory disorders , and mental disorders, no previous experience of using TENS before the study. Exclusion criteria were the need for analgesics during the intervention or the development of cardiac dysrhythmia or vasovagal response during CTR. All patients were selected in the morning shift and underwent CABG with an identical surgical procedure performed by an identical surgeon. The size of chest tube for all of them was 14–16 French. All participants and the person who performed pain assessment were blind to the group allocation, but we explained the purpose of the study to the participants and after finishing the procedure they were given an educational pamphlet about TENS and cold therapy.Sample size was calculated to be thirty using the results of a former study  and withData collection instruments were a demographic questionnaire, a clinical data sheet, and a visual analogue scale. The items of the demographic questionnaire were related to age, gender, educational level, body mass index, occupation, pain tolerance, history of chronic disease, history of cigarette smoking, and family history of coronary artery bypass graft surgery. The clinical data sheet included items on chest tube characteristics, namely chest tube size, duration of chest tube use, and chest pain. The visual analogue scale for pain assessment was scored from zero (“No pain”) to 10 (“Highest possible pain”). This scale has been used in previous studies for pain assessment among patients with cardiac surgery , 29 and Study intervention for all participants in all groups was implemented 15 min before CTR. In the cold compress group, the skin surrounding the chest tube insertion site was cleansed using alcohol and then, a cold compress with a temperature of – 5 °C was applied to the site for 15 min so that it covered an area of 10-cm diameter around the chest tube insertion site. A sterile gauze was placed between the skin and the cold compress in order to prevent the direct contact of the compress with the skin. In the TENS group, a TENS device named stimulator 615 k  with two pads sized four by 6 cm was used. TENS electrodes were placed on the skin next to the chest tube insertion site and TENS was started at a frequency of 80–100 Hz, the mode of the device was on normal mode and the intensity of the device was set to 6 mA  and a cuThe data were entered into the SPSS program for Windows (v. 22.0) and were described using the measures of descriptive statistics, namely mean, standard deviation, and frequency. Groups were compared respecting participants’ demographic and clinical characteristics using the Chi-square, Fisher’s exact, and Kruskal–Wallis tests and the one-way analysis of variance. Moreover, the repeated measures analysis of variance was used for the within- and the between-subject comparisons of the variations of the mean score of CTR-associated pain across the four measurement time points. The level of significance was set at less than 0.05.This study has the approval of the Ethics Committee of Rafsanjan University of Medical Sciences, Rafsanjan, Iran (code: IR.RUMS.REC.1397.174) and was registered in the Iranian Registry of Clinical Trials (code: IRCT20131228015965N18). Permissions for conducting the study were obtained from the authorities of the above-mentioned university and provided to the authorities of the study setting. The study aim was explained for all participants and informed consent was obtained from them. They were also informed about the confidentiality of their data and the voluntariness of participation. The study intervention was implemented by an experienced nurse in the study setting. Finally, study findings were provided to the authorities of the study setting.P > 0.05) . The mean score of pain intensity in all groups was at its highest level during CTR and gradually decreased afterwards. The results of the repeated measures analysis of variance showed that the effects of group, time, and time-group interaction were statistically significant respecting the variations of the mean score of pain intensity across the four measurement time points even after controlling the confounding effects of participants’ educational level (P < 0.001). The mean score of pain intensity reduction in the compress-TENS group was significantly greater than other groups . This is in line with the findings of former studies , 30, 32.We also found that pain intensity at 15 min after CTR in the compress-TENS group was significantly less than both cold compress and TENS groups. Similarly, two former studies reported that after CTR for 15 min, CTR-associated pain in the cold compress group was significantly less than the control group . Contrary to our findings, a study showed that cold compress had no significant effects on CTR-associated pain . AnotherOur findings also showed that although cold compress, TENS, and combined cold compress-TENS were effective in significantly reducing CTR-associated pain, the effects of combined cold compress-TENS were significantly greater than both cold compress and TENS. Combined methods are more effective than separate methods in reducing pain , 33. A sThis study concludes that the combination of cold compress and TENS is more effective than both cold compress and TENS in significantly reducing CTR-associated pain among patients with CABG. As independent nursing measures, cold compression and TENS are safe, inexpensive, and easy to use methods for pain management and hence, their combination is recommended for the effective management of CTR-associated pain among patients with CABG.One of the study limitations was the limited number of eligible patients in the study setting. Another limitation was the limited number of studies into the effects of cold compress and TENS on CTR-associated pain. Future studies are recommended to compare the effects of pharmacological and non-pharmacological methods on pain management among different patient populations.


Depression is highly prevalent among individuals with chronic back pain. Internet-based interventions can be effective in treating and preventing depression in this patient group, but it is unclear who benefits most from this intervention format.N = 504), we explored ways to predict heterogeneous treatment effects of an Internet-based depression intervention for patients with chronic back pain. Univariate treatment-moderator interactions were explored in a first step. Multilevel model-based recursive partitioning was then applied to develop a decision tree model predicting individualized treatment benefits.In an analysis of two randomized trials . Using univariate models, only back pain medication intake was detected as an effect moderator, predicting higher effects. More complex interactions were found using recursive partitioning, resulting in a final decision tree with six terminal nodes. The model explained a large amount of variation (bootstrap-bias-corrected R2 = 45 %), with predicted subgroup-conditional effects ranging from di = 0.24 to −1.31. External validation in a pilot trial among patients on sick leave  pointed to the transportability of the model.The average effect on depressive symptoms was The studied intervention is effective in reducing depressive symptoms, but not among all chronic back pain patients. Predictions of the multivariate tree learning model suggest a pattern in which patients with moderate depression and relatively low pain self-efficacy benefit most, while no benefits arise when patients' self-efficacy is already high. If corroborated in further studies, the developed tree algorithm could serve as a practical decision-making tool. •Effect moderators of a depression intervention for pain patients were explored.•Multilevel tree learning was used to create a precision treatment rule.•di = 0.24 to −1.31.Predicted treatment effects varied considerably, from •The resulting tree model could be useful as a practical decision-making tool. It is linked to numerous adverse outcomes including loss of quality of life, excess mortality, and large economic costs . DepressThere is evidence that cognitive-behavioral therapy (CBT) is effective in chronic pain patients with comorbid depression, including back pain patients . HoweverInternet-based interventions have been discussed as a promising way to reduce the treatment gap among patients with chronic pain . DigitalInternet-delivered CBT interventions have been found to be effective in chronic pain patients, both for depression and pain-related outcomes . HoweverThe WARD-BP  and PRODThese findings underline the need to identify those patients for whom Internet-based interventions to treat or prevent comorbid depression provide added benefits, and for whom they do not. Previous research has identified various factors that may influence the effectiveness of psychological interventions for chronic pain patients. For instance, k = 20 studies, found that findings on moderators of CBT for chronic pain were highly inconsistent and inconclusive, as well as hampered by methodological limitations. Despite these promising results, systematic reviews and meta-analyses have revealed significant limitations in the current literature on working mechanisms of psychological treatments for chronic pain patients. Several approaches have been proposed to address this issue. In this study, we therefore aim to identify patient characteristics that modify the effect on post-test depressive symptoms of the Internet-based intervention for back pain patients evaluated in the WARD-BP and PROD-BP trials. Furthermore, our goal is to derive a model that allows to assess expected benefits of the intervention based on identified effect modifiers. We focus on univariate associations first, and then apply a multivariate model-based machine learning approach to construct a decision tree predicting individualized treatment effects.2We analyzed patient data of two large randomized controlled trials evaluating the efficacy of an Internet-based depression intervention in patients with chronic back pain  in person, by clinic staff at discharge from eight orthopaedic rehabilitation clinics, or (ii) online, via information forms distributed by 74 German orthopaedic rehabilitation clinics after client discharge. All included participants reported persistent depressive symptoms as measured by the Patient Health Questionnaire PHQ-9;  criteriaIndividuals in both studies also had to meet the following criteria to be included: (i) 18 years or older, (ii) back pain  and self-reported pain chronicity of at least six months, (iii) sufficient German language skills, (iv) Internet access. Exclusion criteria were: (i) an ongoing or planned psychotherapy, or psychotherapy within the previous six months, (ii) current suicidality or suicidal attempts within the past five years, (iii) a severe depressive episode. A more detailed description of the participants and procedures can be found elsewhere . For the2.2In both studies, participants in the intervention group received “eSano BackCare”, a guided Internet- and mobile-based intervention (IMI), as well as unrestricted access to treatment as usual (TAU). Participants allocated to control received TAU only. The “eSano BackCare” training consists of six obligatory modules and three optional modules which should be completed weekly. The intervention is based on CBT and includes psychoeducation, behavioral activation, and pain-related elements. After each session, semi-structured written feedback was delivered by trained and supervised psychologists (E-Coaches). Participants could additionally receive automated text messages which were intended to maintain motivation. E-Coaches could be contacted on demand. Booster sessions were offered two, four or six weeks after the last module. A more detailed description of the intervention can be found elsewhere .2.3The target outcome in this study, self-rated depression severity at 9-week post-test, was measured using the PHQ-9 . The PHQ2.4As putative moderators, we included baseline sociodemographic variables, measures of the symptom severity and health-related quality of life, as well as pain-related risk factors. The set of analyzed predictors was determined a priori (see “measured variables” section in the preregistration).2.4.1As sociodemographic indicators, we selected age, gender, marital status, level of education, Internet affinity, method of recruitment, and amount of social support. Regarding baseline healthcare utilization, intake of depression and back pain medication, sick leave, and previous claim of psychotherapy for depression were included . Presence of a clinician-rated lifetime Structured Clinical Interview for DSM-5® SCID;  diagnosi2.4.2Symptom severity variables included baseline depressive symptoms, as measured by the clinician-rated Hamilton Depression Scale . Judgements were based on criteria of the Cochrane Collaboration risk of bias assessment tool 2.0 RoB; . The RoB2.6R, version 4.1.0  under a missing at random (MAR) assumption. To develop the imputation model, we first examined missingness patterns and predictors of missingness in the target variable . Since the substantive analysis models employed in this study are hierarchical , a multilevel imputation model was developed. Numeric variables were estimated using a two-level normal model , while pmice”  and “miciceadds” . Due to 's rules . The Rub2.6.2A one-stage meta-analysis model was used to calculate the overall effect of the intervention on depression severity at post-assessment. To circumvent issues of singularity and downward-biased standard errors, the same “pseudo-Bayesian” MPL estimation framework as used in the imputation model was applied. For the random effects variance-covariance matrix, we set a Wishart prior with dex RCI; , and tes2.6.3blme” package  model-based trees are constructed. One-third of the included moderators are randomly selected as splitting variables in each tree, leading to more stable and less sample-specific predictions. Nodes in each tree were considered for further splitting if the Bonferroni-corrected p-value of any partitioning variable in that node fell below α = 0.05, allowing a minimum of 20 observations in each node. The underlying objective was to preselect a more parsimonious set of variables for the subsequent multivariate analysis . Cohen's d was calculated as a standardized measure of the “individualized” conditional average treatment effect (CATE) prediction in each terminal node subgroup. We also calculated the rates of reliable improvement and calculated effect sizes in the complete case subsample in each terminal node as a sensitivity analysis. Furthermore, to explore the robustness of our results, we additionally fitted a multivariable linear mixed model with a LASSO penalty .Model-based recursive partitioning (MOB) trees as introduced by  penalty . This moB = 1000 bootstrap samples. To explore the transportability to a plausibly related setting , and n = 251 individuals to the control group (CG). An overview of the risk of bias assessment for both studies is depicted in Fig. S5 in the Supplement. Participant characteristics at baseline are summarized in SD = 8.55). The mean level of PHQ-9 depressive symptoms at baseline was M = 10.06 , indicating moderate depression across both trials.An overview of participant enrolment and loss to follow-up is depicted in 3.1β = −2.07 95 % CI: −3.31 to −0.83; t = −3.29, p < 0.01), resulting in an estimated effect of d = −0.43 (95 % CI: −0.68 to −0.17) favoring the intervention. The estimated between-study heterogeneity variance of the treatment effect was 2 = 0.48. Similar results emerged in a sensitivity analysis focusing only on participants with complete baseline and post-test PHQ-9 data . More participants in the intervention group  achieved reliable improvement compared to the control group .At post-test, the mean change in PHQ-9 scores from baseline was −0.97 points in the control group (95 % CI: −1.51 to −0.44), and − 2.94 points (95 % CI: −3.51 to −2.37) in the intervention group. The difference between IG and CG on PHQ-9 at post-test was significant (3.23.2.1p < 0.05). Higher effects were predicted for patients who take back pain medication , and lower effects for those whose do not . All other first-order interaction effects were not significant (p ≥ 0.05). The complete case analysis mirrored these findings (see S7 in the Supplement).Results of the univariate analysis of treatment-covariate interactions are displayed in p = 0.035), whereby higher baseline symptom severity predicted higher treatment effects (β = −0.779). The same pattern of findings also emerged in the complete case sample (see S9 in the Supplement).Results of the sensitivity analysis employing OLS regression are presented in S8 in the Supplement. Findings were comparable to the ones of the main model analysis, except that baseline PHQ-9 scores were additionally found as a significant moderator , whereby patients with medication intake experienced an additional average decrease of 2.05 points on the PHQ-9 compared to patients without pain medication. A plot of the control and intervention group change in PHQ-9 scores for different percentile groups based on baseline PHQ-9 is provided in S11 in the Supplement. Examining the point estimates alone revealed that higher baseline PHQ-9 scores were associated with higher decreases in PHQ-9 scores . However, we did not find that this difference was significant overall (p = 0.319), nor did we find that any direct comparisons of change scores between percentile groups were significant .Results of the change score analysis are presented in S10 in the Supplement. Findings closely mirrored the ones of the main analysis. Only previous back pain medication emerged as a significant predictor of differential treatment effects .Fifteen of all 20 putative moderators had positive permutation importance values and were thus selected as partitioning variables for further analyses . Age, gender, sick leave, previous depression medication and previous claim of psychotherapy had negative importance values and were therefore excluded. Variable importance was highest for baseline symptom severity assessed via PHQ-9 and HAM-D-17, health-related quality of life, pain self-efficacy and disability, with values ranging from 6.75 to 0.32. A similar finding emerged when only complete cases were considered (see S14 in the Supplement). In S12 in the Supplement, we display the intercorrelation of all putative moderators as well as their predictive association with the target outcome. Intercorrelations ranged from |3.2.3p < 0.001), which roughly coincides with the sample mean. The subgroup with values ≤ 10 was further split based on a PHQ-9 score of 6, which lies approximately one standard deviation below the sample mean (p < 0.001). The resulting subgroup with PHQ-9 > 6 was then split into two groups again based on individuals' self-reported health-related quality of life, using an AQoL-6D score cut-point of 43. Overall, estimated subgroup-conditional effects in the terminal nodes were very similar for all PHQ-9 ≤ 10 pathways , and comparable to the average treatment effect (di = −0.58 to −0.44 versus d = −0.43).n = 112 (22.2 %) patients with both PHQ-9 scores ≤15 and low-to-moderate baseline pain self-efficacy (PSEQ ≤ 38), estimated intervention effects were much higher than the average effect , while a non-significant negative effect was found in individuals with high pain self-efficacy . The model predicted an effect of di = −0.58 (95 % CI: −1.07 to −0.07) for individuals with very high depressive symptom severity . Similar findings emerged when only complete cases were considered (see S15 in the Supplement). Results on reliable improvement in the terminal nodes mirrored the estimated effect sizes. In the 10 < PHQ-9 ≤ 15 subgroup, 75 % (n = 45) of all intervention group participants with low pain self-efficacy showed reliable improvement, significantly more than in the control group . This contrasts with IG patients with high pain self-efficacy, where improvement rates were considerably lower  and did not differ significantly from the control group . Comprehensive results are presented in S16 in the Supplement.In contrast, effect estimates varied greatly in patients with baseline PHQ-9 values >10. In the subgroup of R2app = 52 %. A roughly comparable amount of variation was explained by the multivariable LASSO model (R2app = 47 %), in which the PSEQ also emerged as a main predictor of differential treatment effects . The bootstrap bias corrected performance of the tree model was R2adj = 45 %. External validation of the model in the “Get.Back” pilot trial resulted in a predictive performance of R2adj = 33 %.The apparent performance of the decision tree model in predicting PHQ-9 depressive symptom severity at post-test was 4d = −0.43 (95 % CI: −0.68 to −0.17) on depressive symptom severity at post-test (9 weeks). This result is comparable to meta-analytic effects found in Internet-delivered CBT interventions across different types of chronic pain . In the additional change score analysis, we also found that benefits were larger in patients with high baseline symptom severity when looking at the point estimates alone, but this relationship also did not reach conventional levels of significance. Overall, this suggests that the divergent findings could be explained by statistical power, and that baseline symptom severity may very likely also be an effect modifier.In the main mixed model, depressive symptom severity was not a significant predictor of differential treatment effects. This is a surprising finding, given that this variable is frequently reported as an effect moderator in Internet-based interventions . Howeverdi = −1.31). A non-significant negative effect was found in patients with high pain self-efficacy (di = 0.24). In all other identified groups, predicted treatment benefits (di = −0.58 to −0.44) remained close to the pooled effect established via one-stage meta-analysis (d = −0.43). Additionally, we found that the tree model still explained about one third of the outcome variation when applied to unseen data of the pilot trial by A clearer picture emerged when we investigated higher-order interactions using multilevel model-based decision tree learning. We found that baseline depressive symptom severity was indeed involved in explaining heterogeneity of treatment effects when examined in combination with other baseline indicators. This finding was most pronounced among individuals with moderate depressive symptoms (viz. PHQ-9 scores between 11 and 15), where low-to-moderate pain self-efficacy predicted very large treatment effects  receive the Internet-based intervention. Future studies may investigate which of these assignment regimens is the most useful to maximize clinical benefits across all patients.These findings provide evidence that a decision-tree model can be used to explain and predict treatment effect heterogeneity of the studied intervention. It provides a simple decision-support algorithm that allows to determine if predicted benefits are in line with the average treatment effect, or if substantially higher or lower effects are to be expected. A maximum of two self-report questionnaire scores is needed to make individualized predictions, suggesting that such an algorithm is economical enough to be useful in practice. If corroborated in further studies, the tree model could be implemented as a simple screening tool within the Internet-based intervention. This would allow to identify patients for whom the program is not expected to have any meaningful effects, and to initiate a more intensive evidence-based treatment  instead. Previous studies have determined that an effect size of spective . Using tThe tree structure itself also points to a possible working mechanism of the intervention: in patients with moderate depressive symptoms, the intervention may increase the confidence in being able to perform activities despite chronic pain , and only represents one plausible intervention context. Further validation studies are needed to confirm that the tree structure established in this study is indeed robust and clinically useful. Furthermore, we only considered a narrow range of algorithms in this study, and it could be explored if other modelling approaches provide additional benefits. Another limitation is that, to allow for joint analyses, we used self-reported PHQ-9 scores at 9-week post-test as the target outcome. At the same measurement point, observer-masked clinician-rated depression obtained via the HAM-D-17 was used as the primary outcome in This study has some limitations. Although we pooled data of two trials for this analysis, more data would have been valuable. Univariate moderator analyses typically require much more statistical power than analyses of the average treatment effect, especially if interactions are subtle . In thisIn sum, our findings suggest that an Internet-based intervention can be effective in reducing depressive symptoms among chronic back pain patients. Additional intake of back pain medication was associated with higher effects. Results of a decision tree model point to a more complex interaction pattern, whereby low-to-moderate pain self-efficacy predicts very high treatment effects in patients with moderate depression, but no benefits if patients already experience high self-efficacy at baseline.Bavarian Research Institute for Digital Transformation (BIDT), an institute of the 10.13039/501100007306Bavarian Academy of Sciences and Humanities. WARD-BP was funded by the German 10.13039/501100002347Federal Ministry of Education and Research . PROD-BP was additionally funded by the 10.13039/501100001659German Research Foundation .MH is supported by a fellowship of the HB, LBS, and DDE developed the concept of the present study. HB, LBS, SP and SaS contributed to the development of the Internet-based interventions, coordinated the clinical trials, and collected data. MH and PK performed the analyses. MH, DDE, and PK drafted a first version of the manuscript. All authors contributed to the further development of the manuscript, as well as read and approved the final manuscript.DDE reports to have received consultancy fees or served in the scientific advisory board from several companies such as Novartis, Sanofi, Lantern, Schön Kliniken, Minddistrict, and German health insurance companies . DDE and MH are stakeholders of the Institute for Health Trainings Online (GET.ON/HelloBetter), which aims to implement scientific findings related to digital health interventions into routine care. HB reports to have received consultancy fees, fees for lectures or workshops from chambers of psychotherapists and training institutes for psychotherapists and license fees for an Internet intervention.


The beneficial effect of virtual reality (VR) on pain management in the context of transrectal MRI-guided prostate biopsy is not well established. However, it remains unclear whether an adjunctive of VR also improves pain management. This study aimed to evaluate the impact of VR as adjunctive in pain management in transrectal MRI-guided prostate biopsy (PB).We retrospectively evaluated the pain intensity incidence in the 153 patients with PB indication (of which 102 were naïve of PB) who were admitted to our hospital since the acquisition of the Healthy Mind virtual reality headset on 19 January 2021.N = 78) and patients who received VR associated with PPNB  were largely similar. One PB with general anesthesia was excluded. The mean pain score at day zero was respectively 3.4 (±2.5) and 2.9 (±2.3) for SOC and VR (p = 0.203). However, the mean pain score at day zero was significantly lower in naïve PB patients with VR [2.7 (±2.0)] than in naïve PB patients with SOC  when patients were stratified in PB status. Similar results were found on day 3 for the analysis including naïve-PB patients with SOC vs. with VR .Baseline characteristics of patients who received local anesthesia with 1% lidocaine periprostatic nerve block (PPNB) (Group SOC, The pain intensity was significantly lower in naïve PB patients with VR than in naïve PB patients with SOC. There were no side effects from VR and tolerability was excellent. Prostate cancer ranks third in cancer deaths in men, with 8,512 estimated deaths in 2015  or trans-perineally (the needle is inserted through the skin between the bursa and the anus to the prostate). It is a painful examination that requires local anesthetic and the preparation time can lead to anxiety in the patient.Over the past decades, virtual reality (VR) has been proposed as a new way to manage pain in a non-pharmacological way. By diverting attention away from the symptoms and immersing the participant in a virtual environment, VR can profoundly alter pain perception . SeveralThe purpose of this prospective study was to compare the efficacy and tolerability of virtual reality associated with periprostatic nerve block and periprostatic nerve block alone in patients undergoing transrectal MRI-guided biopsy.2.2.1.The department database is a prospective cohort initiated in the acquisition of a virtual reality headset on January 2019 that records all patients admitted for care in the Department of Urology, Chalon-sur-Saone Hospital (France). We included in our analysis all patients enrolled from 2019 to January 2021 meeting the following criteria: PB performed in the department. Exclusion criteria included the presence of general anesthesia or lack of a minimum follow-up of 3 days (Day 0 and Day 3) .The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki revised in 2013 and actual French legislation, and the database was approved by our institutional review board. All patients included in the database signed the informed consent before undergoing prostate biopsy.A total of 154 patients were retrospectively included in this analysis. All patients undergoing an MRI-guided prostate biopsy because of abnormally elevated PSA levels (>4 ng/ml) or/and abnormal digital rectal examination in our hospital were included. Two groups were formed: 78 participants in Group SOC received local anesthesia with 1% lidocaine periprostatic nerve block (PPNB) as recommended  and 75 pDemographics data, PSA levels, prostatic data , characteristics of MRI-lesion , patients' treatment , and past biopsies were reported for all patients. One patient was excluded because the probe could not be introduced, and general anesthesia was necessary.2.2.In Group SOC, the subjects were placed in the lithotomy position. An intrarectal instillation of an anesthetic gel was applied first. Then, the examiner realized the digital rectal examination and introduced the ultrasound (US) probe to practice the periprostatic nerve block. It took five minutes for the analgesia to have an effect and to do the ultrasound and MRI target mapping. The same steps were completed for Group VR and we also gave the patient glasses and a VR headset shortly after the positioning. The VR headset was provided by the Healthy Mind company in Paris. Subjects chose between three landscapes: snow world, forest walk, or zen garden. The glasses and the headset were removed at the end of the biopsy.For each subject, a twelve-biopsy scheme combined with four biopsy cores per target was performed as recommended , 11. The2.3.At the end of the procedure, the patient's pain was assessed by using the visual analog scale (VAS) in which 0 represents no pain and 10 represents the worst pain ever felt . For patThen, the secretary called the patient within three days of the biopsy and asked them to quote the VAS on the third day. She also recorded if there were complications such as haematuria, urine retention, or fever. The patient was reviewed in consultation by the urologist for the diagnostic announcement 1 month after the biopsy. The pain felt during the biopsy was recorded again with a new VAS score. Patient satisfaction with the anesthesia technique was evaluated by asking the question “Are you satisfied with the current anesthesia method for prostate biopsy?” and afterward, “If you need to repeat the biopsy later, would you prefer general anesthesia?”. Their answers were recorded as “yes” or “no”.2.4.Results were reported as mean and standard deviation (SD) for continuous variables and as percentages for categorical variables. Differences were assessed using the Mann–Whitney U test for continuous variables and the chi-square or Fisher exact tests for categorical variables.The comparison of mean pain scores was stratified and performed according to the VR status (classified as group VR vs. group SOC) and assessed by Student tests. In the second step, naïve PB patients were selected and stratified according to the VR status (classified as group PB naive with VR vs. group PB naive with SOC) and assessed by Student tests.P < 0.05 in univariate analysis. All statistical tests were 2-sided, and p < 0.05 was considered statistically significant. R software version 4.1.2 was used for all statistical analyses.Finally, the effect of VR adjunctive on survival was analyzed using a multivariate using logistic regression ANCOVA model that incorporated all covariates having 3.p = 0.35).There was no significant difference between the two groups in the baseline variables . The meap = 0.9); no other kind of cancer was found. Few adverse biopsy events such as hematuria or urinary retention were observed (p = 0.7). A total of 59 patients agreed to return for the same analgesia in Group SOC and 63 patients in Group VR (p = 0.6). Only 11 patients in each group would have preferred general anesthesia (p = 0.9).observed . Four anp = 0.2), respectively. The mean pain score on day 3 was 0.39 (±1.5) and 0.27 (±1.0) for Groups SOC and VR (p = 0.5), respectively (There was no significant difference found between Group SOC and Group VR on the primary outcome. The mean pain score at day 0 was 3.4 (±2.5) and 2.9 (±2.3) for Groups SOC and VR (ectively .p = 0.013)] at day 0. Similar results were found on day 3 for the analysis including naïve-PB patients with SOC vs. with VR  (When stratification on PB status (naïve or non-naïve) was used, the VR effect on pain score was slightly lower between non-naïve PB patients but remained highly significant between naïve-PB patients as compared to SOC vs. VR  .p = 0.023].By multivariate analysis of the predictive factors of pain score at day 0 , only onp < 0.0001]. Hematuria and urinary tract infection were not predictive factors. Finally, the analgesia technique (PPNB or PPNB and VR) did not affect the VAS pain score on day 30.Moreover, regarding pain score at day 30 , only on4.The objective of this study was to evaluate the effect of VR as adjunctive in pain management in transrectal MRI-guided prostate biopsy in patients who underwent PB without general anesthesia in our urology department. For that purpose, we retrospectively analyzed the overall pain intensity reported in the Department database, a repertoire of patients admitted for care at Chalon Hospital . We also limited the heterogeneity of the population by analyzing the subgroup of patients, including only naïve PB patients enrolled between 2019 and 2021, who received local anesthesia with a 1% lidocaine periprostatic nerve block (BPNP).We found in this population a more pronounced pain score reduction in naïve patients with PPNB associated with VR than in naïve patients with PPNB . This stOur study population is quite similar to other studies' populations. Indeed, mean age , 16, 17 A considerable amount of literature has been published on prostate biopsy analgesia. Regarding pain intensity, visual analog scales in literature were mostly lower than 4, which is consistent with our observation where the mean pain score was 3,18 , 24. PaiSeveral investigations have revealed that periprostatic plexus block in prostate biopsy, alone or in combination with intrarectal analgesia or sedation, is an effective method to reduce pain in comparison with placebo or intrarectal analgesia alone . But no In reviewing the literature, no data was found on the assessment of VR as analgesia in prostate biopsy. Only one case report from 2005 about VR in urology was found and concerned transurethral microwave thermotherapy: association of PPNB, sublingual fentanyl, and lidocaine gel with VR revealed a pain decrease . A systeMoreover, pain score intensity was different from other VR investigations. A meta-analysis showed higher pain scores in control groups  for the pain management of burnt patients undergoing dressing change or physical therapy . Their mOther components such as patients' age are important. Multivarious analysis showed that other variables such as age, prostate volume, and number of biopsy cores did not influence VAS scores as previously shown in the prostate biopsy literature , 16, 27.The estimation of the effect of VR on pain management in the context of PPNB is subject to various sources of bias. The most problematic one is the bias of selection, i.e., the fact that patients who have already experienced prostate biopsy do not feel the same anxiety and pain as naïve patients and those patients have different demographic characteristics compared to others. Despite non-significant differences in overall patients, our investigation had strengths and showed the selection bias included in other studies, making it difficult to evaluate the effect of VR in this specific population. In this study, the analysis performed in naïve patients is consistent and robust. Our sample of the target population is comparable to many studies' populations, with few subjects and similar groups included in comparable studies. Including more subjects could have improved our study power.Another limitation concerned the absence of pain score adjustment on biopsy steps. Indeed, pain scores may be higher during probe introduction than during anesthesia injection or core retrieval . In our In addition to this, the main study limitation is the lack of anxiety data. Several studies showed VR reduced fear and anxiety during dental procedures , 29. FurThis study supports the hypothesis that VR associated with periprostatic nerve block is better than periprostatic nerve block alone as analgesia for naïve PB patients undergoing transrectal MRI-guided biopsy. A VR treatment benefit may potentially exist in patients with previous experience of PB in terms of reduction of anxiety and increasing comfort. Further studies will be needed to evaluate whether this VR effect is specific to naïve PB patients or also exists in other biopsies procedures.


Patients undergoing corneal abrasion as part of Descemet membrane endothelial keratoplasty (DMEK) under general anesthesia suffer from early burning pain postoperatively. This pain appears to be poorly treatable with systemic analgesics. This study aims to evaluate postoperative pain management using topical lidocaine gel after DMEK with iatrogenic corneal abrasion.Retrospective analysis of 28 consecutive patients undergoing DMEK with corneal abrasion from October 19, 2021, to November 12, 2021, at a German university hospital. Patients during week 1 and 2 received peri-operative standard pain treatment (cohort S) and additional local lidocaine gel during week 3 and 4 immediately postoperatively (cohort L).13 patients were included in cohort S and 15 patients in cohort L. At awakening all patients (100%) in cohort S reported burning pain, and six of 15 patients (40%) in cohort L reported burning pain. Burning pain scores were significantly lower in cohort L . No significant differences between cohort S and cohort L were detected concerning surgical outcome during 1-month-follow-up .Patients undergoing DMEK with corneal abrasion suffer significant pain in the recovery room. A single dose of topic lidocaine gel reduces the early postoperative burning pain sufficiently and does not affect the surgical outcome. What is already known on this topic:Descemet membrane endothelial keratoplasty (DMEK) normally causes low levels of pain.What this study adds:When corneal abrasion is required during DMEK surgery under general anesthesia, patients experience pain sensations that can severely affect their well-being.An immediate postoperative single dose of topical lidocaine gel applied by the surgeon reduces the early burning pain sufficiently and does not affect the surgical outcome.To reduce postoperative pain levels and to improve the postoperative well-being of patients, all patients undergoing DMEK with corneal abrasion should receive topical lidocaine gel at least once. However, this simple intervention should still be investigated in prospective studies. Descemet membrane endothelial keratoplasty (DMEK) is a standardized therapy for corneal endothelial diseases.  DMEK canThe responsible ethics committee (No: 22-1025) of University Hospital of Cologne, Cologne, Germany approved the study and, also waived the requirement to obtain informed consent from patients to review and use the data. The medical records of all patients who underwent DMEK in general anesthesia from October 19, 2021, to November 12, 2021 were reviewed. The study was conducted in accordance with the Helsinki Declaration on Patient Safety in Anesthesiology. .All patients (twenty-eight) undergoing DMEK with the need for corneal abrasion in general anesthesia during October 19, 2021, to November 12, 2021 were enrolled in this retrospective study. During the initial 2-week period, all patients who underwent DMEK received systemic opioid/non-opioid combination therapy as usual for postoperative pain management (cohort S). During the following 2-week-period, patient´s pain after DMEK was treated with this standard combination and additional local lidocaine gel  administered by the surgeon at the end of surgery (cohort L). The relevant data on pain scores were recorded by hand in standardized anesthesia protocols. 1-month-follow-up examination was documented in standard patient record. Later, the medical record was transferred to the digital patient record via scan. These data were retrospectively reviewed and evaluated for quality assessment of the additive pain therapy intervention.All patients underwent general anesthesia with propofol (2–3 mg/kg bodyweight) and remifentanil (1 µg/kg bodyweight) for induction and sevoflurane (up to 1 MAC) and remifentanil (0.1–0.3 µg/kg/min) for maintenance. The airway was established with a laryngeal mask (second generation) in all patients. All patients received dexamethasone 4 mg and granisetron 1 mg. Patients received piritramide intravenously 10 min after induction of anesthesia , and in the absence of a contraindication, they received additional parecoxibe 40 mg. DMEK was performed under deep general anesthesia as described previously (7). In all patients around 5 mm epithelium was removed centrally. The opacified epithelium was removed using a hockey knife to enhance visibility during surgery. No exact measurement was done at time of scraping. In group L, the surgeon applied 0.5 cm of lidocaine gel to the surface of the affected eye at the end of surgery. Furthermore, remifentanil was discontinued, the laryngeal mask was removed, and the patient was transferred to the recovery room. After awakening and every 10 min in the recovery room, pain scores  were measured by the nurse in charge. Before discharge to normal ward, pain scores were measured by the attending physician in charge and the nurse. A numeric rating scale  was used to evaluate overall pain, and a verbal rating scale  was used to evaluate burning pain. One month after surgery, a follow-up examination regarding ophthalmologic outcome was routinely performed.The statistical analysis was carried out using SPSS version 27.0 .Distribution of demographic data  is presented as mean , since there was no normal distribution. Further data are given as mean (+/- standard deviation) and mean (+/- standard error of mean). Descriptive data are given as numbers (proportion). ANOVA analyses and Mann-Whitney-U-Test were performed to test for significant changes in pain sensations and in opioid use. All p values below 0.05 were considered statistically significant.Between October 19, 2021, and November 12, 2021 a total of 28 patients underwent DMEK with corneal abrasion in general anesthesia. 13 patients were included in cohort S and 15 patients in cohort L. The mean age in cohort S was 65.4 years , body weight was in mean 91.8 kg . Cohort L had a mean age of 66.4 years  and a mean body weight of 89.4 kg . Surgical procedures lasted between 25 and 42 min, with no significant difference between cohorts.Before surgery, all included patients denied pain in the affected eye.All patients in cohort S reported burning pain at awakening with maximum VRS of 3. Six of 15 patients (40%) in cohort L reported burning pain, the maximum was VRS 2. Pain scores see Tables Using ANOVA analyses measured burning pain scores were significantly lower in cohort L  piritramide, patients in cohort L received 0.0474 mg/kg (0.0337–0.0611). There was no significant difference between cohorts regarding dose of piritramide (p = 0.389). ANOVA analyses showed a significant correlation between NRS level and opioid received per kg (p < 0.001). The VRS score for burning pain showed no significant correlation with opioid use (p = 0.146).12 patients from cohort S and 14 patients from cohort L underwent follow-up examination one month after surgery: no significant differences between cohort S and cohort L were detected , p = 0.419 for BCVA without limitation of visual acuity). Re-Bubbling was necessary in 2 of 13 patients (15.4%) in cohort S and in 2 of 15 patients (13.3%) in cohort L, after which graft attachment was 100% in both cohorts.A clear corneal graft was present in 11 of 12 patients (91.7%) in cohort S and in 14 of 14 patients (100%) in cohort L.In this monocentric, retrospective feasibility analysis, we found that a single local application of 2% lidocaine gel at end of surgery significantly reduced early postoperative burning pain sensation as measured by VRS in patients undergoing DMEK with corneal abrasion under general anesthesia Fig. . A trendThe early postoperative burning pain sensation seems to be an underestimated problem in patients undergoing DMEK with corneal abrasion under general anesthesia, as all patients in cohort S reported burning pain sensation. Remarkably, few patients reported burning pain to recovery room staff, even when asked about the overall pain using the NRS. In the authors’ clinical experience, a second question about burning pain was necessary to obtain this information, which the results of the present study suggest.Even ocular surgery can lead to a relevant pain burden, although it is often considered to be less painful. –9 To theIn the authors’ experience, patients’ well-being in the recovery room is severely affected by pain sensations after corneal abrasion. In addition, it may falsely suggest a painful IOP rise due to intracameral gas tamponade.  StandardWith respect to the efficacy of the topical anesthesia three aspects have to be taken into account: (i) the number and function of corneal nerves shows significant interindividual variations , (ii) seThe results of the present study suggest that patients undergoing corneal abrasion as part of DMEK have relevant pain sensations in the recovery room, although the literature shows that pain is low in the subsequent postoperative days.  Burning The limited number of patients included is due to the research topic. The retrospective nature of this study causes all known limitations. Future prospective trials will have to analyze the effect of additional topical analgesia for the later postoperative period and the effects of early analgesia on later pain symptoms.


They were followed up over 2 years with visits every 6 months (V1–V4). At each visit, pain was assessed for the joints treated with CGs using a visual analogue scale . Additional measures were obtained to assess neuropathic pain (painDETECT questionnaire), proprioception/balance , and functional independence, amongst others. Data were analyzed for 67 patients with EDS . For the most painful joint, the mean VAS rating was 71.5 ± 22.8 mm at V0; this decreased to 53.5 ± 25.5 mm at V1 and 45.7 ± 29 mm at V4 (t-tests: p < 0.0001). From V0 to V4, improvements were also seen for pain at the other joints, neuropathic pain, functional independence, proprioception/balance, and the incidence of sprains and dislocations/subluxations, although not all comparisons were statistically significant (p < 0.05 level). These results indicate that CGs may effectively reduce the pain and joint instability in non-vascular EDS patients.Patients with Ehlers-Danlos Syndrome (EDS) frequently suffer from severe chronic pain. We carried out an observational cohort study to assess the effectiveness of compression garments (CGs) for reducing this pain. Patients with non-vascular EDS were given custom-made Cerecare The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary diseases that affect the connective tissues. They are characterized by skin hyperextensibility, joint hypermobility, and soft tissue fragility. They are caused by abnormalities in the synthesis or structure of extracellular matrix proteins, particularly collagen, and they affect approximately one in five thousand people . HoweverA new classification for EDS was published in 2017, which recognized thirteen different subtypes . Of thesSevere chronic pain is one of the most challenging features of EDS, and it disproportionately affects patients with the hEDS subtype . One stuThe mechanisms underlying the chronic pain in EDS are thought to be complex and may involve different factors ,12. For As there is no known cure for EDS, treatments are symptomatic. A multidisciplinary approach is usually required, often involving physiotherapy, occupational therapy, orthoses, and complementary therapies . A variety of approaches can be adopted to treat the chronic pain. Patients may be given analgesics such as non-steroidal anti-inflammatory drugs, paracetamol, or morphine for the nociceptive pain, and drugs such as ketamine, anticonvulsants, and tricyclic antidepressants for the neuropathic pain. However, these are not always well-tolerated by patients and traditional analgesics do not provide adequate pain relief for most patients ,13. OtheWhen various therapeutic options were tried and found to be insufficient, compression garments (CGs) were sometimes used . They arp = 0.096).At present, few studies assessed the effects of CGs on pain in patients with non-vascular EDS. In one recent study, Chaléat-Valayer and colleagues  assessedIn 2010, the French National Health Authority (HAS) decided to reimburse the cost of prescription CGs for patients with EDS. However, given the lack of evidence for their effectiveness, the companies supplying the garments were required to set up an observational study to assess their effectiveness over a period of two years, in collaboration with the health authorities. Here, we present the results of this study, which focused on the effectiveness of CGs for reducing pain. It was hypothesized that the CGs would be effective for reducing pain in patients with non-vascular EDS after a period of 6 months. Effects on other measures were also examined over two years, including proprioception/balance, joint instability, fatigue, and functional independence.This study was an observational, prospective, multi-center, non-comparative, descriptive cohort study. The study was registered on clinicaltrials.gov (identifier: NCT03451188) and was carried out in accordance with French law (the ‘loi Jardé’), the Declaration of Helsinki, and the principles of good clinical practice.The study was carried out in several specialist centers for EDS, all in France: the Raymond Poincaré Hospital in Garches, the Bouffard-Vercelli Center in Perpignan, and the Estaing University Hospital in Clermont-Ferrand. Patients were recruited for the study between 11 June 2018 and 24 July 2019. Each patient was prescribed CGs, which were received after around one month. The patients were then followed up over a period of two years, up until 30 November 2021, the date of the last study visit.® CGs. In addition, to be included, patients were asked not to modify their usual care, if possible, such as analgesics, physiotherapy, occupational therapy, or other therapies .Patients were included from the three specialist EDS centers mentioned above. All patients were aged 16 years or older and were diagnosed with EDS, according to the 2017 diagnostic criteria , by a phPatients were excluded if they had a known allergy to one of the materials in the CGs; experienced pain resulting from gentle pressure or a light touch ; experienced acute and unpredictable pains that were not being medically treated at the time of the screening session and would require additional analgesics; were participating in another study; were under guardianship or deprived of liberty; or were pregnant.Patients were recruited during medical appointments with the clinical investigators. Patients who met the eligibility criteria were provided with oral and written information concerning the study. After a period of reflection, the adult patients provided oral consent to participate in the study; those younger than 18 signed a consent form, and at least one of their parents also signed the form.Each patient visited the clinic six times as part of the study over a period of two years: an initial inclusion visit, a visit around one month later to receive the CGs (V0), then follow-up visits after 6 months (V1), 12 months (V2), 18 months (V3), and 24 months V4; . For eac® CGs  for their most painful and/or unstable joints. The garments were selected according to the patients’ needs and personal preferences. The patients received two sets of the garments at the medical center after a delay of around one month. Additional sets were given to patients every 6 months, if required. The CGs are similar to those used for severe burns, but they apply less pressure: 10–13.5 mmHg for an area with a perimeter of 24 cm and 6–10 mmHg for an area with a perimeter of 55 cm. The fabric was made of polyamide and elastane, it had >100% elongation for both the warp and the weft (two-way stretch), and it was non-irritant. The CGs included vests with or without long/short sleeves; shorts with or without a long/short extension; gloves/mittens with or without fingers/short sleeves; socks with or without the toes; elbow sleeves; and knee sleeves. For the purposes of this study, treatment compliance was defined as wearing the CGs for at least 6 h per day.Patients were prescribed custom-made CerecareThe effectiveness of the CGs was assessed by the change in joint pain from V0 (prior to wearing the CGs) for the joint that was judged to be the most painful at V0. Pain was assessed using a visual analogue scale (VAS) from 0 to 10 , where the participants were required to indicate their level of pain on the scale for the month preceding the visit . The maiJoint pain for the other joints treated with CGs, as assessed using a VAS from 0–100.Neuropathic pain, as assessed using the painDETECT questionnaire (translated into French) . For thiJoint instability, as assessed by the number of sprains and dislocations/subluxations for each patient. For this, the patients kept a notebook at home in which they recorded any sprains, dislocations, or partial dislocations from the time of inclusion to the end of the study (V4). As this included the month during which the CGs were being made (first month), the events were compared to this baseline period without CGs.Proprioception/balance, as assessed using the Berg Balance Scale . This scFatigue, as assessed using the Fatigue Severity Scale . This assesses fatigue using a Likert scale for nine different items  . If the Quality of life, as assessed using the Short Form 12 questionnaire (SF-12) . For thiThe use of medication or other therapies , as recorded by the clinical investigator at each visit.Functional independence, as assessed using the Functional Independence Measure (FIM) . This meIncidence of skin problems, as assessed by asking patients the following question: ‘Since your last appointment with your EDS medical specialist, have you noticed any skin changes in terms of bruising, wounds, scars, or stretch marks?’ Patients selected one of the following responses: aggravation, stable, improvement, or not known.® compression garments?’ (response: yes/no), and ‘Are you satisfied overall with the Cerecare® compression garments?’ .Patient satisfaction, as assessed using the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST) questionnaire at V1 and V4 . For thiCompliance, which was assessed by asking the patients how many hours the CGs were worn each day (assessed at each visit from V1).The secondary outcome measures assessed the effectiveness of the CGs for improving various measures over a period of 2 years (up to V4). The following measures were obtained:A calculation was run to determine the sample size that would be needed to detect a VAS reduction of at least one point (10 mm) after 6 months, with an alpha risk of 5%, a power of 90%, and with 10% of patients lost to follow-up at 6 months. The standard deviation was set at 2, based on the previous literature ,35,36. T® version 13.0 . All of the analyses were two-tailed tests with an alpha level of 5%. The statistical analyses were run for the study participants with VAS pain data at V1, irrespective of whether or not they completed the whole study or had other missing data. Additional analyses were also run to support the results, which only included participants who completed the entire study without any major deviations from the protocol.Statistical analyses were run using JMPt-tests or Wilcoxon tests for the quantitative variables, and McNemar’s tests or Cochran’s Q tests for the nominal variables.The data for each study visit were summarized and compared to the baseline values (at V0). Descriptive statistics were presented according to the type of data: means and medians for the quantitative variables along with measures of dispersion (standard deviation and range), and frequencies/percentages for the nominal variables. The values obtained were compared between time points using paired A total of 77 patients were recruited for the study. After checking the eligibility criteria, 76 patients were included. Of note, one patient was included who did not fulfill the hypermobility criterion (Beighton score), and another was included who was expected to lose weight. These deviations were accepted by the clinical investigator, as the former patient was diagnosed with EDS by several physicians, and the latter patient was to undergo bariatric surgery, which would be unlikely to have a marked effect on the body areas covered by the CGs . For the main outcome measure (VAS pain at V1), data were available for 67 patients . The maiThe characteristics of the 67 patients who were included in the main data analyses are shown in ® CGs. These are shown in The patients were prescribed various CerecareThe approximate length of time each CG was worn per day was recorded at each visit. The durations were grouped into four categories: all day (24 h), 12–24 h, 6–12 h, and <6 h. The percentage of patients who wore the garments for these different durations is shown in n = 76) between the inclusion visit and V0, and mean delays of 6.5 months , 12.6 months , 19.2 months , and 24.9 months  between V0 and each study visit.The patients in the study were followed up for two years. The delays between the study visits were generally well-respected, with a mean delay of 1.2 months  of the patients, the knee for 17.9% (n = 12), the ankle for 17.9% (n = 12), the hip for 16.4% (n = 11), and the wrist for 14.9% (n = 10). A smaller number of patients reported the elbow  or the fingers  to be the most painful . This shows that the patients’ most painful joint was judged to be less painful after 6 months with the CGs.The mean VAS pain rating was 71.5 ± 22.8 mm for the most painful joint at V0. The pain was assessed again at V1, and the mean rating was found to be 53.5 ± 25.5 mm for the same joint n = 67; . This ret-test, p < 0.0001), which indicates that the CGs are effective for reducing pain over relatively long periods of time.The pain ratings on the VAS for the most painful joint were analyzed for the remaining study visits after V1. The mean values are plotted in p < 0.05). The differences for the other joints were not statistically significant, but this may be due to a lack of data  and the wrist .We ran further analyses to examine changes in pain for all joints that were treated with CGs, not just those that were the most painful at V0. The mean levels of pain for each joint, assessed using the VAS at each visit, are shown in t-test, p = 0.28). Similarly, the rating of the average pain intensity over the last 4 weeks decreased between V0 and V4, from a mean rating of 5.9 ± 1.9 to 5.7 ± 1.5, but again, this was not statistically significant . However, the rating for the strongest pain felt over the last 4 weeks was found to be significantly lower at V4 compared to V0, with mean ratings of 8.3 ± 1.6 and 8.8 ± 1.3, respectively . These results are shown in Neuropathic pain was assessed using the painDETECT questionnaire, which included several measures of pain. The results showed that the mean pain experienced at the time of completing the questionnaire was rated to be 5.7 ± 2.3 at V0 , and this decreased to 5.4 ± 2.4 at V4. This difference was not statistically significant  of the patients at V0 and 61.2% (30/49) at V4. The next most common pattern was pain attacks with pain between them, reported by 26.9% (18/67) of patients at V0 and 22.4% (11/49) at V4. Few patients reported the other patterns: persistent pain with slight fluctuations  and pain attacks without pain between them .t-test, p = 0.049). The results are shown in The painDETECT questionnaire also asked patients to indicate their main area of pain, and they were asked several questions about different sensations and pain responses at this area. The responses were then converted into scores (from 0–5: ‘never’ to ‘very strongly’) and analyzed. The results showed that the measures all improved from V0 to V4, although this was only statistically significant for pain resulting from slight pressure  and knees . The mean number of dislocations/subluxations was also calculated for each joint (p = 0.0012), knees , hips , and wrists .For each visit, we counted the number of sprains and dislocations/subluxations reported by the patients for the joints with a CG prescription. Analyses were then run, which only included a patient’s data for joints where the CGs were worn from V0 up to V4 for at least 6 h per day. The mean number of sprains is shown in ch joint B, and agt-test, p = 0.001; The patients’ functional independence was assessed using the Functional Independence Measure. The mean score at V0 was 117 ± 8.1 and this increased to 119.8 ± 7.0 at V4. This difference was statistically significant , had significant difficulty with everyday activities , and felt that their emotional or physical state prevented them from doing certain things . They also mainly reported that their pain was very bothersome at work or during activities at home . These results remained relatively stable throughout the study.Satisfaction with the CGs was assessed at V1 and V4 using the QUEST questionnaire and two additional questions. It was found that most patients were satisfied or very satisfied with the CGs at both V1  and V4 . Only 9.5% (6/63) were not at all satisfied with the CGs at V1 and 0% (0/49) at V4. The responses showed that 68% (34/50) of the patients were satisfied with the effectiveness of the CGs and 52% (26/50) were satisfied with the level of comfort (results at V4). At V1, 52.3% (34/65) of the patients reported not having any difficulty putting the CGs on; this was 57.1% (28/49) at V4.At each visit, patients were asked about the condition of their skin relative to their last visit in terms of skin wounds, scars, bruising, and stretch marks. It was found that the skin condition remained relatively stable throughout the study. The results are shown in We examined the adverse events (AEs) that were recorded for all 76 patients who received CGs as part of this study. There were a total of 170 AEs, 104 of which related to the CGs, but none of the latter were serious. The AEs included cases of rashes and itching. The AEs led to a temporary discontinuation of the CGs in 59.6% of patients (34/57), and they led to ending the CG treatment in 15.8% of patients (9/57). The AEs that were related to the CGs needed to be treated in 7.6% (13/170) of cases, and in 8.8% (15/170) of cases some other action was required, mainly adjusting the relevant CG.p < 0.0001). For the other comparisons, there were few differences in terms of those that reached statistical significance at the p < 0.05 level. The only differences found were in the patterns of significance for the different joints, both for the pain rating  and for the number of sprains (significantly lower for the ankle at V4) and dislocations/subluxations . In addition, for the measures of neuropathic pain at the most painful area, sudden pain attacks alone were found to be significantly lower at V4.We repeated the statistical analyses using data from the 30 patients who completed the entire study with no major deviations from the protocol. These analyses focused on the results at V4. The results were found to be in line with those presented above and, for certain measures, the improvements were found to be even greater. Importantly, the VAS pain rating was significantly lower at V4 compared with V0 . Reductions in pain were also consistently found for the other joints and for measures of neuropathic pain (from V0 to V4), although not all comparisons were statistically significant. These findings indicate that CGs are appropriate for treating chronic pain in patients with EDS. They may also be effective for preventing recurrent ankle sprains and subluxations/luxations of the wrists, shoulders, knees, and hips, as well as increasing patients’ functional independence.This study provided evidence that CGs are effective for reducing pain in patients with non-vascular EDS. The improvements were particularly striking for the most painful joint, where the decrease was found to be substantial (around 25%) and statistically highly significant  may be most effective for treating patients’ pain.As one of the main underlying causes of pain in EDS is thought to be injury resulting from dislocations, subluxations, and sprains , we examp = 0.053). As the patients’ scores were generally high, with 85.1% (57/67) having a score above or equal to 41 at V0, it was concluded that most of the patients did not have deficits in balance control and were at low risk of a fall. To better understand our findings, additional work is required to further explore the potential links between proprioception, joint injury, and pain in EDS.Previous work suggested that CGs may improve proprioception in patients with EDS and that this may lead to decreased pain . In lineOur study assessed neuropathic pain using the painDETECT questionnaire. This included questions concerning different sensations and pain responses, such as tingling sensations and pain resulting from slight pressure. The responses to these items showed that most patients experienced these sensations ‘slightly’ or ‘moderately’, thus indicating that they did not have high levels of neuropathic pain. However, for each item, there were patients who selected the maximum response (‘very strongly’), thus indicating that strong neuropathic pain may be limited to certain patients with EDS. This would be in line with a previous study on 31 patients with hEDS, which found small fiber neuropathy in less than two-thirds (61%) of the patients . Our resWhen considering the decreased pain ratings in our study for patients wearing CGs, it is relevant to note that the pain levels remained far from negligible, with mean pain ratings of around 40/100 mm on the VAS. This could explain why the patients’ use of medication and other therapies did not decrease over the course of the study, and it could also account for why there was no noticeable effect on their quality of life or levels of fatigue. These findings indicate that CGs should be used alongside other treatments as part of a multidisciplinary approach.® CGs are generally well-adapted to the skin of patients with EDS.A difficulty with CGs is that they are necessarily tight and may irritate the skin. This is an important consideration for patients with EDS, as the disease is associated with skin fragility and an increased susceptibility to bruising and scarring . In our Despite these encouraging findings, some patients in our study reported dissatisfaction with the CGs: 9.5% reported that they were not at all satisfied (at V1). This led to a certain number of patients dropping out of the study, while others completed the study without wearing the CGs as required. Nevertheless, the feedback from patients at the end of the study was generally positive, with over half (52%) reporting satisfaction with the level of comfort and most (57%) having no difficulty putting the garments on. This indicates that the design of the CGs is generally well-suited to patients with EDS, although there is still room for improvement.This study had several limitations. Firstly, many of the study measures were subjective and, thus, subject to bias, such as the VAS and painDETECT questionnaire. For instance, patients may have expected to have reduced levels of pain with the CGs and this may have led to a bias towards reporting improvements. However, as pain is a subjective sensation, it can be challenging to assess using objective measures . This isAs a final note, this study focused on patients with EDS, but CGs are regularly used to treat patients with burns, lipedema, lymphedema, and orthostatic hypotension. However, these conditions are difficult to compare to EDS. Compression garments are also used to enhance the performance and recovery of athletes , who mayThe results of this study indicate that CGs can be effective for reducing pain in patients with EDS. They may also reduce the incidence of sprains, dislocations, and partial dislocations, and improve patients’ functional independence. However, they may not improve the patients’ fatigue, which can be severe , or redu