Nonspecific chronic neck pain (cNP) is common in adult violinists and violists and is often treated with osteopathic medicine (OM), although the effectiveness of this treatment has not been determined to date. This study aimed to evaluate the effectiveness and safety of OM in adult violinists and violists with cNP.In a two-armed randomized controlled single-center open trial, adult violinists and violists, including music students, with cNP (⩾12 weeks) were randomized to either five individualized OM sessions (OM group) or to no intervention  in the outpatient clinic for integrative medicine, Charité - Universitätsmedizin Berlin, Germany. All patients received a musicians’ medicine consultation and paracetamol on demand. The primary outcome parameter was the neck pain intensity on a visual analog scale  after 12 weeks. Secondary outcomes included neck pain disability  after 12 weeks. The last follow-up visit was after 52 weeks. Statistical analysis included analysis of covariance adjusted for respective baseline value.n = 28), CG (n = 34); 81% female; mean age, 41.6 ± 11.1 years; mean baseline neck pain, 55.9 ± 11.6 mm]. After 12 weeks, OM was associated with an improvement in the OM group versus the CG in neck pain on the VAS , and neck pain disability as determined by the NDI . Some improvements were maintained until 52 weeks of follow-up. No serious adverse events were observed.Altogether, 62 outpatients were included [OM group : U1111-1173-5943.WHO Trial Registration  A multimodal approach, including manual treatments, advice, muscular stretching and exercise can be used to address cNP.39 Approximately 80% of professional musicians, including music students, experience health problems during their career that affect their performance, particularly neck pain and low back pain.1017 For the purpose of the study, adult violinists and violists are professional musicians who perform in orchestras or as soloists and earn their living by making music or are music students playing the violin or viola. The high prevalence of neck pain18 in adult violists and violinists is attributed to the special playing demands, including frequent complex repetitive movements with long static and dynamic loads on the muscles in an asymmetric playing posture.19 Violists and violinists hold their instrument between the chin and shoulder, often using a shoulder rest and/or a chin rest to support this position. The left hand holds the instrument, the left fingers need to move freely to precisely pinch the note, performing fast and repetitive movements between a high position and a low position, while the right arm engages in repetitive bowing.20 Further risk factors include excess muscle tension, muscle fatigue, insufficient rest, long practice sessions, repertoire scheduling, poor posture, stress, poor injury management, performance anxiety, lack of fitness and insufficient warm-up.21 These risk factors can be addressed by prevention as practiced in musicians’ medicine.22 In adult musicians, only a few controlled intervention studies addressing musculoskeletal pain relief can be found.23 However, in musicians with cNP, trigger point therapy has been reported to be effective in pain reduction and functional improvement.24 In violists and violinists, manual treatments combined with musicians’ medicine have, to the best of the knowledge of the authors, been published only in case reports.26Neck pain is a global burden and is reported to be a leading cause of ill health.23 OM relies on manual contact for diagnosis and treatment and focuses on the structural and functional integrity of the body, including skeletal, arthrodial and myofascial structures and related vascular, lymphatic and neural elements27 in the so-called musculoskeletal, visceral and craniosacral systems. OM is commonly administered as a diagnosis-related and individualized treatment and additionally offers advice on self-training for postural improvement,28 as is performed in this study. A previous systematic review and meta-analysis in the general population indicated effectiveness for pain reduction with OM compared with heterogeneous comparison interventions, including physiotherapy, sham manipulation or no specific intervention, in patients with cNP.29Osteopathy and osteopathic medicine (both summarized in this paper under OM) are part of complementary and integrative medicine. OM is used by musicians for musculoskeletal symptoms.30 Previous studies have indicated that OM may be cost effective for the management of neck pain in the general population; however, the published comparative effectiveness and health economics studies are of insufficient quality and quantity to draw further conclusions.3134 To our knowledge, studies investigating the effectiveness, safety, costs, or cost effectiveness of OM in musicians with cNP are not available.35 The primary study aim was to evaluate the effect of five OM treatments in comparison with no OM treatment during 12 weeks on the subjectively perceived neck pain intensity in adult violinists and violists, including music students, with cNP. Further aims were to explore the impact of such therapy on the neck pain disability, stress intensity, quality of life, intake of analgesics, days of inability to work, days with restrictions in daily routine safety and cost effectiveness.For patients receiving complementary and integrative medicine, pain reduction and lower costs have been reported from a hospital perspective in a noncontrolled retrospective analysis.In a two-armed randomized controlled single-center open clinical trial, adult violinists and violists, including music students, with cNP were randomized to either five individualized OM sessions within 10 weeks (OM group) or to no OM intervention . All patients equally received a musicians’ medicine consultation addressing playing-related problems and paracetamol on demand.The study was performed at the outpatient clinic for integrative medicine of the Charité – Universitätsmedizin in Berlin, Germany, between September 2015 (first patient in) and May 2018 (last patient out after 52 weeks of follow-up).36 and the ICH-GCP guidelines.37 It was approved by the Ethics Committee, Charité – Universitätsmedizin Berlin . All patients gave oral and written informed consent before inclusion in the study.This study was registered at the German Clinical Trials Register before enrollment of the first patient (DRKS00009258) and followed the standards of the Declaration of HelsinkiSupplement 1) were included in the study. A 40-mm cutoff point for study inclusion was selected by the study team based on the literature, including a randomized controlled trial (RCT) investigating OM in patients with cNP38 and earlier pain studies in our group.40 A 40-mm cutoff point allows defining a population with at least medium pain severity to provide some homogeneity in pain intensity and to make recruitment of the study population feasible. Within the last 4 weeks before the start of the study, patients had used no therapy or only drug therapy for cNP. The exclusion criteria were defined as follows: peripheral or central neurological symptoms; known vascular anomaly, such as aneurysm; known or suspected primary or secondary bone tumor; neck pain caused by recent trauma; rheumatic disease; prior surgery on the cervical column; suspected osteoporosis; OM treatment within the last 6 months before the beginning of the study; neck pain treated by complementary medicine or physical therapy within the last 3 months before inclusion; obesity (body mass index > 30 kg/m2); current intake of centrally acting analgesics; pregnancy; presence of other acute or chronic disease impairing participation in the study intervention; presence of other psychic or somatic condition impairing participation in the study intervention; alcohol or substance abuse; planned or actual use of therapy with possible impact on cNP, such as physiotherapy, acupuncture, massage, neuroreflex therapy, or the Feldenkrais method, during study participation; insufficient German language skills; current application for a benefit; and participation in another clinical trial during the 6 months before the study or parallel to the study.Patients were recruited from various professional orchestras in Berlin and nearby federal states  and Berlin music schools/universities. We used posters, flyers, newspapers, electronic listings and digital media for recruiting. Violinists and violists who were active professional orchestral musicians, soloists, or music students of both sexes aged 18–65 years with a clinical diagnosis of cNP for at least 12 weeks prior to study onset and an average pain intensity within the last 7 days of at least 40 mm on a 100-mm horizontal visual analog scale  by a computer-generated block randomization process in the study center with variable block length. The allocation was performed in the study center by a study nurse and was concealed.16 The musicians’ medicine consultation and handout addressed risk factors for cNP in violinists and violists, especially excess muscle tension, muscle fatigue, insufficient rest, long practice sessions, repertoire scheduling, poor posture, stress, poor injury management, performance anxiety, lack of fitness and insufficient warm-up.14 The consultation included behavioral advice regarding playing practice, lifestyle recommendations, instrument-specific ergonomics and occupational environment and advice for the work organization, which included the number of working hours and sufficient breaks. The details of the handout are provided in the supplemental material online (Supplement 2).Before randomization, all patients received a 45-minute semi-standardized musicians’ medicine consultation addressing playing-related problems with one of two experts in musicians’ medicine , supported by a handout. The musicians’ medicine consultation and handout were established by a consensus of experts, which included a review of the literature.All patients were allowed to take 500 mg of paracetamol on demand up to four times daily during the first 12 weeks. Twelve weeks after randomization, patients in both groups were allowed to use any additional physical or psychological treatment.Within the first 12 weeks after randomization, patients in the OM group received five individualized diagnosis-related OM treatment sessions that were 45 min long each at an approximately 2-week interval. Each session started with a short interview and physical examination of the musculoskeletal, visceral and craniosacral systems according to medical and OM principles. Based on the interview and physical examination, the actual treatment strategy following OM principles was determined for each session. According to the individually necessary treatment techniques in the musculoskeletal, visceral and craniosacral systems, patients were treated in a sitting or lying position with or without active participation of the patient. We chose an individualized diagnosis-related OM treatment approach, as is commonly administered in OM. Advice for postural improvement during instrument playing was included in the OM treatment. Therefore, all musicians were examined during one of the five OM treatment sessions while playing the instrument. The study intervention was applied by one medical doctor (and osteopath) with special expertise in musicians’ medicine (GR).Patients in the CG received no OM treatment within the first 12 weeks. After 12 weeks, patients of the CG could receive five OM treatments free of charge, if desired.Supplement 1) after 12 weeks.41 We used the VAS for pain measurement because it is validated, widely used, easy to use and takes less than 1 min to complete.42 Recently, the minimal clinically important difference (MCID) on the VAS for neck pain was reported to be within a range between 4.6 mm and 21.4 mm.43 During the planning of the study, we considered publications with an MCID of 13.7 mm on a 100-mm VAS for pain measurement,42 of 8 mm on a 100-mm VAS for neck pain,44 and of 1.5 points  on a numeric rating scale for neck pain.45 Based on the literature and our expectations for our study population, we decided to select an MCID of 15 mm on a 100-mm VAS to measure neck pain. The criterion for a substantial clinical benefit (SCB) was reported to be 26.5 mm.44Parameters were measured at baseline and after 6, 12, 26, and 52 weeks using standardized patients’ questionnaires. The primary outcome was neck pain; patients rated their average perceived neck pain within the last 7 days on a horizontal VAS 54 or 9.8%  with an SCB of 29%.44 Further secondary outcomes were stress intensity as determined by a horizontal VAS for stress. We used the VAS for stress measurement because it is validated,55 easy to use and takes less than 1 min to complete. Patients rated their average perceived stress within the last 7 days on a horizontal VAS ,55 with no MCID for VAS stress determined, and health-related quality of life measured by the 12-item Short Form Health Survey .5659 We used the SF-1259 because it is a short form of the well-accepted SF-3657 and is commonly used.VAS neck pain levels after 6, 26, and 52 weeks were considered secondary outcomes. A further secondary outcome after 6, 12, 26 and 52 weeks was neck pain disability assessed by the Neck Disability Index  in a validated German version.60 the days of inability to work due to cNP within the last 12 weeks (baseline) and within the last 6 weeks , and the days with restriction in daily routine due to cNP within the last 12 weeks for baseline and within the last 6 weeks  by the  question: “On how many days in the last 12 (respective 6) weeks have you been restricted in your daily routine due to cervical spine pain?” Safety (adverse events and serious adverse events) was assessed by the study physician during the interviews in the OM group; additionally, patients were encouraged to contact the study center in the case of any adverse events. Patients also rated the changes in their complaints due to musculoskeletal pain within the last 6 weeks, and patients receiving OM rated the effectiveness of the OM treatment with reference to the last 6 weeks . Sociodemographic data, including age, sex, and education, were also assessed at baseline.Furthermore, we assessed the intake of analgesics in a diary, which we applied despite reported tendencies toward inaccuracy regarding the time and reliability of entries,We decided to apply patient-relevant outcomes by using patient-reported outcome measures and not to add objective parameters. Therefore, blinding of outcome assessors (patients) was not feasible.38 a Berlin RCT investigating Tui Na in cNP,61 and an older pre–post pilot study investigating OM in patients with cNP and subchronic neck pain,62 including literature about the MCID for the VAS for pain, ranging from at 8 mm in patients with cNP44 to 13.7 mm for pain,42 and including the MCID of 1.5 points (0–10) on a numeric rating scale.45 As a result, a mean difference between the OM group and the CG of 15 mm was considered,38 and the common standard deviation was assumed to be 25 mm. Thus, with 45 patients per group , a two-sided t-test with a significance level of 5% would have a power of 80%. To compensate for potential dropouts, 100 patients were intended to be randomized (50 patients per group).Sample size: For the primary outcome (VAS score of neck pain after 12 weeks), the sample size was calculated based on a consensus considering a previous German RCT in OM for cNP,p < 0.05). Post hoc Cohen’s d was calculated for the VAS score of neck pain after 12 weeks. Cohen’s d and all following analyses were considered explorative. The secondary outcomes for the VAS score of neck pain (after 6 weeks), neck pain disability as determined by the NDI, VAS score for stress, SF-12, quality-adjusted life years (QALYs), and total costs over the first 12 weeks were analyzed similar to the analysis of the primary outcome, that is, by ANCOVA adjusted for the respective baseline values. The results are reported as adjusted group means with 95% confidence intervals (CIs) and the p-value for the treatment group comparison. The p-values are only reported for the first 12 weeks as participants in the CG also received OM after week 12. All tests and CIs were two sided. All data were analyzed based on the intention-to-treat-principle using the full analysis set (FAS) with all available data without imputing missing data. All analyses were performed according to the original assigned groups. Adverse events are presented descriptively by frequency for each treatment group. In addition, a number of sensitivity analyses were performed. A per-protocol (PP) analysis was performed for the primary outcome, excluding patients if at least one of the following criteria was met: no complete data available for the primary endpoint, namely, the VAS score for neck pain at 12 weeks; not treated according to the allocated group; fewer than five interventions in the first 12 weeks (OM group only); and OM treatment (elsewhere) during the first 12 weeks (CG only).The primary analysis of the primary outcome was performed using an analysis of covariance (ANCOVA) with a fixed-factor treatment group adjusted for the baseline value of the VAS score for neck pain. The assumptions for normal distribution were both tested with reviewing histograms and Q–Qplots. The assumptions of equal regression slopes, outliers and linearity were checked with scatter plots, the assumption of variance homogeneity was tested with the Levene’s test. The significance level was established as <5% , reflecting the add-on costs for realizing one QALY gained.In addition, a cost-effectiveness analysis was carried out for the period 12 weeks after baseline. Therefore, the achieved QALYs were linked to cNP-related total costs from a societal perspective (including direct and indirect costs). Data on utilization of medical resources, sick leave days and working hour reductions related to cNP were systematically collected using patient questionnaires and valued by using standardized German national unit cost assumptions. Costs arising due to the OM intervention were considered to be 85.80 Euro per session, according to a notification from the study center financial department. An algorithm developed by Brazier and Robertsn = 28; CG, n = 34). Despite strong efforts, it was not possible to include more patients in the study, and the targeted sample size of n = 100 was not reached. After randomization, one patient in the CG dropped out due to noncompliance; after 12 weeks, another patient in the CG dropped out due to personal reasons. All other patients remained completed 52 weeks of follow-up and returned the questionnaires  patients in the OM group, n = 26 (81.3%) patients in the CG]. The physical examination at baseline revealed pathologic findings in the musculoskeletal system in 11 (39.3%) patients in the OM group and 9 (26.5%) patients in the CG.At baseline, the mean age was 41.6 ± 11.1 years (mean ± standard deviation). Fifty patients (80.7%) were female. The mean duration of cNP symptoms was 14.0 ± 10.9 years in the OM group and 13.8 ± 9.5 years in the CG . At basep < 0.001] (d) for the VAS score for neck pain after 12 weeks was d = 1.4 . The sensitivity analyses for baseline differences and PP analyses for the VAS score for neck pain, neck pain disability as determined by the NDI, VAS score for stress, and SF-12 were also similar to the above-reported FAS analyses. The responder analysis for 50% pain reduction after 12 weeks revealed a point estimate (odds ratio) of 13.8 .After 12 weeks, the primary outcome, the VAS score for neck pain, was significantly and relevantly lower in the OM group  with an adjusted group difference of −26.2 mm  . The effp < 0.001]. Furthermore, we observed  differences in the baseline value-adjusted mean neck pain disability as determined by the NDI in favor of the OM group after 6 weeks  and 12 weeks . The baseline value-adjusted mean VAS score for stress was lower in the OM group after 12 weeks  but not after 6 weeks . Regarding the SF-12, although better results in favor of OM were found for the baseline-adjusted mean difference for the physical component scale after 6  and 12 weeks , the differences were not clinically relevant. There were no relevant effects on the mental component scale of the SF-12 in the OM group in comparison to the CG after 6  or 12 weeks  (The VAS score for neck pain after 6 weeks (secondary outcome) showed a clinically relevant difference favoring the OM group  −5. For sAfter 12 weeks, 28 patients (82.4%) in the CG also received OM within the 52 weeks of follow-up. Among them, 24 patients (70.6%) received all five OM treatment sessions, and 27 patients (79.4%) received at least four OM treatment sessions within 52 weeks after baseline. After 52 weeks, patients in the OM group reported a VAS score for neck pain of 19.7 mm , while patients in the CG reported a VAS score for neck pain of 30.6 mm  .Analgesic use within the first 12 weeks was low overall and comparable between the two groups. In the OM group, only five patients (17.9%) took 24 pills of paracetamol in total, and in the CG, four patients (11.8%) took 23 pills of paracetamol in total. Regarding analgesics other than paracetamol, one patient in the OM group used arnica pain ointment, and others used 400−600 mg of ibuprofen or did not specify the dose of ibuprofen. In the OM group, two patients (7.1%) took a total of 16 analgesic doses . In the CG, four patients (11.8%) took 43 analgesic doses (ibuprofen) altogether.Furthermore, we found a decrease in the days with inability to work due to cNP in the OM group within the first 12 weeks, which could not be observed in the CG. Days of inability to work due to cNP were measured at baseline (for the last 12 weeks) in the OM group and CG, with a mean of 1.0 , and 0.7 , respectively; after 6 weeks (for the last 6 weeks) in the OM group and CG, the mean was 0.1  and 0.3 , respectively; and after 12 weeks (for the last 6 weeks), in the OM group and CG, the mean was 0.0  and 0.5 , respectively.versus the CG  within the first 12 weeks . Most patients in the OM group rated the intervention as very effective after 12 weeks.Days with restrictions in daily routine due to cNP improved in the OM group 12 weeks . PatientNo serious adverse events were observed. Two patients reported transient mild adverse events after OM (tiredness and dizziness).p = 0.147), in favor of the OM group. For the same time period, a mean adjusted cost of 497.54 EUR  and 704.54 EUR  occurred in the OM group in the CG, resulting in an adjusted mean difference of −207.00 EUR , in favor of the OM group. The additional direct costs due to the OM intervention seemed to be mainly compensated for by lower indirect costs due to work absenteeism in the OM group. An ICER was not calculated since the differences in QALYs and total costs were not statistically significant between the groups.During the first 12 weeks after baseline, the OM group experienced 0.1789 adjusted QALYs  compared with patients in the CG, with 0.1734 QALYs . The adjusted mean QALY difference was 0.0055   indicating a good clinical result, even if the criterion for an SCB at −26.5 mm44 was missed. The failure to meet the SCB criterion might be due to various factors: First, patients in the CG improved as well, which could be due to study effects and to the semi-standardized musicians’ medicine consultation, which was provided equally for both groups. The musicians’ medicine consultation included a variety of playing and performance-related information. In particular, posture, optimization of shoulder rest/chin holder, and practice scheduling were determined to be important factors of cNP among violinists and violists and can be addressed by musicians’ medicine.6872 Overall, the improvement in pain in the CG during the first 12 weeks also indicates (in addition to study effects) that a musicians’ medicine consultation might be helpful.We considered the adjusted group difference for the VAS score for neck pain, with –26.2 mm (with a large effect size, Cohen’s 73 However, within trials with a smaller study population, there can be baseline differences despite randomization by chance. In order to adjust for the risk of baseline differences between the groups regarding educational level and the VAS score for stress, we performed sensitivity analyses with adjustments for these factors and additionally for sex regarding the primary outcome of the VAS score for neck pain. The results of the analyses were robust.We used a computer-generated block randomization method as it helps to prevent accidental bias and to achieve balance between groups.41 NDI,47 VAS for stress55 and SF-12.5659 In this RCT, we aimed to answer a research question with high personal relevance for adult musicians, as cNP is common in adult violinists and violists, including music students. The OM treatment was performed by an osteopath, who was also a medical doctor and orthopedic surgeon, by applying the usually performed individualized diagnosis-related osteopathic treatment.The main strengths of this trial are the randomized study design, the relatively large sample size for a single-center interventional trial on OM, the implementation of musicians’ medicine, including a job-specific subjective assessment, treatment and outcome measurements, the high patient adherence rate, the long follow-up, and the comprehensive range of patient-reported outcomes, including neck pain, neck pain disability, quality of life, perceived stress, medication intake, and job-specific parameters. Furthermore, we considered health economics parameters. Additionally, validated and widely accepted clinical outcome measures were used, including the VAS for pain,74 Nonetheless, the lack of blinding of outcome assessors could have led to an overestimation of the treatment effects. We used mostly validated measurement tools but also included nonvalidated tools, such as the assessment of the intake of analgesics in a diary, the assessment of days with restrictions in daily routine and the assessment of changes in complaints by patients and the rating of the effectiveness of OM treatment. These results must be considered orienting and hypothesis generating, and must be interpreted with caution. There is some discussion in the literature on how to best analyze the VAS. One analysis for example including more than 200 patients concluded that VAS might be nonlinear and thus ordinal and should be analyzed as such.75 However, this can be specific to the data at hand and after checking the data in our study, we saw no reason to not use ANCOVA. It is considered to be a robust method, and many researchers such as Heller et al.76 and Philip77 recommend parametric analyses methods as the pragmatic choice with equal power. Further, in our study the ANCOVA was also the predefined analysis strategy, which should be followed as closely as possible to minimize the possibility of bias.However, the study also has limitations. This study employed a single-center setting, with the involvement of only one therapist with very specific training, and there was a high percentage of women in our study population; these factors clearly limit the generalizability of our results. The calculated sample size for the primary outcome parameter was not achieved; however, the difference in the primary outcome between the treatment groups was larger than expected. The study design had more potential sources of bias: participants in the OM group received more time and attention than those in the CG, and the blinding of patients or the therapist with regard to group allocation was not feasible within the study design. The patients themselves assessed the outcomes with patient-reported outcome measures; therefore, blinding of outcome assessors was not feasible. The primary outcome, neck pain, was measured subjectively. The lack of additional blinded objective outcome parameters is a limitation of the study. However, recently, the importance of blinding in RCTs has been discussed, as a meta-epidemiological study found no evidence for an average difference in estimated treatment effects between trials with and without blinded patients, healthcare providers, or outcome assessors.Another limitation is that a number of patients in both groups did not adhere to the study protocol and used additional treatments during the first 12 weeks. However, the results were robust with respect to the sensitivity analyses regarding the PP population.We considered the relatively short period of 12 weeks for an intergroup comparison necessary to recruit patients and ensure compliance in the CG. If the period between treatments had been longer, approximately 3–4 weeks, as is often the case in OM, we would have expected a stronger improvement in pain and function.From a health economics point of view, the relatively short period is a limitation. If the period of the intergroup comparison had been longer than 12 weeks, it might have been possible to obtain more robust results with respect to the cost-effectiveness analyses. Another limitation is that adverse events were not assessed by patients in diaries but by interviews and reports to the study center. This could have led to an underreporting of adverse events, especially mild adverse events, because patients might have forgotten to report these events at the time of the interviews.To the best of our knowledge, this was the first study to compare OM with no treatment option in adult violinists and violists with cNP. We found only one nonrandomized clinical trial that was a thesis for a Bachelor’s degree in the British College of Osteopathic Medicine treating 23 healthy violinists with one strain–counterstrain session, as a technique applied in OM, in comparison with positive visualization reporting improved range of motion in the OM group. This thesis showed that nine musicians felt calmer and more relaxed after the strain–counterstrain treatment, and 19 musicians felt calmer and more relaxed after positive visualization.78 The authors found no benefit of scapula taping regarding pain during violin playing. Other randomized trials investigating therapy options for musculoskeletal pain in a variety of adult musicians reported some improvement after exercise80 or Tui Na treatment82 but no clear benefit after yoga.83Regarding other therapy options in adult violinists and violists, one pre–post study with a crossover design investigated scapula taping while playing the instrument in eight professional orchestra musicians.et al.32 stated that despite some positive findings, published comparative effectiveness and health economics studies of OM are of insufficient quality and quantity to inform policy and practice. However, OM was reported to be a cost-effective strategy in patients with neck pain when compared with usual care, although it involved additional costs.31 In former publications,34 the cost–utility analysis identified reported improvements in pain and quality of life in patients with neck or back pain at a cost of £3760 per QALY gained.32To our knowledge, this was also the first study investigating the costs and cost effectiveness of OM in musicians with cNP. Our results tended to be in favor of OM but were not statistically significant. This conclusion is consistent with the literature. Steel Future studies should investigate efficacy by investigating specific therapeutic effects of OM in comparison with a sham procedure and with other effective therapy methods. Possible sham procedures could include nonspecific light touch procedures in patients naïve to osteopathic treatment. The nonspecific touch procedures should include the whole body and be applied by nonosteopaths. Regarding the comparison with other effective therapy methods, these could be single therapies, such as physiotherapy and analgesics, or could include multimodal approaches. Blinding of study patients, outcome assessors and statisticians should be considered in future trials, especially if a sham procedure is developed. A future trial on OM should include multiple centers, therapists with different levels of training, a comparison with other best care options, and a more balanced sample regarding sex. Adverse events should be reported by patients in diaries.The results of this study suggest that OM might be effective in reducing the pain intensity in adult violinists and violists, including music students, with nonspecific cNP. Nevertheless, in terms of cost effectiveness, OM treatment was not superior to no OM treatment during a 12-week observation period. Further multicenter studies should investigate the efficacy of OM in comparison with an OM sham procedure and the effectiveness of OM in comparison with other therapy methods.Click here for additional data file.Supplemental material, sj-pdf-1-tab-10.1177_1759720X20979853 for The effect of osteopathic medicine on pain in musicians with nonspecific chronic neck pain: a randomized controlled trial by Gabriele Rotter, Isabel Fernholz, Sylvia Binting, Theresa Keller, Stephanie Roll, Benjamin Kass, Thomas Reinhold, Stefan N. Willich, Alexander Schmidt and Benno Brinkhaus in Therapeutic Advances in Musculoskeletal DiseaseClick here for additional data file.Supplemental material, sj-pdf-2-tab-10.1177_1759720X20979853 for The effect of osteopathic medicine on pain in musicians with nonspecific chronic neck pain: a randomized controlled trial by Gabriele Rotter, Isabel Fernholz, Sylvia Binting, Theresa Keller, Stephanie Roll, Benjamin Kass, Thomas Reinhold, Stefan N. Willich, Alexander Schmidt and Benno Brinkhaus in Therapeutic Advances in Musculoskeletal DiseaseClick here for additional data file.Supplemental material, sj-pdf-3-tab-10.1177_1759720X20979853 for The effect of osteopathic medicine on pain in musicians with nonspecific chronic neck pain: a randomized controlled trial by Gabriele Rotter, Isabel Fernholz, Sylvia Binting, Theresa Keller, Stephanie Roll, Benjamin Kass, Thomas Reinhold, Stefan N. Willich, Alexander Schmidt and Benno Brinkhaus in Therapeutic Advances in Musculoskeletal DiseaseClick here for additional data file.Supplemental material, sj-pdf-4-tab-10.1177_1759720X20979853 for The effect of osteopathic medicine on pain in musicians with nonspecific chronic neck pain: a randomized controlled trial by Gabriele Rotter, Isabel Fernholz, Sylvia Binting, Theresa Keller, Stephanie Roll, Benjamin Kass, Thomas Reinhold, Stefan N. Willich, Alexander Schmidt and Benno Brinkhaus in Therapeutic Advances in Musculoskeletal Disease


Purpose Hepatic arterial infusion chemotherapy (HAIC) is one of the options to treat unresectable hepatocellular carcinoma (HCC). The majority of HCC patients suffer great pain in the course of HAIC treatment. To improve the quality of life and the efficacy of HAIC treatment, the causes of pain, the choice of an analgesic regimen, and the relationship between pain and prognosis of HCC were analyzed. Methods A total of 376 HCC patients under HAIC in our hospital were recriuted between March 2017 and September 2019. Multivariate linear regression analysis (stepwise) was used to calculate the potential factors related to the severe pain in HCC patients under HAIC. Analgesics treatments were carried out based on the results of the visual analogue scale (VAS) score which was used to evaluate the pain. Results The mean value of the VAS score is 3.604, which indicates that the pain in most patients is mild and endurable. Intra-arterial lidocaine injection is an effective method in most patients , and the total score of VAS is reduced from 1355 to 195 following lidocaine injection. Multivariate analysis suggestes that oxaliplatin (OXA) preparation time, hepatic artery diameter and OXA manufacturers (R2 = 0.859) are influential factors for pain scores. Conclusion This study demonstrates an effective way to systematically assess and ease pain in HCC patients with HAIC treatment. OXA preparation time, hepatic artery diameter, and OXA manufacturers are the potential influencing factors for pain. This work presented here will provide a detailed understanding of the clinical application of HAIC in advanced HCC patients. Primary hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death in the world . About 2The blood supply of HCC and liver metastases is mainly from the hepatic artery, while the blood in normal liver cells are is mainly supplied by the portal vein . HepaticHAIC has been reported to be safe and effective for treating unresectable advanced HCC. However, clinical studies found that some patients experienced severe pain during arterial chemotherapy, and sometimes even reached visual analogue scale (VAS)10, leading to a significant reduction in patient tolerance and compliance with this treatment regimen. To improve patients’ quality of life and treatment efficacy of HAIC, this study collected clinical data of 376 patients with HAIC in our hospital from March 2017 to September 2019, and evaluated the causes of pain, the choice of an analgesic regimen, and the relationship between pain and prognosis of HCC.From March 2017 to September 2019, a total of 376 patients with primary HCC were confirmed by radical surgery and pathology in our hospital. This study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. Patients in this study received necessary antiviral (Entecavir) and immune (Thymopeptide) treatments after surgery. The clinical data were collected including age, gender, hepatitis status, OXA manufacturers, B lymphoblastoid cell line (BLCL) staging, Child-Pugh score classification, analgesic measures, catheterized hepatic artery diameter, OXA preparation time (formulation to use), intrinsic hepatic artery diameter, microcatheter, visual analogue scale (VAS) score, pain level, lidocaine in arteries, effectiveness of lidocaine, and valid N (listwise).Inclusion criteria: 1) Age ≤ 75 years; 2) Primary HCC was confirmed by radical surgery and pathology; 3) Child function grade A to B; 4) No other anti-tumor treatment; 5) Survival time > 3 Month; 6) Written consent was obtained; 7) Patients with no pathology needed to meet the criteria for diagnosis and treatment of primary liver cancer (2017 Edition); (8) All patients had not received any form of anti-tumor treatment before their visit to our hospital.Exclusion criteria: 1) Patients with cholangiocarcinoma after surgery or puncture; 2) Patients with a second primary tumor other than HCC.2 OXA was injected through the hepatic artery. A total of 2 courses of treatment were carried out (one course every 4 weeks).The femoral artery was intubated by the Seldinger method for 3 weeks after the operation. The catheter was sent to the hepatic artery or left and right hepatic artery for angiography. After the fixation of the catheter, 85 mg/mVAS scoring system included: 1) Homemade measuring ruler: a cardboard with a length of 10 cm and a width of about two horizontal fingers was chosen. A layer of white, slightly hard paper had no scale on one side, and only a black straight line was drawn in the middle. There was a scale of 0 to 10 on the other side: 0 on one end meant no pain. 10 on the other end meant severe pain, and middle part for different levels of pain: 1 to 3 pain was mild, and could be tolerated. Sleep was not affected; 4 to 6 pain affected sleep, tolerable; 7 to 9 represented the gradually increasing pain, unbearable; 10 meant severe pain. 2) Self-made facial expression chart for cancer pain assessment: based on the VAS measuring ruler, the facial expression chart of paint was pasted on cardboard of corresponding length and width. On the other side was a scale engraved with 0 to 10. It was suitable for the elderly, children, patients with low education levels, patients with impaired expression and patients with cognitive impairment. 3) Evaluation: in clinic, the graduated side of the measuring ruler was turn back to the patient, and the straight line was drawn where the patient facedd. A point was marked on the straight line that represented the degree of pain, and the patient’s pain intensity score was on the back according to the corresponding scale. The facial expressions were used in the same way as the VAS measuring ruler.In this study, different measures were taken according to different VAS scores: 0 meant no analgesic measures; 1 meant the use of weak opioids for analgesia; 2 meant the use of strong opioids for analgesia; and 3 meant the use of enhanced opiates Analgesic. The evaluation of the analgesic effect was performed according to the following criteria: ineffective; effective indicated that the pain score decreased by more than 3 points; and obviously effective meant that the pain score was decreased by more than 6 points.http://www.R-project.org) were used for statistical analysis. The data that conformed to the normal distribution were described by mean ± standard deviation (SD). Counting data are described as percentages. The stepwise method was used in this study. P < 0.05 was considered statistically significant.Statistical Product and Service Solutions (SPSS) version 22.0 statistical software  and R software . As shown in Table In this study, we divided all patients into 4 different groups based on the pain levels. For pain level = 0, there were 134 patients (35.6%). For pain level = 1, there were 72 patients (19.1%). For pain level = 2, there were 85 patients (22.6%). For pain level = 3, there were 85 patients (22.6%). More than half of patients had pain levels less than or equal to 1. However, it was worth noting that 45.2% (170) of patients were suffering from a pain index greater than or equal to 2 , OXA preparation time and hepatic artery diameter (R2 = 0.821), and OXA preparation time, hepatic artery diameter, and OXA manufacturers (R2 = 0.859) were found to be influential factors for pain scores.Multivariate linear regression analysis (stepwise) were used to probe the potential relationships of different factors such as hepatic artery diameter, OXA preparation time, OXA manufacturers. The results suggested that OXA preparation time  over 2 h . It was Cancerous pain is mostly caused by tumor development and invasion. Specific pain manifests as knife-cut pain, burning pain, colic, tingling pain, radiation pain, and penetrating pain. Analgesics including opioids such as oxycodone and ibuprofen are often used in the clinic to relieve pain and supplemented with antidepressants and anticonvulsants . TraditiThe VAS scoring method is a widely used method for measuring sensory intensity at the current clinical stage. It is worth noting that the elderly and those with mental disorders and advanced cancer patients are generally not good at using VAS evaluation. The more intuitive facial expression map will work well to evaluate the degree of pain and reduce the interference of other factors . There aIn summary, an effective way was demonstrated in this study to systematically assess and ease pain in HCC patients with HAIC treatment. OXA preparation time, hepatic artery diameter, and OXA manufacturers were the potential influence factors for pain of HCC patients under HAIC. This work presented here will provide a detailed understanding of the clinical application of HAIC in advanced HCC patients.


Pelvic girdle pain (PGP) refers specifically to musculoskeletal pain localised to the pelvic ring and can be present at its anterior and/or posterior aspects. Causes such as trauma, infection and pregnancy have been well-established, while patients with hypermobile joints are at greater risk of developing PGP. Research exploring this association is limited and of varying quality. In the present study we report on the incidence, pathophysiology, diagnostic and treatment modalities for PGP in patients suffering from Hypermobility Spectrum Disorder (HSD) and Hypermobility-Type Ehlers-Danlos Syndrome (hEDS). Recommendations are made for clinical practice by elaborating on screening, diagnosis and management of such patients to provide a holistic approach to their care. It appears that this cohort of patients are at greater risk particularly of mental health issues. Moreover over, they may require a multidisciplinary approach for their management. Ongoing research is still required to expand our understanding of the relationship between PGP, HSD and hEDS by appropriately diagnosing patients using the latest updated terminologies and by conducting randomised control trials to compare outcomes of interventions using standardised patient reported outcome measures. Pelvic girdle pain (PGP) refers specifically to musculoskeletal pain localised to the level of the posterior iliac crest and the gluteal fold, and occasionally over the anterior and posterior elements of the bony pelvis . There aJoint hypermobility (JH) places a great level of strain on an affected individual’s musculoskeletal system. JH occurs secondary to increased elasticity of the soft tissues that support a joint, tendons and ligaments, which allows a greater range of motion . A tool Patients with joint hypermobility (JH) are classified according to their position on the hypermobility spectrum, which ranges in severity from asymptomatic joint hypermobility, to hypermobility-type Ehlers-Danlos Syndrome (hEDS) . This alThe classification framework for overall Joint Hypermobility (JH) and Ehlers-Danlos Syndrome subtypes were updated in 2017, before which the definitions were quite different. Prior to this, the commonly used terms were ‘joint hypermobility syndrome’ and hEDS alone. ,16 One mEhlers-Danlos Syndrome (EDS) is a genetically inherited connective tissue disorder characterised by hypermobile joints, friable tissues and hyperextensible skin. The first attempt to classify the condition was in 1936 by Weber, who termed it ‘Ehlers-Danlos Syndrome’ in honour of early published cases by these authors  In 2017,As there is no investigation to diagnose hEDS, it is still diagnosed clinically. Attempts to find a genetic test have proved difficult due to the clinical and genetic heterogeneity of this syndrome ,19,20. AGiven the relatively recent changes in 2017 used to describe JH, HSD and hEDS, it is difficult to determine the exact prevalence of these conditions. The distribution of hypermobility between the genders is however well reported to show a female predominance ,25,26,27The purpose of our narrative literature review is to explore the current incidence, pathophysiology, diagnostic and treatment modalities available for musculoskeletal pelvic girdle pain and HSD/hEDS, identify potential relationships between them, and finally to discuss gaps for future research.A literature search was conducted on the 9 September 2020, using MEDLINE and EMBASE databases. The dates for this search were from 1 January 1970 to 9 September 2020. Given the variety of names used for pelvic girdle pain, a broad selection was used to identify as many relatable papers as possible. These were attached to the common keyword ‘hypermobility’ to identify papers which discuss or investigate hEDS or any other sub-category of the HSD. The following Boolean search was conducted: ((pelvic girdle pain) OR (pelvic pain) OR (pelvic instability) OR (pubis symphysis dysfunction) OR (pubic symphysis dysfunction) OR (sacroiliac dysfunction)) AND (hypermobility). This translates into the following MeSH terms used: Pelvic Girdle Pain (entry term Symphysis Pubis Dysfunction), Joint Instability (entry term Hypermobility). This was supplemented by a manual search of relevant citations from papers identified via MEDLINE/EMBASE, and focused searching using Google Scholar in order to identify the most current guidelines and evidence used in the diagnosis and management of PGP, HSD and hEDS.Studies were excluded due to lack of access to full articles, language not being English, or them being deemed irrelevant after closer investigation of the full articles. Due to the nature of the broad search and the overlap of terminology used in past literature, many of the excluded articles included those discussing non-musculoskeletal causes of pelvic pain, such as gynaecological, urological and gastrointestinal for example. Extracted details of interest included studies reporting on prevalence of hypermobility in musculoskeletal pelvic girdle pain populations, as well as papers elaborating on the pathophysiology of this association.Overall, 112 results were generated from this search. After screening relevance and eligibility from the titles and abstracts for these articles, 23 were identified for further investigation. Of these 23 articles, 10 were deemed eligible and related to our literature review, which are summarised in all types of EDS was rare. The paper itself confuses the diagnosis of JHS with HSD and hEDS, and also states that HSD/EDS is common, and was challenged for inaccurate statements: combining a common condition with a rare one and stating that together they are common does not make sense. Furthermore, given the change in the 2017 criteria definitions, it is impossible to define how HSD and hEDS split out from JHS. It is estimated that the combined prevalence of all EDS subtypes is 1 in 5000, of which an estimated 80–90% are believed to be hEDS [There are no current studies quantifying the accurate prevalence specifically of hEDS and HSD within the general population. This could be a difficult task for several reasons including recent changes to definitions of hEDS and HSD, undiagnosed cases, reliability of diagnosis, limited awareness of the disease, and coding issues where patients are labelled with EDS and not the particular subtype. A study by Demmler et al. (2015) did attempt, though, to investigate the diagnosed prevalence of EDS and HSD in Wales, UK . The fin be hEDS ,42.Epidemiological studies have estimated JH to have a prevalence between 2–35% ,44,45,46PGP is a common feature experienced by pregnant women, with reports of it affecting between 23–65% of pregnant ladies ,48. The The exact incidence and prevalence of HSD/hEDS has been difficult to establish due to the different definitions and diagnostic means used. The diagnosis has largely become one of exclusion once visceral, musculoskeletal, soft tissue infection and obstetric complications are investigated before HSD/hEDS is labelled as one’s cause of pelvic girdle pain.EDS is a group of inherited connective tissue disorders affecting proteins in the extracellular matrix, including collagen. Given the wide variety of proteins that can be affected, this disease can present with several phenotypes. This has led to many subclassifications of this condition such as classical, vascular and hypermobile variants. The 2017 International Classification System for EDS aims to not only identify each subtype on clinical presentation, but also genetic and molecular testing for diagnostic confirmation of each subtype. The most common inheritance pattern of transmission is autosomal dominant, as is the case for hEDS, which is the focus of this review paper. Autosomal recessive and de novo mutations have also been reported . Unlike A framework for the classification of joint hypermobility and related conditions’ by Castori et al. which was published in the same issue as the EDS classification system [The 2017 international classification system for EDS also provides advice for the diagnosis of HSD as suggested by the paper ‘n system . This frn system . The phen system ,55.Studies investigating the pelvic joints and hypermobility have found that pelvic pain is often secondary to altered biomechanics and transmission of forces via the spine . This isTheories have suggested that altered biomechanical loading and kinematics secondary to JH and instability can overload and injure joints, as repetitive microtrauma to its supporting structures can cause soft tissue injuries and arthralgias . This isSoft tissue structures surrounding the pelvis play a primary role in its stabilisation. They can be divided into subgroups known as the longitudinal, anterior oblique and posterior oblique pelvic slings which group muscles to their particular role in stabilisation . Poor coThe exact mechanisms that lead to the development of PGP from pregnancy remain uncertain. A variety of approaches have been proposed that suggest hormonal, biomechanical, traumatic, metabolic, genetic, and degenerative etiologic implications . The horJoint hypermobility can be diagnosed using either the Beighton score , or the As discussed by Castori et al. HSD diagnoses are intended as alternative labels to describe symptomatic hypermobile joints based on their distribution, in individuals who do not meet the criteria for EDS, hEDS, or other causes of hypermobile joints such as neurological disorders, myopathies, chondrodysplasia and other connective tissue disorders. Findings for each subtype are summarised in Diagnosed by the Beighton score , with cu≥6 for pre-pubertal children and adolescents≥5 for pubertal men and women up to the age of 50 years≥4 for those >50 years of ageIf the Beighton score cannot be used, due to acquired hypomobility due to surgery and amputations for example, the Five-Point Questionnaire (5-PQ)  is to beGeneralised joint hypermobilitySystemic manifestations of generalised connective tissue disorderPositive family history, with one or more first degree relatives with hEDSMusculoskeletal complications associated with hypermobile joints, including pain, instability and dislocationsAssociated features—divided into a further three subgroups A, B and C, where two or more of these subgroups are positiveExclusion of other subtypes of EDS and other soft tissue disorders.The precise criteria for a diagnosis of hEDS is well described in the 2017 international classification and developed around three criteria which have been summarised below :GeneralDiagnosis of PGP can be difficult and is guided mainly using tests conducted to provoke and elicit the pain. The SIJ and posterior elements of the pelvic girdle can be examined using the P4 posterior pelvic pain provocation test, Patrick’s FABER  test, active straight leg raise, palpation of the long dorsal sacroiliac ligament and Gaenslen’s test ,69,70,71The use of radiography and computerised tomography (CT) have not been promoted by the European guidelines for PGP as they provide little information on early degenerative disease. If magnetic resonance imaging (MRI) is available, it allows superior visualisation of early joint degeneration and inflammatory changes in the bones and surrounding soft tissues, as well as reducing exposure to radiation ,72. RadiTreatment of pelvic girdle pain (PGP) requires a holistic approach to address the many symptoms a patient may experience, but also the underlying aetiology. Pain control is of utmost importance to ensure comfort and continuation of function for the patient. This can be addressed using the analgesic ladder as well as the incorporation of neuropathic analgesia if indicated by signs of nerve irritation .It is also important to consider the impact of PGP on one’s mental health. Several studies have shown that females with chronic pelvic pain are at a significantly increased risk of suffering from anxiety and depression, even when compared to pain-free controls or population norms ,75,76,77p = 0.008) [Furthermore, it has been hypothesised that pain-related fear can lead patients into a vicious cycle where pain and injuries can persist because of emotional and behavioural responses to this pain . It has = 0.008) .The management pathway of PGP first requires assessment to identify the possible underlying aetiology. This is crucial especially if a diagnosis of EDS is suspected, where a formal assessment by a Rheumatologist or specialist centre would be advocated to investigate systemic manifestations of the condition . This isIndividuals with postpartum-PGP should be managed initially with a non-operative approach. A prospective cohort study investigating 130 women with PGP during and after pregnancy reported good prognosis from postpartum-PGP with 83% of individuals reporting substantial recovery within 6 weeks of delivery, 44% of whom recovered within 2 weeks . The 200In those with non-pregnancy related aetiology, physiotherapy is also the first step. As previously discussed, much of the pain is due to altered biomechanics throughout the pelvis. Physiotherapy attempts to restore the balance of the pelvis by manipulation of the soft tissues, whether it involves strengthening, stretching, improving flexibility, posture development, or core stabilisation to improve the biomechanics of one’s pelvic girdle ,89. ThisIf pelvic pain is persistent and not responsive to oral analgesia or conservative management, a more invasive approach may be adopted. Injection with a long-acting corticosteroid to the concerned joint(s) can be used ,91,92. NThe 2008 European pelvic girdle pain guidelines make no recommendations for surgery, but discuss the role of fusion surgery as a last resort in patients with resistant PGP, of pregnancy or traumatic aetiology, after poor response to other therapies . A crossp = 0.32 and p = 0.21 respectively. Although PROMs were used for the long-term follow-up, the initial short-term outcome was analysed using CT scans conducted 1-year post-surgery with a vague assessment of its impact on quality of life by grading impact on the participants work. It would have been best if the PROMs were standardised and used for both short and long-term outcomes.It was concluded that 1-year post-surgery outcomes were maintained 23 years after surgery with good reported outcome by the patients, however this was not statistically different to those managed without surgery. This study is beneficial for the insight of joint fusion in PGP; however, it is limited by its lack of randomisation, making it prone to selection bias at the time of deciding the management option. In addition to this, the group sizes varied significantly with 50 individuals in the surgical group, and only 28 in the non-surgical. The symptomology of patients in each intervention arm were not elaborated on. However, information broadly assessing functional status by enquiring about impact on occupation and use of mobility aids showed no significant differences between the two groups, A further study conducted by Kibsgård et al. used a prospective design and standardised PROMs for assessment pre- and post-surgery in individuals with severe PGP . This stFusion of the pelvic joints is indeed a significant process with postoperative care that can be limiting to patients. Full weight bearing is to be avoided for at least 8 weeks to allow the fusion process to occur ,97. Thisp values < 0.001. It also reports a lower revision surgery rate for the minimally invasive technique, 3.5%, compared to 44% revision rate for open fusion cases [There are two broad categories of SIJ fusion, open and minimally invasive techniques. The open approach to the SIJ was first described in 1921 by Smith-Petersen which mentions a posterior transiliac approach to the SIJ . Anterioon cases . The finp < 0.05 for VAS and ODI) implying a significant improvement in pain as well functional outcomes of patients undergoing these procedures. Statistical analysis was not conducted against open SIJ fusion, nor between the different options for minimally invasive surgery [p < 0.001), ODI (p < 0.001) and EuroQol 5-Dimension (EQ-5D) (p < 0.001) 24 months post-procedure [Notably, several minimally invasive implants which utilise either dorsal or lateral approaches in surgery are available, including triangular titanium implants, hydroxy-appetite coated screws, Simmetry and hollow modular anchorage screws. Martin et al. conducted a meta-analysis by assessing the impact of minimally invasive surgery for SIJ fusion on VAS and ODI, and found that both PROMs had significantly reduced ( surgery . A randorocedure .This shows the benefit of minimally invasive techniques that can be provided to patients receiving SIJ fusion. A questionnaire to Spinal Surgeons enquiring about their experiences and preferences of minimally invasive and open found that minimally invasive techniques were the preference, with 80% of 121 surgeons reporting that they would not perform an open SIJ fusion procedure if it was the only option available .Access to the pubic symphysis is typically obtained by an anterior approach using a Pfannenstiel incision for the purpose of fusion ,100,109.Previous studies have investigated the role of bone morphogenetic proteins in joint fusion, and have found them to be a safe and effective method of facilitating joint arthrodesis, by taking advantage of its ability to activate osteogenic pathways ,110,111.PGP is a complex disorder that is difficult to diagnose when considering its overlap in presentation with pathology of the pelvic viscera and spinal pathologies, making it primarily a diagnosis by exclusion. Assessment of existing literature is further challenged by the variety of names used to describe this condition, with similar difficulties associated with HSD and hEDS. Modern literature has however become more standardised by using PGP and HSD since the creation of newer classifications and guidelines ,68. ThisRegardless, this review has identified HSD as a potential risk factor for the development of PGP, requiring a multidisciplinary approach to manage, provide adequate support, and appropriately diagnose rare conditions such as EDS. If not already incorporated into current clinical care pathways, a suggestion would be made to involve a rheumatologist if there is suspicion of HSD/hEDS, in order to ensure a holistic approach is pursued to identify any associated connective tissue problems, particularly those that are life-threatening such as aortic dilatations. Increasing awareness of patients and clinicians is also vital to ensure appropriate labelling of diagnoses related to PGP or HSD, as there is concern of incorrect or underdiagnosis of disease, with unknown exact prevalence .A further challenge we face when interpreting current literature on management of outcomes is related to the broad variety of PROMs used in studies, particularly global health measures such as the SF-36, ODI, EQ-5D and Short Musculoskeletal Function Assessment which are not disease-specific as well as limiting translation and comparison of study findings, particularly where identical questionnaires were reported on differently ,114. PROSeveral recommendations can be made based on the findings of this literature review. Upon diagnosis of PGP, completion of appropriate PROMs would be advised to monitor global health, functional status, and mental health using validated measures. This allows further assessment as to whether patients with impaired mental health would benefit from a psychological or psychiatric referral to improve their symptoms and rehabilitation. In addition, it would allow monitoring of functional status which can be repeated throughout treatment and allow more meaningful assessment of post-intervention outcomes. For pregnancy-related PGP, we would advise the use of the Pelvic Girdle Questionnaire as it is well-validated as previously discussed. For other causes of PGP we advise the use of validated global measures such as the VAS, EQ-5D and SF-36 or ODI, which can be compared to population norms, as the application of pelvic-specific outcomes for this population require further assessment ,128,129.Diagnosis’ section. Patients should be screened for further features of EDS to assist in the decision to make a referral to a Rheumatologist or EDS specialist, so patients have access to appropriate support services.It would also be advised to screen patients for JH in a formal manner using the Beighton score, or Five-Point Questionnaire if the Beighton score cannot be applied in clinic, or due to contraindications described earlier in the ‘The findings included in this study have several limitations with regard to generalisation and of their approach toward JH. Self-diagnosis of JH would be deemed insufficient and question the validity of findings; diagnosis by a trained physician would be best. Moving forward, to improve the quality of available research, utilisation of the correct terminology and sufficient clinical examination is required to diagnose patients with PGP, HSD and EDS. To further develop our understanding of management options in this population, a multi-centre randomised control trial comparing conservative against surgical management is required utilising the latest available technologies and methods with the incorporation of validated disease-specific PROMs . A multiIn summary, ongoing literature would benefit from authors using the most recent and appropriate terminology and classifications for the diagnosis of PGP, HSD and hEDS. Patients presenting with PGP should formally be assessed for hypermobile joints, with support from connective tissue specialist colleagues for a formal diagnosis of HSD or hEDS. Standardised PROMs should be used in clinical practice and future research to facilitate translation and comparison of findings when monitoring post-intervention patient outcomes. Combining these points with a large randomised control trial will allow us to improve our understanding of the management of PGP in patients with a diagnosis of HSD and hEDS.


Does liposomal bupivacaine reduce postoperative pain and supplemental opioid use more than standard bupivacaine in cardiothoracic and vascular surgical patients?In this randomized clinical trial including 280 participants, no significant difference in pain control was observed between liposomal vs standard formulation bupivacaine.These results do not support superior performance of liposomal bupivacaine compared with bupivacaine for postoperative pain control in cardiothoracic and vascular truncal incisions. This randomized clinical trial investigates the effectiveness of liposomal bupivacaine vs standard bupivacaine for postoperative pain in patients with truncal incisions for cardiothoracic or vascular procedures. Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.Patients were randomized to standard bupivacaine or liposomal bupivacaine.Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models  to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1  and 2  but not day 3 , irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine  Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine . On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.A total of 280 patients were analyzed, with 140 in each group . Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = −0.87; SE = 0.11; mixed model regression In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.NCT02111746ClinicalTrials.gov Identifier:  Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.6More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trialCONSORT) reporting guideline  were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 . Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.Stopping rules were prespecified, with 22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),25 patient satisfaction with postoperative pain ratings , and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine . Mean . Daily values for the pain scales are shown in the P = .23) and a significant main effect for postoperative day , indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group  on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine  during 3 postoperative days. Daily values for supplemental opioid use are shown in the P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2  and postoperative day 3 . In nonparametric mixed model analysis, the main effect of drug was not significant , but the main effect of postoperative day was significant  and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (t differ . One patP < .001), but treatment group  and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine  were significant . Total opioid use was not different . Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1  and 2  but not day 3 , irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group , liposomal formulation was associated with less pain control than standard formulation , but no treatment-by-day interaction was identified.Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types  by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.


The visceral analgesic efficacy of erector spinae plane block (ESPB) is still a matter of debate. This study attempted to investigate the visceral analgesic efficacy of ESPB in clinical setting. After randomized, we performed ultrasound-guided bilateral rectus sheath block (RSB), which was aimed to prevent postoperative somatic pain on all patients who underwent laparoscopic cholecystectomy (LC). Ultrasound-guided bilateral ESPB at T7 level was performed only to the intervention group to provide the visceral analgesic block. The intraoperative requirement for remifentanil (P = 0.021) and the cumulative fentanyl consumption at postoperative 24-hours was significantly lower in the ESPB group  compared to non-ESPB group. The ESPB group consistently showed lower accumulated analgesic consumption compared with those in the non-ESPB group at all observed time-points  after 2 hours and the degree of the accumulated analgesic consumption reduction was greater (P = 0.04) during the 24-hour postoperative period. Pain severity was lower in the ESPB group at 6-hours postoperatively. The significantly reduced opioid consumption in ESPB group may imply that while preliminary and in need of confirmation, ESPB has potential visceral analgesic effect. Therefore, performing ESPB solely may be feasible in inducing both somatic and visceral analgesia. Targeting the space between the erector spinae muscle sheath and the transverse process of a vertebra, the injected agent spreads craniocaudally, resulting in the blockage of multiple vertebral levels, covering a wide area. Of note, it penetrates anteriorly into the paravertebral space where it can theoretically block not only the dorsal and ventral rami, but also the rami communicantes3, which suggests the potential of both somatic and visceral pain blockage.Since its first description in 2016 by Forero 4. The components of acute postoperative pain are consisted of somatic, visceral, and referred pain. Visceral pain is considered to be the co-dominating pain component, along with somatic pain, within 24 hours after LC6. Furthermore, early visceral pain is associated with an unexplained chronic pain development 1-year after LC7.Laparoscopic cholecystectomy (LC), although minimally invasive compared to open surgery, is associated with significant levels of postoperative pain8. For these reasons, ESPB is gaining popularity quickly despite it being a recently introduced technique. To date, its analgesic efficacy has been described in abundance in case reports9; however, only few controlled clinical trials after abdominal11, cardiac13, and breast surgery14 have been reported. Few cadaveric studies have showed that the injected dye penetrates to paravertebral space and spread into rami communicantes3, however, controlled clinical studies evaluating the visceral analgesic efficacy of ESPB have not been performed. In the previous study by our group, the preoperative rectus sheath block (RSB) effectively reduced the analgesic requirement15, however most of the patients complained the residual visceral pain, referring it as “pain from inside”.In this setting, performing ESPB as postoperative analgesic method may efficiently provide somatic and visceral pain block and overcome the current limitations of neuraxial and peripheral regional block. It is considered as a peri-paravertebral regional analgesia technique with a mechanism of action similar to that of the paravertebral block; however, it is technically easier and has lower risk of major complications, such as pneumothorax or accidental neuraxial injectionTherefore, we designed this randomized, single-blind trial to investigate the efficacy of ESPB in visceral pain analgesia. Specifically, we performed RSBto prevent somatic sensory pain in patients undergoing LC and hypothesized that ESPB may provide additional pain relief by alleviating the visceral pain. The primary outcome was to assess the effect of ESPB on the cumulative consumption of a rescue analgesic over 24 postoperative hours. The secondary outcomes were the intraoperative remifentanil requirement and postoperative pain score.A total of 60 patients were enrolled and 53 were included in the final analysis Fig. . Of all,The intraoperative requirement for remifentanil was significantly lower in the ESPB group compared to that in the non-ESPB group  during the 24-hour postoperative period. The mean difference in cumulative analgesic consumption at 6 postoperative hours was 41.9 mcg , which significantly increased to 77.2 mcg  at 24 postoperative hours.The NRS score at 6 hours postoperatively was significantly lower in the ESPB group than in the non-ESPB group (2 2-3) vs. 3 (3-5), P = 0.029); however, there was no difference in the NRS scores between the other time points  and there is no difference in NRS between the two groups. In this study, the RSB was performed in all patients to prevent the somatic pain, which reduced postoperative pain and decreased opioid consumption in the control group15. In addition, because of rescue analgesics was administered when NRS was ≥ 4 or when the patient needed pain relief, we thought that the NRS was not significantly difference between two groups. “Due to the design of the current study, routine analgesia was not provided but only upon the patients’ request or NRS ≥ 4, which may have resulted relatively higher NRS score in current study compared to the data reported by previous studies. Although ESPB is an effective analgesia approach especially in the first 6-8 hours, the patients should receive routine analgesia not to develop a pain-memory”. Furthermore, based on these reasons, the current study does not justify using two different blocks in patients undergoing LC. The value of our results lies that it is the first to report the effectiveness of ESPB focusing on the visceral analgesic effect in clinical setting, which may assist broadening the ESPB indication in perioperative pain management.Our study has several limitations. First, we did not check the sensory distribution of ESPB. One of the reasons is the postoperative hyperaesthetic state of the abdomen due to the pneumoperitoneum, and the other is that the use of opioid after surgery may have changed the pain threshold. Taken together, the exact dermatome by pin-prick test would not be feasible. However, we visually confirmed that the local anaesthetics were well spread in the transverse and the sagittal view in all patients receiving ESPB with ultrasound, therefore we may speculate that ESPB was well performed. Second, we did not provide somatic pain block for the epigastric and subcostal 5 mm trocar area. However, it is reported that the port size is related to pain and 5 mm is shown to induce less postoperative pain after laparoscopic surgeryUltrasound-guided ESPB with RSB reduced the intraoperative remifentanil requirement and cumulative analgesic consumption in the first 24 hours in patients undergoing LC compared to that in patients using RSB only, suggesting the potential visceral analgesic effect of ESPB. Although further clinical studies are needed to clarify the extent of analgesia, our results show that ESPB may be an effective technique for the management of postoperative visceral pain.This is a single-center, prospective, randomised, single-blind trial. All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Institutional Review Board of Asan Medical Center, Seoul, Republic of Korea (2018-1320). This study was registered on December 07, 2018 at clinicalTrials.gov (NCT03767816) prior to patient enrolment.33, those with a single port insertion, patients with intraoperative bile duct injury, and those who maintained percutaneous drainage after surgery. Patients were randomized into two groups (ESPB group and non-ESPB group) according to a computer-generated randomization schedule created before the study start. Patients in the ESPB group received bilateral ESPB before general anaesthesia induction, whereas bilateral RSB were performed immediately after anaesthesia induction. In non-ESPB group, only bilateral RSB were performed immediately after induction and prior to incision. The regional blocks and anesthesia were performed by one of two investigators (H.-M. Kwon or J.-H. Lee). Subsequent data collection was performed by the blinded study research coordinator or a blinded study investigator.Patients scheduled for elective LC between December 17, 2018 and January 29, 2019 were screened for eligibility. Patients aged 20–80 years with an American Society of Anesthesiologists physical status class 1 or 2 were eligible for the study. Exclusion criteria were as follows: contraindications for regional anaesthesia, such as history of local anaesthetic allergy or steroid complication; use of anticoagulants; pregnancy or breastfeeding; history of previous abdominal surgery; pre-existing vertebra or chest wall abnormality; and refusal to participate. The study also excluded patients with severe intraperitoneal inflammation or adhesions of cholecystitis (Parkland grade > 3)et al.1. After placing the patient in a prone position, a NextGen LOGIQe ultrasound console  with a 12 MHz high-frequency linear ultrasound transducer was placed in a longitudinal orientation 3 cm lateral to the T7 spinous process. Since ribs articulate posteriorly with the corresponding thoracic vertebra, we visualized the 12th rib and counted from there to the 7th rib to confirm the location of T7 thoracic vertebra. After identifying the fascia of erector spinae muscle superficial to the tip of the transverse process, under aseptic conditions, a 22-gauge Quincke needle  was inserted in a caudal-to-cephalad direction by in-plane technique, until the needle tip touched the tip of the transverse process of T7 vertebrae and was laid in the fascial plane on the deep aspect of the erector spinae muscle. The location of the needle tip was confirmed by a visible linear spread of fluid lifting the erector spinae muscle off the transverse process on ultrasonographic imaging. A total of 20 mL of 0.20% ropivacaine was injected on one side. The same procedure was performed with 20 mL of 0.20% ropivacaine on the contralateral side.ESPB was performed according to a standardized method, as previously described by Forero RSB was performed after identifying the rectus abdominis muscle by placing the ultrasound probe in a transverse orientation next to the incision site, which was 1 cm below the umbilicus, and a 22-gauge Quincke needle  was inserted in-plane, medial-to-lateral direction to place the needle tip in the plane between the lateral side of the rectus abdominis muscle and the posterior rectus sheath. After confirming the needle tip by visible linear spread lifting the rectus sheath muscle, 15 mL of 0.20% ropivacaine was administered, and the same procedure was repeated on the opposite side.LC was performed using a three-port surgical technique according to our hospital protocol. In all patients, a 12 mm port was placed at the 1 cm below umbilicus, 5 mm port in the epigastric area, and another 5 mm port was placed on the right subcostal area. Non-humidified and non-heated CO2 were used to achieve pneumoperitoneum and the intra-abdominal pressure was maintained to be lower than 13 mm Hg in all patients.34. Changes of the intraoperative blood pressure were maintained within 20% from the baseline values. After emergence from anaesthesia, patients were transferred to the post-anaesthetic care unit (PACU) where pain was assessed and recorded by nursing staff using an 11-point Numerical Rating Scale (NRS). Intravenous fentanyl bolus (0.4 µg/kg) was administered upon patients’ request or when analgesia was insufficient (NRS ≥ 4). Administration of fentanyl was repeated until NRS < 4 or the patient did not request further pain relief. After transferring to the general ward, 50 mg of dexketoprofen, and 50 mg of tramadol or 25 mg of meperidine were administered in sequence only upon patient request or NRS was ≥ 4.In the operating room, routine monitoring included electrocardiography, non-invasive blood pressure measurement, and pulse oximetry. After induction of anaesthesia using propofol (2 mg/kg), rocuronium (0.6 mg/kg) was administered and endotracheal intubation was performed. Balanced anaesthesia was maintained using desflurane (5–6%) in 50% oxygen and a continuous infusion of remifentanil . Remifentanil was maintained under 2.7 ng/ml to avoid postoperative hyperalgesiaThe primary outcome was the difference in the 24-hour postoperative cumulative rescue analgesic consumption between patients in the ESPB and non-ESPB group. Secondary outcomes were intraoperative remifentanil consumption and postoperative pain score, evaluated by NRS.35. Cumulative analgesic consumption and the NRS were measured at 0, 0.5-, and 1 h at the PACU, and at 2-, 6-, 12-, 18- and 24-h at the general ward after the surgery.The baseline pain level prior to surgery was evaluated by a single investigator to exclude any underlying visceral pain. Because this study was intended to evaluate the efficacy of ESPB in alleviating visceral pain, the patients with predominant somatic pain after the RSB were exclude from further analysis. Given that objectively differentiating pain component is difficult in clinical setting, an investigator, who was blinded to the treatment allocation, asked the patients if they had any ‘resting superficial pain’ and further confirmed by giving pressure on the umbilical port incision site to check for any residual resting somatic pain at PACU. Postoperative pain intensity was assessed using a single 11-point NRS (in which 0 = no pain and 10 = worst pain imaginable). Nursing staff blinded to the randomization administered intravenous rescue analgesics and recorded the total doses of rescue analgesics during the 24-hour postoperative period. The doses of all opioids and nonsteroidal anti-inflammatory drugs administered to patients were converted to intravenous fentanyl equianalgesic doses based on previously published conversion factors (intravenous fentanyl 100 μg = ketorolac 30 mg = tramadol 100 mg)33 by the operating surgeon based on visual inspection. The surgical procedure characteristics related to visceral pain, such as the duration of surgery, peak abdominal gas pressure, severity of gallbladder bed injury during surgery, or rate of intraoperative bile leakage, were also compared between the groups. The severity of gallbladder bed injury was reported by the surgeon as follows: 1. insignificant injury to the liver; 2. mild injury to the liver; and 3. moderate injury to the liver. Vital signs were recorded, such as mean blood pressure (mm Hg) and heart rate (beats per minutes), measured before the incision, and the maximum value after the incision and before the induction of pneumoperitoneum. Furthermore, the adverse effects of analgesics, such as nausea and vomiting, and the complications associated with ESPB or RSB procedure, such as hematoma or pneumothorax, if any, were also recorded.Additional factors associated with visceral pain, such as the severity of adhesions and the cholecystitis inflammation status were graded according to the Parkland scale (range 0–5)15, we expected that the postoperative 24-hour cumulative fentanyl consumption would be 220 ± 86 μg in patients receiving RSB. Sample size estimation, with a power of 80% and an alpha error of 0.05, showed that 25 patients in each group would be needed to reach significance of the 20% reduction of the 24-hour fentanyl consumption in patients receiving RSB and ESPB. To be able to compensate for an incomplete data collection or patients dropping out, a total of 60 patients were recruited.Based on our previous study36Continuous parameters were summarized as mean (± standard deviation) or median (interquartile range), and categorical parameters as frequency (percentage), as appropriate. Between-group comparisons were evaluated using the Student’s t-test or Mann–Whitney U-test for continuous variables, and the Chi-square or Fisher’s exact test for categorical variables, as appropriate. The repeated measurements of cumulative fentanyl consumptions were performed using a linear mixed-effect model to evaluate the interaction of time and treatment between the ESPB and non-ESPB groups. Statistical significance was set at P < 0.05. Data manipulation and analyses were performed using R software, version 3.6.2 Supplementary Information.