N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 . Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)—an open-label, global, multicohort trial—evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 ( In a phase 3 trial, selection of non-small cell lung cancer patients based on high blood-based tumor mutation burden did not improve clinical response to the checkpoint blockade inhibitor atezolizumab, as compared with standard of care platinum-based chemotherapy. TMB in both tissue and blood is currently being explored in non-small cell lung cancer (NSCLC)3. tTMB, determined by whole-exome sequencing, is associated with clinical benefit from multiple checkpoint inhibitors at various cutoffs10. Assessing TMB using large comprehensive gene panels to target a portion of the genome has been shown to correlate with whole-exome sequencing15. TMB is associated with predicted neoantigen load and also predicts clinical benefit of anti-programmed death-ligand 1 (PD-L1)/programmed death 1 (PD-1) treatments in NSCLC16. Evidence from mostly retrospective analyses of clinical trials in the first- (1L) or second-line treatment of NSCLC suggests that TMB predicts the efficacy of PD-L1/PD-1 inhibitor monotherapy, but not in combination with chemotherapy3, and that tTMB is positively correlated with bTMB17. In NSCLC, retrospective analyses have shown TMB is independent of PD-L1 expression and seems to be potentially predictive of progression-free survival (PFS) benefit, but not of overall survival (OS), with checkpoint inhibitor monotherapy20. However, prospective Phase 3 trials using TMB as a predictive biomarker are lacking.TMB has emerged as a biomarker for cancer immunotherapy as demonstrated by the approval of pembrolizumab for the treatment of selective solid tumors that are tissue-based (t)TMB highEGFR/ALK alterations whose tumors have high PD-L1 expression. The Phase 3 IMpower110 trial (N = 572) enrolled patients with NSCLC with PD-L1-positive tumors. Patients with high PD-L1 expression, defined as ≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells assessed by the SP142 immunohistochemistry (IHC) assay (Ventana), showed a median OS of 20.2 months with atezolizumab monotherapy versus 13.1 months with platinum-based chemotherapy (hazard ratio (HR), 0.59; 95% confidence interval (CI): 0.40, 0.89; P = 0.0106)18. However, OS benefit was not observed in the patient subgroup consisting of high or intermediate PD-L1 expression (≥5% of tumor or tumor-infiltrating immune cells). Additionally, among patients with any tumor PD-L1 expression and bTMB of ≥16 ; Foundation Medicine, Inc, Cambridge, MA), patients given atezolizumab had longer PFS than patients given chemotherapy , suggesting a cooperative predictive value between these independent biomarkers18. Therefore, a biomarker such as bTMB that is independent of PD-L1 and can select patients who benefit from PD-L1/PD-1 inhibitors could help broaden access to 1L chemotherapy-free treatment options. Furthermore, given that up to 30% of patients have insufficient tissue at diagnosis for comprehensive biomarker testing21, a blood-based assay for TMB that would obviate the need for tTMB analysis could identify patients who benefit from atezolizumab therapy22.Atezolizumab monotherapy is effective for the 1L treatment of patients with squamous or nonsquamous advanced or metastatic NSCLC without N = 152) was the first prospective Phase 2 study evaluating bTMB as a biomarker for 1L atezolizumab monotherapy in locally advanced or metastatic NSCLC23. The primary efficacy objective of this single-arm open-label trial was objective response rate (ORR); the primary biomarker objective was the relationship of investigator-assessed (INV) PFS in patients with bTMB of ≥16. The trial met its primary efficacy endpoint but not the primary PFS-related biomarker objective. However, incremental increases in ORR were observed with increasing bTMB cutoffs.B-F1RST  is a global, open-label, multicohort trial evaluating the safety and efficacy of targeted therapies or immunotherapy in patients with previously untreated unresectable Stage IIIB–IV NSCLC selected for several different biomarkers, including driver mutations and TMB, using a blood-based next-generation sequencing assay  Companion Diagnostic (CDx) next-generation sequencing assay is a United States Food and Drug Administration-approved assay that targets 0.8 Mb and reports bTMB as the number of mutations per megabase. Here, we report primary results from BFAST cohort C and the exploratory outcomes when using the F1L CDx assay results.The Blood First Assay Screening Trial  or chemotherapy , ROS1 (n = 1), RET (n = 1), HER2 exon 20 insertion (n = 1) and EGFR exon 20 insertion (n = 1).Patients were enrolled at 120 centers across 25 countries. From 22 September 2017 to 21 November 2019, 6,507 patients were screened, 1,437 of whom (22.1%) had a score of bTMB of ≥10; 472 patients were enrolled in the intent-to-treat (ITT) population and randomized to atezolizumab  in the chemotherapy arm at 12 months and 14%  versus 1% , respectively, at 18 months , the minimum follow up in the bTMB ≥16 population was 6.0 months . For the primary efficacy endpoint, INV-PFS, there was no significant difference in PFS between arms, with 243 (84%) of events having occurred , respectively, at 18 months  in the atezolizumab arm versus 10.3 months  in the chemotherapy arm , there was no difference between treatment arms in either PFS , with a median treatment duration of 3.5 months (Supplementary Table P < 0.1), including liver or bone metastasis, higher baseline SLD, squamous histology and presence of KEAP1 mutations. In the chemotherapy arm, early progression was associated with liver, adrenal gland or brain metastasis, or greater number of metastatic sites overall, higher SLD or tumor mutations in SMARCA, ASXL1 or CDKN2A (P < 0.05).In general, this exploratory analysis suggested that early progression ≤4 months) in the bTMB ≥16 population was associated with greater disease burden at baseline, as shown by the presence of more metastatic sites or higher sum of the longest diameters (SLD) compared with late progression  in the chemotherapy arm at 12 months, and 12%  versus 1% , respectively, at 18 months  for atezolizumab versus 4.2 months  for chemotherapy , respectively, at 18 months  with atezolizumab versus 10.6 months  with chemotherapy  and a median OS of 23.9 versus 13.4 months . Although there was no significant difference in PFS observed in BFAST between atezolizumab and chemotherapy in the population with high bTMB, progression-free rates were 24%  in the atezolizumab arm versus 7%  in the chemotherapy arm at 12 months and 14%  versus 1% , respectively, at 18 months. Therefore, the later timepoints for PFS may better represent the outcomes of the study than the HR, as shown by the shape of the Kaplan–Meier curves, suggesting that the proportional hazards assumption may not have been met. Progression rates were initially higher in the atezolizumab arm than in the chemotherapy arm. However, the curves crossed at approximately 4 months and eventually favored atezolizumab. This Kaplan–Meier ‘crossover gap’ in PFS has been observed in multiple other Phase 3 trials of anti-PD-L1/PD-1 monotherapy versus chemotherapy and may reflect a subset of patients who respond better to cytotoxic chemotherapy and are refractory to an anti-PD-L1/PD-1 agent27. Similarly, although secondary endpoints were not formally tested, patients in the atezolizumab arm had a numerically longer OS than the chemotherapy arm. Furthermore, a greater percentage of patients achieved longer-term survival at 12 and 18 months, with the Kaplan–Meier curves crossing. Moreover, the overall safety profile of atezolizumab monotherapy was consistent with that seen previously across indications28.Although checkpoint inhibitor therapy has been demonstrated to improve OS versus chemotherapy in several Phase 3 trials in the first-line treatment of advanced stage NSCLC, only a minority of patients sustain long-term survival benefit, regardless of PD-L1 status. Thus, there is a continuing unmet need to define additional predictive biomarkers of the efficacy of checkpoint inhibitors. In this regard, TMB has been shown to be largely nonoverlapping and complementary to PD-L1 status in multiple retrospective analyses29. Lung adenocarcinoma in particular displays a bimodal distribution consisting of high mutation (smokers) and low mutation burden (never/light-smokers and oncogene-driven cancers)30. Furthermore, there are also qualitative differences related to highly neoantigenic tobacco-related transversion mutations, which are more common in squamous lung cancers29. Among patients with nonsquamous histology in BFAST, those with bTMB ≥16 showed a greater benefit of atezolizumab versus chemotherapy. In contrast, bTMB level was not effective in predicting immunotherapy activity in those with squamous histology, characterized by a more homogeneous smoking status29 and a higher TMB31 than with nonsquamous histology. In this disease context, a distinct nonantigenic pattern of mutations, including subclonal smoking-related alterations, might explain the heterogenous pattern of clinical outcomes from atezolizumab monotherapy when patients are selected based on high bTMB.In the PFS analysis for atezolizumab versus chemotherapy in subgroups defined by baseline disease characteristics, the nonsquamous histological group with bTMB ≥10 had an HR of 0.82 , while those with bTMB ≥16 had an HR of 0.68 . In the squamous group, those with bTMB ≥10 had an HR of 1.00 , and those with bTMB ≥16 had an HR of 1.14 . Smoking-related mutational burden, a large contributor to overall mutation burden, is reported to differ both quantitatively and qualitatively between squamous lung cancers and lung adenocarcinoma. Those with squamous histology have a higher TMB and, most importantly, a more homogeneous TMB distribution than those with nonsquamous histology18), CheckMate 026 (ref. 4) and 227 (ref. 25) and MYSTIC9, as well as in real-world settings32, the population enrolled in this study, albeit bTMB-selected, seemed to have more indicators of a poor prognosis: SLD at baseline was higher and the proportion of steroid use required for adverse events was higher. However, the prevalence of ever-smokers was higher, which may have contributed to greater benefit of atezolizumab versus chemotherapy33. The rate of patients receiving subsequent therapy . bTMB determined by F1L CDx also showed improving PFS HRs at higher cutoffs, suggesting that the predictive power of bTMB may be improved by the selection of a different cutoff. This trend also suggests that bTMB is a continuous biomarker of outcomes. Selecting a single cutoff for a biomarker of clinical response, while perhaps more practical for clinicians to identify patients, has the disadvantage of making it more difficult to achieve statistical significance with a given sample size. Trial designs that dichotomize the clinical outcomes around a single cutoff can lose as much as a one-third of their statistical power34. In contrast, adaptive trial designs that can accommodate continuous and even nonlinear predictive effects  may more accurately model the characteristics of bTMB and be able to categorize patients who benefit from treatment35. Furthermore, differences in the computational pipeline between the bTMB CTA and F1L CDx may also play a role in the differences observed. Insertion and deletion mutations (indels) were not included in the bTMB calculation for the bTMB CTA but were included in the calculation for F1L CDx. This might have contributed to the slight differences in clinical outcomes, due potentially to the greater association of indel mutations with antitumor antigenicity compared with SNVs, for example36. Therefore, further study is required to validate bTMB as a standalone biomarker for the benefit of immunotherapy.A formal clinical bridging study was planned if the trial was positive to establish clinical concordance between bTMB cutoffs from the bTMB CTA and the F1L CDx assay. However, because the trial was negative, the analytical concordance and corresponding efficacy analyses were exploratory. Interestingly, PFS in cohort C using F1L CDx was longer with atezolizumab than with chemotherapy, with a PFS HR of 0.71  MSAF patients.Additional factors that can impact either the bTMB score or the predictive power of bTMB include the overall fraction of tumor DNA measured in the blood, and variants derived from clonal hematopoiesis of indeterminant potential (CHIP). Patients with very low or undetectable tumor content, as measured by MSAF, have shown better responses and PFS with atezolizumab compared with patients who have high MSAF39, and the bTMB calculation uses an allele frequency cutoff of ≥0.5%. Second, many CHIP alterations are also cancer driver mutations that are filtered from the final bTMB score39. Therefore, low MSAF and CHIP mutations likely did not contribute to the negative BFAST results.CHIP mutations have the potential to inflate the bTMB score, although we estimate their impact on this assay to be mitigated for the following reasons. First, it has been shown that CHIP variants tend occur at low allele frequencies40. Cancer immune surveillance can be abrogated not only by exhaustion of the T cell response, but also by impaired neoantigen presentation because of somatic HLA-I LOH. TMB and HLA-I LOH are independent predictors of OS41. However, refinements of TMB that can account for HLA-I LOH are under investigation42.Loss of heterozygosity (LOH) at the human leukocyte antigen class I (HLA-I) locus could be a method to improve the utility of TMB. High TMB is assumed to increase production of tumor neoantigens and hence lead to increased specific T cell response44. Notably, STK11 loss might lead to immune evasion through methylation-induced suppression of STING.Other factors have also been shown to induce antitumor activity via type 1 interferon and T cell recruitment, which have not been evaluated in BFAST. For example, analyses have suggested that cytosolic DNA fragments derived from defective DNA damage response and repair mechanisms influence the response to immune checkpoint inhibitors by triggering the stimulator of interferon genes (STING) signaling pathwayCXCL9, CD8A, CD274 and CXCL13)10. A recent analysis suggests that the prediction of clinical benefit using the bTMB assay may be further optimized by incorporating it into multiparameter models45.Although the current results based on the bTMB CTA did not support bTMB ≥16 as a standalone predictive biomarker in 1L immunotherapy of NSCLC, the utility of bTMB as a predictive biomarker may be improved when combined with other relevant biomarkers, such as genes for immune infiltration 23 and, consequently, to the lack of predictive value for bTMB in this study.A main limitation of this study is that PD-L1 status was not known because tissue collection was not mandated and PD-L1 testing information was not collected from local sites. Additionally, during the enrollment period, pembrolizumab monotherapy was the preferred option for the 1L treatment of patients with a PD-L1-staining tumor proportion score ≥50% and was available in many countries in combination with pemetrexed and cisplatin or carboplatin, regardless of PD-L1 expression. Therefore, enrollment in the trial was potentially biased considering that eligible patients had the choice between these two pembrolizumab-based regimens or participating in BFAST, in which the control arm was chemotherapy only. This bias potentially contributed to approximately 20% of patients eligible by bTMB level either choosing an alternative treatment or withdrawing consent before randomization—a substantial proportion that could have affected the external validity of the primary results. Furthermore, approximately 7% of patients in the chemotherapy arm did not receive the planned treatment. Although we and others have shown that TMB is independent of PD-L1 IHC in predicting the benefit of single-agent anti-PD-L1 therapy, we have also shown that patients who are positive for both PD-L1 expression and TMB derive the most benefit18. Further studies are needed to explore such associations.In summary, although using the bTMB CTA at a cutoff of ≥16 was not a predictive biomarker for atezolizumab outcome as tested in this study, the 18-month PFS and OS both numerically favored atezolizumab in the bTMB ≥16 group. By using the F1L CDx assay at an equivalent cutoff of bTMB ≥13.6 mutations per megabase, atezolizumab showed improved PFS versus chemotherapy. Additional exploration of bTMB to identify and validate optimal cutoffs or employ new adaptive trial designs to accommodate the continuous and complex nature of bTMB are warranted, as are studies to account for confounding factors such as HLA-I LOH. bTMB may have utility in combination with other relevant biomarkers  to identify subgroups that may be responsive to 1L treatment with checkpoint inhibitors in NSCLC–1) as detected via the bTMB CTA and a treatment-free interval of ≥6 months if they had received previous neoadjuvant or adjuvant treatment. Key exclusion criteria included untreated brain metastasis, history of malignancy other than NSCLC in the past 5 years and presence of an oncogenic EGFR mutation or ALK fusion. As the goal of this study was to evaluate bTMB as a predictive biomarker to identify treatment for most of the patients in the 1L setting, including those who are not able to submit adequate tissue for molecular profiling, tissue was not required for enrollment. However, patients were stratified by investigator-reported tissue availability. Due to the umbrella design of the trial, in which numerous therapies were tested in biomarker-selected populations, results of local biomarker tests were not collected because of the number of tests available. Patients were also stratified by bTMB cutoff (bTMB ≥16 (13.6 mut Mb–1) versus between bTMB ≥10 and bTMB <16), ECOG PS (1 versus 0) and histology (nonsquamous versus squamous). Cancer driver genes were defined based on their status in the Catalog of Somatic Mutations in Cancer46 or evidence from literature supporting their pathogenicity status. This literature evidence must demonstrate that the mutations in the tumor suppressor gene results in loss of function. The cancer driver genes are maintained in a database at Foundation Medicine Inc. (FMI) that is updated over time as new clinical evidence emerges. Pathogenic mutations in CHIP-related genes were filtered from the bTMB calculation. Single nucleotide substitutions detected at an allele frequency of ≥0.5% were filtered for germline and driver mutations and were included in the bTMB score17. Samples with low tumor content within a circulating free DNA sample as measured by MSAF < 1%, were below the limit required to make reproducible bTMB determinations. bTMB was shown to be a continuous variable, and a cutoff of bTMB ≥16 was selected for further investigation based on a retrospective analysis of PFS in patients with NSCLC treated with second-line or later atezolizumab monotherapy47. Validation of the assay using Phase 3 data in the second-line or later NSCLC treatment setting48 showed PFS benefit at bTMB ≥16 , and the lowest cutoff with PFS benefit was bTMB ≥10 17. Based on these results, BFAST cohort C defined the bTMB CTA enrollment criterion as bTMB ≥10 mutations, and the primary endpoint was evaluated at the bTMB ≥16 cutoff. Enrolling at the bTMB ≥10 cutoff while stratifying at the bTMB ≥16 cutoff enabled clinical evaluation of multiple cutoffs within cohort C.BFAST is an ongoing global, open-label, multicohort trial. Cohort C used a randomized, Phase 3 trial design. The study protocol is available as a The study was conducted in accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki, and all patients provided written informed consent. The study protocol was approved by institutional review boards of participating institutions, including the Ontario Cancer Research Ethics Board (OCREB)  and the University of Saskatchewan Biomedical Research Ethics Board (Saskatoon Cancer Centre).–2 in combination with cisplatin (75 mg m–2) or carboplatin (area under the concentration curve 5 or 6) IV with optional maintenance pemetrexed allowed. Patients with squamous disease received gemcitabine 1,250 mg m–2 plus cisplatin 75 mg m–2 or gemcitabine 1,000 mg m–2 plus carboplatin area under the concentration curve 5 IV for four or six cycles per local standard of care.Patients were randomized 1:1 by a stratified permuted-block randomization procedure via interactive voice or Web-based response system to receive atezolizumab 1,200 mg intravenously (IV) every 3 weeks until disease progression or loss of clinical benefit, or platinum-based chemotherapy every 3 weeks for four or six cycles per local standard of care. Patients with nonsquamous disease received pemetrexed 500 mg m–1) by F1L CDx.The primary endpoint evaluated in the bTMB ≥16 population, as determined by the bTMB CTA, was INV-PFS, defined as time from randomization to disease progression according to RECIST 1.1 or death. Secondary endpoints included OS, defined as time from randomization to death from any cause, in the bTMB ≥16 population, INV-PFS and OS in the bTMB ≥10 (ITT) population, PFS by independent review, ORR and DOR by INV and independent review. Safety and tolerability were assessed by incidence, type and severity of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse events v.4.0. A post hoc exploratory analysis compared the bTMB CTA used to select patients in BFAST with the F1L CDx assay, and clinical outcomes were analyzed in patients who were bTMB positive , histology (nonsquamous versus squamous), and tissue availability (yes versus no). In the bTMB ≥10 population, the stratification factors were ECOG PS (0 versus 1), histology (nonsquamous versus squamous), bTMB cutoff (bTMB ≥10 to <16 versus bTMB ≥16), and tissue availability (yes versus no). If significant, the secondary endpoints were hierarchically tested at the two-sided α = 0.05 significance level (for each endpoint) in the order of OS in the bTMB ≥16 population, PFS in the bTMB ≥10 population then OS in the bTMB ≥10 population. Clinical analyses were performed using SAS (v.9.4). Biomarker exploratory analyses were performed using R (v.3.6.1).Approximately 440 patients were planned to be enrolled in the bTMB ≥10 population, including 280 in the bTMB ≥16 population based on a one-sided significance level of 0.025 each for the comparison in the bTMB ≥10 and bTMB ≥16 populations and 95% power to detect an HR of 0.6 in the bTMB ≥16 population and 0.65 in the bTMB ≥10 population. The primary PFS endpoint in the bTMB ≥16 population was statistically tested at the P < 0.1. Fisher’s exact test was used to assess the association between early disease progression and binary clinical variables. For continuous clinical variables, a t-test was used.To explore factors associated with early disease progression, patients whose disease had progressed within 4 months were analyzed for baseline characteristics and genomic alterations. The analysis included the bTMB ≥16 population and was performed in each treatment arm, and in both arms combined, with a significance cutoff of The F1L CDx assay was intended to be the assay for CDx registration but was not available at the time of study start. Per the prespecified statistical analysis plan, a clinical bridging study would have been executed to bridge the efficacy of the study from the bTMB CTA to the CDx. However, due to the negative outcome of the primary endpoint, only an analytical concordance was performed with the bTMB CTA, and efficacy analyses were exploratory.The analysis set for the concordance study comprised available samples from all enrolled patients, excluding those who withdrew consent, for a F1L CDx biomarker-evaluable population of 426  for the first 48 weeks following treatment initiation and then every 9 weeks thereafter, regardless of dose delays, until disease progression per RECIST v.1.1 or loss of clinical benefit for patients receiving atezolizumab past disease progression. Whole blood for laboratory assessments was collected at screening, Day 1 (±3 days) of each treatment cycle and discontinuation. The incidence and severity of adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v.4.0 at each patient contact.Further information on research design is available in the Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-022-01933-w.Supplementary InformationSupplementary Tables 1–7.Reporting SummarySupplementary DataBFAST study protocol v.6.


To manage chronic pain, multidisciplinary interventions have been increasingly deployed, mostly in secondary or tertiary care settings. Evidence on the effectiveness of multidisciplinary intervention within primary care is scarce. This study examined the effectiveness of a primary care multidisciplinary treatment for chronic pain compared with treatment as usual (TAU). The intervention consisted of pain neuroscience education and treatment by a GP, psychologist, and physiotherapist. Both groups filled out patient-reported outcome measures at baseline, 6 months, and 12 months. The results indicated there were no statistically significant differences for the primary outcomes of pain intensity, number of pain sites, and health-related quality of life (HR-QoL). There was a statistically significant difference in the secondary outcome perceived health change in favor of the intervention group. None of the other differences were statistically significant. A post-hoc analysis showed that there were statistically significant effects on patients’ illness perceptions in favor of the intervention group. Based on the results, the findings do not support effectiveness of a low intensity outpatient multidisciplinary primary care treatment to treat chronic pain compared with TAU. However, as a result of several study limitations, it is considered unwarranted to conclude that multidisciplinary treatment in primary care is not valuable at all.  Chronic pain is a significant problem for a large number of people. It is estimated that about 20% of the European population suffers from chronic pain . The majMulti- or transdisciplinary assessments and treatments are recommended because chronic pain is a biopsychosocial problem, in which pain is influenced and maintained by physical, psychological, and social factors . NegativGiven the above, current guidelines for the treatment of chronic pain recommend a multidisciplinary approach within the primary-care setting ,14,15. WThere are several potential barriers that obstruct the implementation of such an approach, such as the readiness of different health disciplines, structural supports from the health system, scheduling issues, lack of physical space, and the ability to bundle costs . As a reA multicenter, non-randomized, controlled trial was conducted with a 12-month follow-up period.https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6014, accessed on 16 January 2023).Two groups of patients were included in this study: an intervention group and a control group. The study design and informed consent procedure were approved by the Medical Ethics Committee of Amsterdam UMC, location VUMC. The trial is registered under number NTR6014 , we concluded that 28 participants should be included per group to detect a clinically relevant between-group difference of 2 points on the VAS (SD = 2.7). Considering a dropout rate of 30%, it was concluded that a total of 80 participants should be included in this study (40 participants per group). The 2-point difference on the VAS was based on the previously identified Minimal Important Change of the NRS (or VAS) of 2 points . In addiBoth study groups consisted of patients with chronic non-specific pain. To be eligible for the current study, patients had to experience chronic non-specific pain for a period longer than 6 months, had to be aged between 18–70 years, had to have consulted a general practitioner for their chronic pain during the last 3 months, and had to have no prior treatment with cognitive behavioral therapy aimed at treating chronic pain-related psychological issues. Exclusion criteria were: pain as a result of cancer or neurological conditions , being diagnosed with cognitive impairments, current severe psychiatric problems, not able to complete online questionnaires, or not able to speak/understand Dutch.Participants for the intervention group were recruited at three general practices. General practitioners (GPs) working at these practices identified eligible patients in their practice, and invited them to take part in the multidisciplinary program. The multi/transdisciplinary program under study was implemented in these practices several years before the trial started. All patients who entered the multidisciplinary program in these practices and met the in- and exclusion criteria were asked to participate in the trial. All patients were provided with an informed consent form, which they were asked to sign upon entering the trial.Participants for the control group were recruited via advertisements on social media . Control group patients did not receive the treatment under study; instead, they received treatment at general practices other than those providing the intervention. To keep both groups as similar as possible, only patients living in the same geographical area as the patients in the intervention group  were recruited for the control group. Upon entering the study, all participants received written information about the study and were to provide informed consent.www.survalyzer.com). All data were anonymized by removing personal information. Data were exported to SPSS and stored on a password-protected computer. The password was changed on a regular basis. Participant files were stored for a period of 5 years after the completion of the study, after which the files were removed.Data were handled in accordance with the Dutch Personal Data Protection Act. Data were gathered electronically using survey software  ≥ 7Central Sensitization Inventory (CSI) > 40Pain Catastrophizing Scale (PCS) > 30Pre-intake: After being referred for a multidisciplinary assessment, patients were asked to fill out patient-reported outcome measures (PROMS), assessing various outcomes, such as pain-related outcome measures and socio-demographic characteristics , somatic and medical factors (S), cognitions and perceptions (C), emotional factors (E), behavioral factors (B), social factors (S), and motivation (M) . Both thDepending on the information found in the assessment and the biopsychosocial factors that were determined, a treatment plan was made through shared decision making. Every patient received pain neuroscience education about their pain ,24, mosta.Pain Neuroscience Education (PNE): This education consisted of two one-hour appointments, following the guidelines by Nijs et al. . The firb.Further treatment: Further possible treatment depended on the presence of patient-specific factors:Depression, anxiety, fear of movement → psychological treatment such as cognitive behavioral treatment, acceptance and commitment therapy, relaxation techniques, and/or exposure therapy. In case of more severe anxiety and/or depressive symptoms, medication such as antidepressants could be (temporarily) prescribed by the general practitioner.Post-traumatic stress disorder (PTSD) → psychological treatment such as trauma therapy .Lack of exercise, avoidance behavior, and/or disuse → physical therapy such as graded activity, pacing programs and/or graded exposure, encouragement of healthy exercise habits Persistence behavior → daily schedule with alternating periods of activity and rest/relaxation. Helping patient decide where to set boundaries, usually under guidance of psychologist and physiotherapist.Use of medication such as opioids → tapering off medication by the general practitioner or switching to less harmful medication (such as antidepressants).www.transcare.nl .Generally, patients saw the psychologist for a total of 5–12 sessions (on average 45 min in duration) and the physiotherapist for 9–20 sessions (on average 25 min in duration). The general practitioner met with the patient during initial assessment for the Pain Neuroscience Education session and then when necessary . More information about this treatment can be found at Education about chronic pain and the biopsychosocial modelNon-drug treatment: advise to seek distraction and support and to find a good balance between relaxation and activity. Possible referral to a psychologist in case of harmful cognitions, emotions, and behaviors; possible referral to a physiotherapist or remedial therapist for exercise programs aimed at an active lifestyle; and possible referral to social worker if social problems play a role.Drug treatment: avoid drug treatment if possible, especially avoid opioids if possible. When prescribing drugs, aim to prescribe for a short period.Referrals: referral to a rehabilitation if patient is experiencing a high degree of limitations due to pain; referral to medical specialist is there is a possible underlying cause that is treatable, etc.Control group participants received TAU for chronic pain. Dutch general practitioners typically work according to the “NHG-Standaard Pijn”, a guideline for general practitioners in managing pain . The keyBaseline measures included demographic variables such as sex, age, civil status, education level, and work status. Effect measures were assessed at baseline, and at 6- and 12-month follow-up points.Pain intensity was determined using an 11-point Numeric Rating Scale (NRS), ranging from 1 (no pain) to 10 (severe pain) .The number of pain sites was measured by the Widespread Pain Index (WPI), on which participants can indicate where the pain is located using an illustration of a human body . The numHealth-related Quality of Life (HR-QoL) was measured using the RAND-36, a self-administered 36-item questionnaire. It consists of 8 subscales, i.e., physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, vitality, pain, and general health perception . In addiSymptoms of central sensitization was measured using the Central Sensitization Inventory (CSI) ,35. The Pain catastrophizing was measured using the Pain Catastrophizing Scale (PCS) , a 13-itPatients’ satisfaction with the received treatment was measured once, at 12 months, using a shortened version of the CQ-Index Module Pain . The queTwo outcome measures, which were not described in the original study protocol as registered in the trial register, were added in a post hoc analysis.Illness perceptions were measured using the Brief Illness Perceptions Questionnaire (IPQ-B ). This iAnxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) . This inp < 0.05 was considered statistically significant.For all analyses, a two-tailed significance level of Descriptive statistics were used to describe baseline characteristics of both groups.The primary analysis was an intention-to-treat analysis. All outcomes were analyzed using a linear mixed model fitted by maximum likelihood, with responses at baseline, 6 months, and 12 months. The model had a 2-level structure, with repeated measures (level 1), nested within patients (level 2). The effect of interest was the overall difference in outcomes between groups during the complete duration of follow-up. Additionally, time by treatment interactions were added to the models to assess the differences in outcomes per time point. Regression coefficients with 95% confidence intervals (CIs) were estimated. To deal with the non-randomized nature of this study, effect differences were adjusted for patients’ propensity score. The propensity score indicates the probability of a patient being assigned to the intervention group, given a set of baseline characteristics. The propensity score was estimated based on the following possible confounding variables: whether patients had other complaints besides pain, whether patients had their pain symptoms for the first time or not, the duration of their pain at baseline, employment status, education level, age, and sex using the pscore package in STATA . As for Differences between satisfaction rating were analyzed using independent t-tests.A post hoc analysis was performed on the IPQ-B and the HADS to gain more insight in how illness perceptions, anxiety, and depression changed over time. This was investigated by a linear mixed model fitted by maximum likelihood as well.All analyses were performed in SPSS v25 and STATA v15.In total, 107 participants were recruited for the study. Of them, 89 filled out the baseline questionnaire  and were included in the study .In The mean differences between groups for the primary outcome measures are shown in The overall differences between both groups for pain intensity ), number of pain sites ) and HR-QoL  were not statistically significant. The average between-group difference on pain intensity (0.9-point difference) was also not clinically relevant (<2 points difference).While the overall effect  was not statistically significant, there was a statistically significant difference between both groups in the number of pain sites at 12 months . In addition, there was a statistically significant difference between both groups in HR-QoL at 12 months. None of the within-group improvements in the intervention group were clinically relevant either . Likewise, the within-group improvements in the control group were not clinically relevant either .The mean differences between groups for the secondary outcome measures can be found in As can be seen in In This study evaluated the effectiveness of a multidisciplinary treatment for chronic pain embedded in primary care and compared with treatment as usual. The results show that there were no statistically significant effects, nor clinically relevant between-group or within-group differences, on the primary outcomes pain intensity, number of pain sites, and HR-QoL. As for the secondary outcomes, there was a statistically significant difference in Health Change (measured on the RAND-36) in favor of the intervention group. There were no statistically significant overall effects on the other secondary outcomes: symptoms of central sensitization, pain catastrophizing, depression, anxiety, physical functioning, role functioning due to physical problems, energy, emotional wellbeing, role functioning due to emotional problems, social functioning, and general health.In the post hoc analysis, there was a statistically significant effect on illness perceptions, with the intervention being significantly more effective in decreasing negative illness perceptions and increasing perceived health after 12 months compared with TAU. However, the changes in illness perceptions in the intervention group were not deemed clinically relevant.The results show that there is no statistically significant nor clinically relevant effect on pain intensity. A possible explanation for the lack of a statistically significant effect on pain intensity and other pain-related outcomes is the duration of pain for the participants in this study. In the current study, both the participants in the intervention group and in the control group had had their pain for a substantial amount of time prior to the intervention (103 months in the control group and 93 months in the intervention group). Chronicity of pain has been shown to be associated with only modest changes in pain severity, self-reported disability, pain catastrophizing, and fear of movement/re-injury . This seFurthermore, the primary health care providers in the intervention were trained to work with the protocol. Some of them were, however, biomedically trained doctors and physiotherapists. It is a possibility that the total amount of training for the primary health care providers was too short to get acquainted with the protocol. Further studies may investigate the effect of more extensive training of the multidisciplinary team providing the intervention, and in addition, check whether the team’s attitude and behavior towards chronic pain did indeed change after training. In addition, the pre-existing relationship  between the patient and the care provider might have been a barrier for changing from a biomedical to a biopsychosocial approach.Previous research has found that the belief that one has control over pain is strongly associated with decreases in pain intensity and patient-rated disability . In thisA post hoc analysis showed that in the intervention group, patients’ illness perceptions changed statistically significantly compared with patients in the control group. This is possibly the result of the pain neuroscience education sessions the intervention group received, which provided patients with an in-depth biopsychosocial explanation of their pain and addressed the often-incorrect somatic perceptions patients had about their pain. The intervention led to the result that patients felt that their pain affected their life less, that they think their pain will continue for a shorter duration, that they were less concerned about their pain, and that they were less affected by their pain emotionally. In addition, patients in the intervention group perceived their health to have improved significantly more the past year compared with patients in the control group. Thus, the intervention seemed to mostly affect patients’ perception of their situation, while not necessarily improving other outcomes.It is possible that reporting on pain and pain-related outcomes itself had an effect on patients’ outcomes in both the intervention group and the control group. Research has shown that attention to pain and mood both alter pain perception, and filling out the self-reports may have drawn attention to the pain and pain-related outcomes and hence influenced the patients’ experience of their pain and its outcomes . HoweverIt was not surprising that there was no statistically significant difference in how patients rated the result of their treatment, as there was no significant difference in most pain-related outcomes. However, patients in the intervention group did feel they were taken more seriously by healthcare professionals compared with patients in the control group.Previous studies found favorable results for multidisciplinary care for chronic pain patients, mostly in intensive inpatient settings. Similar results as the results found in the current study on patients’ beliefs were found by Moss-Morris et al. , which sThe most important strength of this study is that it is one of the first studies investigating multidisciplinary treatment for chronic pain embedded in primary care, as well as its patient-centered approach, the use of propensity scores to deal with its non-randomized design, and the relatively long follow-up period.This study also has several limitations. First, the allocation of the participants across study groups was not randomized. Randomization was not possible at patient or cluster level because of the nature of the intervention and the lack of resources to randomize entire practices. Patients in both the intervention group and control group remained at the general practices that they were already registered at, making it impossible to perform an RCT or CRT. Therefore, convenience sampling was used. This could have caused a selection bias, which we tried to reduce by using propensity score weighting. Second, the sample size was relatively small, and the dropout of participants was considerable . However, the sample size was sufficient and as Twisk et al.  argued, A multidisciplinary treatment for chronic pain embedded in primary care did not result in statistically significant nor clinically relevant improvement in pain intensity, number of pain sites, and health-related quality of life compared with treatment as usual. Secondary analyses showed that it had an effect on patients’ illness perceptions and perceived health, and that patients felt more taken seriously by their healthcare providers compared with patients who received treatment as usual. Based on these results, the findings do not support implementation of a low-intensity outpatient multidisciplinary primary care treatment to treat chronic pain. However, as a result of several study limitations, it is considered unwarranted to conclude that multidisciplinary treatment in primary care is not valuable at all. Future studies may aim to address the listed limitations to aim for a fairer, more detailed comparison between the intervention and TAU. Multidisciplinary treatment in primary care for chronic pain may very well be effective as well as cost-effective, but further research is necessary to investigate how the intervention has to be set up in order for it to be significantly more effective than TAU in managing chronic pain.


Local anaesthetics administered into the peritoneal cavity have been successfully used for post-operative pain relief in minimally invasive laparoscopic procedures. We intended to study and compare nebulized intraperitoneal ropivacaine with and without nalbuphine, with a placebo for post-operative pain relief in these surgeries.P < .05 was considered significant. Time to first rescue analgesia, total opioid requirement, and side effects were also recorded.A prospective, randomized double-blinded study was conducted over a period of 1 year after institutional ethical clearance, in patients undergoing elective laparoscopic cholecystectomy. Subjects were randomized into 3 groups . The pain was assessed in the post-operative period using NRS scores (up to 24 hours). Kruskal-Wallis test was used for comparison, Groups were similar in terms of demographic data. Patients in the placebo group reported higher NRS scores than the other 2 study groups till 4 hours post-operative . The addition of nalbuphine did not cause any statistically significant improvement in post-operative pain relief (NRS) as compared to ropivacaine administered alone. Intraperitoneal ropivacaine nebulization had no significant adverse effect as compared to placebo.Ropivacaine nebulization with or without nalbuphine is more effective than placebo for post-operative pain relief after laparoscopic cholecystectomy without significant side effects. Addition of nalbuphine to ropivacaine nebulization does not significantly improve pain relief after laparoscopic cholecystectomy. The aim was to compare nebulized intraperitoneal ropivacaine with and without nalbuphine, with placebo for post-operative pain relief in laparoscopic cholecystectomies.Patients in the placebo group reported higher pain scores than in nebulized ropivacaine groups.Addition of nalbuphine did not cause any statistically significant improvement in post-operative pain relief as compared to ropivacaine alone.No significant side effects were observed with nebulization with ropivacaine.2 Pain in laparoscopic abdominal surgeries is due to 3 components: somatic (port site incision), visceral , and phrenic nerve irritation (shoulder tip pain).4Acute pain management after surgery is extremely essential. If not controlled adequately, it can worsen overall post-operative (PO) outcomes. The main aim of PO pain management is effective pain relief at appropriate doses of drugs, with minimal adverse effects. In laparoscopic cholecystectomy (LC), adequate control of PO pain helps in early mobility and patient discharge from the hospital, thus better patient satisfaction.5Different modes of PO pain management options include opioids delivered intravenously (iv) or along with local anaesthetics in the form of Transversus Abdominis Plane block, epidural space blocks, peripheral nerve blocks, and nonsteroidal anti-inflammatory drugs given through various routes. Opioids may cause nausea, vomiting, respiratory depression, sedation, delayed return of gastrointestinal motility, and so on given iv.6 Different types of nebulization devices have been used for pain relief after laparoscopic surgeries. Earlier studies have used cumbersome custom-made devices and devices that worked on hot evaporation-based nebulization principle.7 The objective of the present study is to assess the efficacy of intraperitoneal ropivacaine nebulization with and without nalbuphine on PO pain relief in LC compared to placebo, using a high-frequency ultrasonic nebulizer at the end of the procedure.Nebulized drug delivery has been shown to have a better and uniform spread of local anaesthetic drugs compared to conventional drug instillation into the peritoneal cavity.A prospective, randomized double-blinded study was conducted after institutional ethical clearance and registered under clinical registry CTRI/2018/09/015764. Informed written consent was obtained prior to enrolment of patients as study participants. Patients were enrolled for 12 months, and the study was concluded in 1.5 years. The manuscript was prepared in accordance with CONSORT guidelines for randomized studies. Inclusion criteria were all patients aged 18-70 years of either sex, belonging to ASA physical status I and II being planned for LC and free from any pain in PO period (apart from biliary colic). Exclusion criteria were refusal by patient, conversion of laparoscopic approach to open surgery, duration more than 1 hour, the requirement of extra opioid above initial bolus intraoperatively, alcohol use or history of drug addiction, hepatic or renal impairment, allergy to the drugs being studied, any pre-existing source of abdominal pain apart from biliary colic, patients with communication problems, cognitive impairment, pregnancy or lactation, chronic pain treatment involving opioids, anti-epileptic therapy .8 The dose and volume of the drug used in the current study were well below the toxic limit. Surgery was performed by surgeons with at least 5 years of experience, in all 3 groups. After measuring baseline hemodynamic parameters, anaesthesia induction was done using the following drugs: propofol 2 mg kg-1 iv, fentanyl 2 μg kg-1, and vecuronium 0.1 mg kg-1 iv. Maintenance was with sevoflurane 1.5-2% (in 50% O2 + 50% N2O). Cases in which surgery extended more than 1 hour or required additional fentanyl intraoperatively were excluded from analysis , Group R: 7 mL of 0.75% ropivacaine with 1 mL of normal saline, Group RN: 7 mL of 0.75% ropivacaine with 0.1 mg kg-1 of 1% nalbuphine diluted to 1 mL. All 3 groups had a total injection volume of 8 mL to maintain blinding at the level of intervention provider. The final effective concentration of ropivacaine in group R and RN was 0.65%. Reference studies have used drug volumes varying from 4 to 10 mL (0.75%) of ropivacaine.analysis . Pneumop® ultrasonic aerosol delivery device before the removal of trocar. The nebulization unit was in series with the insufflator device (between the device and insufflator tubing) and the nebulized drug was delivered through the tubing and trocar into the peritoneal cavity. Nebulization was done till the completion of 8 mL of drug solution (about 10 minutes). The CO2 gas was carefully evacuated from the peritoneal cavity at the end of surgery with open trocars. In all groups, port insertion sites were infiltrated with local anaesthetic solution . Neuro-muscular blockade was reversed with neostigmine and glycopyrrolate using objective neuro-muscular monitoring (a train of 4 ratio greater than 0.9) uniformly in all groups. Paracetamol 1 g iv QID was given to all patients for first the 24 hours post-operatively.The patients were taught the use of a 0-10 numerical rating scale (NRS) on which 0 represents “no pain” and 10 represents the “worst possible pain.” The research assistant was not allowed inside the operation theater until the study drug solution was ready, in order to maintain blinding. Toward the end of surgery, the drug selected  was nebulized with the help of Aerogen-Pro9 Second level of rescue analgesia was in the form of slow iv diclofenac 75 mg which was given slow iv over 10 minutes if persistent NRS >4 even after 15 minutes of fentanyl injection.10 Incidence of PO nausea and vomiting (PONV) was recorded; such a complaint was treated by ondansetron (4 mg iv). Time to first opioid requirement, total opioid consumption in the first 24 hours post-operatively, and occurrence of adverse events were recorded.The degree of PO pain was assessed using the NRS at 0, 1, 4, 8, 12, and 24 hours post-operatively along with hemodynamic parameters. This assessment was performed by a resident doctor who was blinded to the group allocation and was familiar with the use and interpretation of the NRS. Those patients with NRS > 4 at any of these recordings were administered a bolus of inj. fentanyl 1 μg kg-1 slow iv as rescue analgesia. Subsequent dose of fentanyl if required was not repeated before 4 hours of the previous dose.11 Assuming an alpha error of 5% and power of study being 80%. A final number of 100 was selected to compensate for exclusions. Secondary objectives and outcomes were to assess the incidence of side effects, total opioid consumption, and time to first rescue analgesia. Kruskal-Wallis test was used to compare the 3 groups in terms of Pain Score (NRS) at each of the time points. Chi-square test was used to compare quantitative data. P < .05 was considered statistically significant.Primary objective of this study was to evaluate the efficacy of ropivacaine nebulization  compared to no drug or placebo in the reduction of PO pain in patients after LC. The primary outcome was NRS score at 1-hour PO. Sample size was calculated to be 87 patients (29 in each group), on the basis of 2 previous studies to be able to detect a difference in Pain Score by a scale of 2/10 at 1-hour PO between the study and placebo group.A total of 100 patients were assessed for eligibility, out of which 96 met the inclusion criteria. Ninety patients were included in final data analysis . Ten patP  = .060) (Patients in the placebo group S reported higher NRS scores than the other study groups in the immediate PO period up to 6 hours PO. After that (at 8- and 12-hour measurement) placebo group S had lower NRS score due to earlier administration of rescue opioid dose. Nebulization of ropivacaine with or without nalbuphine had no significant difference in NRS scores at all time intervals. There was no difference in NRS score at 24 hours PO in all 3 groups ( = .060) .P < .001). In the post-hoc analysis performed to determine the origin of the difference, the need for rescue analgesics in the placebo group was higher than in the other 2 experimental groups , but there was no difference between the experimental groups (P > .5)  .Incidence of PO shoulder pain was higher in the placebo group S (3 out of 30 patients) compared to the ropivacaine nebulization groups (no shoulder pain in groups R and RN). Maximum cases of PONV were observed in the nalbuphine group RN (3 out of 30 patients). Group R had 2 out of 30 and group S had 1 out 30 patients. None of the patients enrolled in the study developed pruritus, respiratory depression, subcutaneous emphysema, sedation, or signs and symptoms of LAST or other notable adverse effects post-operatively.15In the current study, patients in the placebo group reported higher NRS scores than other study groups in the immediate PO period. Addition of nalbuphine did not cause any statistically significant improvement in pains scores as compared to ropivacaine administered alone. In addition to the currently studied technique, there are various new regional anaesthesia techniques that have been shown to be effective in minimally invasive surgeries for pain relief. These include erector spinae plane block, serratus intercostal plane block, oblique subcostal TAP, and quadratus lumborum block.18 Nebulization offers a more homogenous spread of the drug intraperitoneally, as compared to instillation.7 Ultrasonic nebulizers which have been used in the current study, use high-frequency sound waves to generate aerosol particles of comparatively more uniform sizes of 1-5 microns compared to 4-10 microns from the conventional atomizers. The concerns with intraperitoneal nebulization are fogging and poor visibility in the cavity which may hamper the surgeon’s view limiting its use intraoperatively.11 Thus, in the current study it was used only at the end of the procedure. There is also a concern of increased systemic absorption of the drug through peritoneal surface. However, studies have shown the serum drug levels of local anaesthetics like ropivacaine to be well below toxic levels.19Local anaesthetics, with or without opioids, are frequently being administered into the peritoneal cavity during minimally invasive procedures such as LC and gynecological laparoscopy by either instillation or nebulization.11 studying efficacy of intraperitoneal nebulization of ropivacaine  for pain control after LC, it was concluded that ropivacaine nebulization before or after surgery reduced PO pain and referred shoulder pain, along with reduced morphine requirement and earlier mobility among patients who receive intraperitoneal ropivacaine nebulization. Similar findings were reported by Somaini et al1 using ropivacaine . In the current study also, similar results were reported with ropivacaine ultrasonically nebulized at end of surgery  showing lower pain scores compared to placebo.In a double-blind, randomized, placebo-controlled trial by Ingelmo et al20 in LC patients with drug instillation in the peritoneal cavity showed decreased PO pain scores in the nalbuphine group. Also, a study by Bhatia et al8 showed better pain relief with fentanyl-ropivacaine intraperitoneal nebulization combination compared to nebulized ropivacaine alone. Recent studies on pre-emptive intravenous nalbuphine use in laparoscopic surgeries have also shown promise. It reduced the PO visceral pain and supplemental analgesic use21 and was also useful in ameliorating PO hyperalgesia induced by high-dose remifentanil use in LC.22In the current study, no difference was found by addition of nalbuphine to ropivacaine. A study by Singh et al2 studied the combined usage of intraperitoneal and incisional ropivacaine for assessing pain severity after LC. Total of 160 patients were enrolled in this study. The main finding of this trial was that intraperitoneal and incisional ropivacaine  at the end of the LC significantly reduced the time of PACU (post-anaesthesia care unit) stay, PO dynamic pain, cumulative morphine requirements, and incidence of PONV. In the current study, lesser volume (8 mL) of 0.65% ropivacaine (52.5 mg) was used with similar efficacy, although no difference was observed in pain scores or total requirement of opioids by addition of nalbuphine to ropivacaine. Time to first rescue dose as well as total opioid requirement with ropivacaine use was significantly less compared to placebo and in keeping with the above study. Another dose finding and pharmacokinetic study concluded there was no enhancement in analgesic efficacy with higher doses  of nebulized ropivacaine compared to 50 mg during LC.18In 2015, Liu et al23 In the current study also, lower pain scores were observed in the ropivacaine groups compared to placebo (immediate to 4 hours PO). From 8 to 12 hours PO, as rescue analgesia was provided in placebo groups earlier, the difference in pain scores between the 3 groups diminished. In the current study, total opioid consumption (fentanyl) was significantly higher in the placebo group compared to the ropivacaine and combined nalbuphine group similar to what was observed in the above-mentioned study.In a study on PO analgesia after laparoscopic ovarian cyst resection comparing intraperitoneal nebulization and peritoneal instillation of ropivacaine, it was concluded that nebulization of ropivacaine  prevented the use of morphine in a significant number of patients and reduced PO pain during the first few hours after surgery.2 where ropivacaine had a lower incidence of PONV. This could be possibly due to the fact that in the current study, the sample was not adequate for the objective of detecting significant differences in the occurrence of PONV and cannot be extrapolated to the general population. No other opioid side effect such as respiratory depression was observed in any of the groups.In terms of side effects in the current study, no major adverse event was noted in any of the groups. Incidence of PONV was similar in all groups, in contrast to the study by Liu et al24The limitation of current study: results cannot be extrapolated to a significant proportion of such cases such as long-duration surgeries, peritoneal spillage, and so on (which were excluded from the current study). Patient’s serum concentrations of study drugs could not be measured due to practical difficulties and/or non-feasibility. Further studies may be required to analyze safety concerns. Precautions taken in our study are keeping the doses of study drugs within permissible safety limits.To conclude, ropivacaine in a dose of 52.5 mg (0.65% in current study), nebulization is more effective than placebo for PO pain relief after LC. Addition of nalbuphine to ropivacaine nebulization does not significantly improve pain relief (NRS scores) after LC. Intraperitoneal ropivacaine nebulization has no significant adverse effect as compared to placebo. There was no adverse effect on the addition of nalbuphine to ropivacaine for intraperitoneal nebulization as compared to ropivacaine alone.


Juvenile idiopathic arthritis (JIA) is chronic inflammatory arthritis of childhood that may result in persistent and disabling foot impairments. Foot disorders are common in JIA with a prevalence estimated at over 90%. Many factors can worsen foot disorders in these patients. The influence of weight on foot disorders is poorly studied.To examine associations between weight and foot disorders in patients with JIA.Patients with a diagnosis of JIA, based on the International League of Associations for Rheumatology (ILAR) criteria were included. Age, gender, weight, characteristics of the disease and of foot pain were noted. A specialized podiatric examination was performed.n = 14). The mean age of disease onset was 8.5 ± 3.9 [3–15]. Only one patient had a triggering factor (elbow fracture). The most common type of JIA was oligoarthritis in 12 cases, then enthesitis-related in 8 cases, polyarthritis without rheumatoid factor in 3 cases, polyarthritis with positive rheumatoid factor in 1 case, psoriatic arthritis in 3 cases, systemic arthritis in 1 case and undifferentiated arthritis in 4 cases.Thirty-two patients were included. The mean age was 12.2 ± 2.9 [5–18]. Forty-three percent of the patients were boys (n = 9) of the children had a normal weight for their age, 41% (n = 13) of them had a low weight for their age and 31% (n = 10) of them had overweight. Ten patients had foot pain: hindfoot pain in 5 patients, midfoot pain in 3 patients, and forefoot pain in 2 patients. Foot deformities were found in 78.1% of the patients (n = 27): flat foot in 39% (n = 13) of the patients and pes cavus in 39% (n = 13).The mean weight was 43.5 kg [17–98]. Only 28%  or hindfoot pain (p = 0.08). However, overweight was associated with a forefoot (p = 0.01) and midfoot (p = 0.01) pain. Overweight was not associated with foot deformities (p = 0.1).There was no association between overweight and foot pain (This study showed that weight is associated with foot pain especially forefoot and midfoot pain. A healthy lifestyle and a normal weight are fundamental to preventing foot pain at an early age in patients with JIA and improving their quality of life.


Successful pain management after outpatient surgery requires proper education leading to correct decisions on the analgesics use at home. Despite different strategies adopted, up to ½ of patients receive little or no information about the treatment of postoperative pain, 1/3 of them are not able to follow postoperative analgesia instructions. This leads to higher rates of unmet needs in pain treatment, post-discharge emergency calls, and readmissions. Structured educational interventions using psychological empowering techniques may improve postoperative pain management. We hypothesize that preoperative education on use of an improved pain scale to make correct pain management decisions will improve the quality of post-operative pain management at home and reduce analgesics-related side effects.A total of 414 patients scheduled for an outpatient orthopedic surgery (knee/shoulder arthroscopic interventions) are included in this randomized (1:1) controlled trial. Patients in the control arm receive standard information on post-discharge pain management. Patients in the experimental arm receive structured educational intervention based on the rational perception of postoperative pain and discomfort , and the proper use of analgesics. There is no difference in post-discharge analgesics regimen in both arms. Patients are followed for 30 days post-discharge, with the primary outcome expressed as total pain relief score at 5 days. Secondary outcomes include the incidence of severe pain during 30 days, changes in sleep quality , and patients’ perception of postoperative pain management assessed with the International Pain Outcomes questionnaire at day 30 post-discharge.The developed intervention, based on an improved pain scale, offers the advantages of being non-surgery-specific, is easily administered in a short amount of time, and can be delivered individually or in-group, by physicians or nurses.ClinicalTrials.govNCT03754699. Registered on November 27, 2018.The online version contains supplementary material available at 10.1186/s13063-022-06387-6. The order of the items has been modified to group similar items  are proposed to patients in order to help manage pain control at home. However, at least 40% of patients are unable to use it correctly in extra hospital settings , and thiPreoperative instruction on the use of a pain scale was found to improve the patient's ability to self-report pain . NeverthWe hypothesize that an educational intervention based on the rational perception of postoperative pain and discomfort, and the proper use of analgesics would improve the quality of pain management at home and reduce analgesics-related side effects.The study evaluates the effectiveness of an educational intervention on pain relief at home in outpatient orthopedic surgery, compared to standard care. The pain relief is assessed during the first five post-discharge days (primary outcome), then on the 10th, 20th and 30th days after surgery (secondary outcome). The prevalence of severe pain (as reported by participants), medication use, side effect of medication, changes in sleep quality, the incidence of neuropathic pain at day 30 after surgery, and overall satisfaction at day 30 will be assessed as a part of secondary objectives.PELOPS is a single-center prospective randomized controlled two-group superiority trial with parallel assignment. This manuscript describes the study protocol and the beginning of the trial in the setting of outpatient orthopedic surgeryThis study is performed at the Hopital de la Croix Rousse, Hospices Civils de Lyon, tertiary university hospital in France. Three departments are involved in the trial - Department of Orthopedic Surgery, Department of Anesthesia, and Outpatient Surgery Department.Adult patients (age more than 18 years old), scheduled for elective outpatient orthopedic surgery in will be recruited. Surgical interventions include knee and shoulder arthroscopy, cruciate ligament repair, and medial patellofemoral ligament (MPFL) repair. These interventions are frequent and are known to produce moderate to severe pain in the early postoperative period .Non-eligible are pregnant or breast-feeding women, patients with contraindication for acetaminophen and anti-inflammatory drugs, with chronic pain beyond the surgical site, outpatient knee and hip arthroplasty , patients without social security coverage, non-French speaking, unable to consent, disagree to participate.Patients will be recruited during the pre-anesthesia visit by a physician anesthesiologist. After meeting inclusion criteria, each patient will be orally informed about the study protocol first. Agreed patients will sign a written consent form and will be randomized to receive either standard information on postoperative pain management or structured education intervention. A physician anesthesiologist, performing pre-anesthesia evaluation and patients’ inclusion, collects the written consent.In a case of an ancillary study with the data collection not covered in the original informed consent form, the new signed consent has to be obtained from every participant. In a case of retrospective use of already generated data, stored in the institutional Electronic Health Record, all patients should be informed about their data use according to the European General Data Protection Regulation. No biological specimens will be collected in this trial.The standard recommendation on postoperative pain management for outpatient procedures is based on the recommendation of the French National Agency for Medication and Medical Products Safety  and the French Society of Anesthesia (SFAR), available through the site of the French national system of health insurance , 22.These recommendations include an example of 11-item numeric pain scale  divided into three levels—light to moderate , moderate to intense , and intense to very intense .Your pain treatment has to be taken starting your return home. To evaluate your pain, use the digital scale from 0 to 10. In a case of light to moderate pain (0-4), you should take paracetamol. For moderate to intense pain (4-7), you should take anti-inflammatory or opioid-containing drugs.The treatment is systematic during first 3 days. Prescribed dosage should be respected.The following narration is used:All patients were free to ask any additional questions about pain management at home.At the end of visit, a diary for data collection is given to a patient, containing the comparator standard pain scale on the first page, and the narration on the second page.All parents (both from the control and intervention arms) receive a standardized analgesics prescription for at-home pain management, including acetaminophen, ketoprophen (non-steroid anti-inflammatory drug), weak opioid formulation (based on opium), and proton pump inhibitors (gastric protector).The structured education intervention is derived from the well-known and validated 11-items pain intensity scale. The intervention allows the anchoring of each level of pain scale on the individual patient’s experience. In the case of outpatient surgery, patients are empowered to act on medical  and social constraints . Patients receive oral, visual (interaction with a clinician), and material support , delivered by a clinician, in a standardized manner.A cognitive bias where a particular reference point would influence an individual’s decision is known as “anchoring effect” . In patiSeveral “comprehensive” patient-developed pain scales are available. Examples include 11-items based Harich’s Comparative Pain Scale  and MankFor the purpose of our trial, we used both scales as a prototype for the Comprehensive Acute Pain Anchoring Scale for the Outpatient Orthopaedic Surgery.We first translated both scales into French, using the process of cross-cultural adaptation of self-reported measures . Two traInvestigators  used the final translation to create a simplified pain anchor-based scale on the ability to have regular daily activities . The French version of the produced scale is presented in Additional file Based on this scale, an educational intervention was developed conjointly with psychologists . The following psychological concepts were used: a recall of the most intense pain experienced in the past  , anchoriEnounce of the purposeRecall of the past pain experienceQuantification of the experience on the scale from 0 (no pain) to 10 (worst imaginable)Qualification of the past pain experience (what was pain felt like)Request to discriminate the weak, moderate, and strong painAnchoring of the recalled pain experience with the experimental scalePrinciples of the transition of mild to moderate and moderate to severe pain explainedPain management principle explained ReinsuranceA standard narration was developed containing nine steps  are free to terminate their participation at any moment. The principal investigator may suspend or withdraw a patient participation for any reason that may conflict with the interest of the patient.Instructions about the purpose of the study and the importance to fill in and to return the diary are thoroughly provided during the inclusion visit. Participating patients will receive a text message via their private e-mail or phone  on the day, where their action to fill in the diary is necessary . The last message on day 30 contains instructions on how to return their diary. Patients are expected to bring the filled diary on day 45  or send it by post. Patients are provided with prepaid envelopes in order to send the diary if no postsurgical visit is scheduled on day 45.Participants are provided with a standard pain treatment order including acetaminophen, ketoprofen, and weak opioids. They are allowed to use any additional medication or non-pharmacological pain relief, in such cases, this should be traced in the diary. In France, the access to non-steroid and opioid analgesics is highly regulated, so the chance that enrolled patients will considerably modify their home treatment is weak. Hypothetically, patients hospitalized during the follow-up period, or deceased, will be considered as lost for follow-up and therefore excluded.Enrolled patients are covered by indemnity for non-negligent harm through the standard procedure. Hospices Civils de Lyon have insurance to cover for non-negligent harm associated with the protocol, including additional health care, compensation, or damages.The primary outcome is the pain relief measured with a percentage of maximum total pain relief (TOTPAR) over 5 days. TOTPAR is a time-weighted measure of total area under the pain relief curve. This measurement assimilates iterative assessments of a subject’s pain over the duration of the study.TOTPAR at day 10, day 20, and day 30 after surgeryThe incidence of severe pain (defined as “severe pain” by the patient)Type, quantity, and doses of taken analgesicsNeuropathic pain prevalence at day 30, detected with DN4 scale The sleep quality measured with Pittsburgh Sleep Quality Index (PSQI)  and compPatients’ perception of postoperative pain management evaluated at with the International Pain Outcome (IPO) questionnaire  on day 3The secondary outcome includes:Patients are followed for 30 days after the discharge from the hospital Table .Table 1TIn the beginning of our study, we were not able to identify any randomized study of educational intervention with TOTPAR as a primary endpoint. It has been reported, that more than 30% of orthopedic patients suffer from “important” pain  during the first 72 h post-discharge , 42. A 2We analyzed the literature, reporting the effect of preoperative education on postoperative orthopedic pain in outpatient settings, and available on the year of the study development. Two studies reported the clinically significant effect from the preoperative education, with calculated OR 1.77 [95%CI 1.12–2.79] to 1.97 [95%CI 1.09–3.57] , 45. HowAs we were not able to find any relevant data for the sample size calculation, we have arbitrarily chosen the OR=2 from the effect of preoperative education, which will produce the decrease of proportion of patients with “important” pain from 30 to 17.6%. Giving this assumption, with the risk alpha of 5% and the power at 80%, allocation 1:1, the calculated sample size was 368 patients. We estimate the loss to follow-up at 10%, therefore the 410 patients will be finally enrolled.Our institution performs at least 50 orthopedic outpatient procedures monthly. Anesthesiologists’ team (6 practitioners) systematically evaluates all patients at least 48 h before the planned surgery. As we do not expect to recruit every patient, we would need at least 48 months for the inclusion target accrual.Enrolled patients will be randomly assigned to a control or interventional group with a 1:1 allocation using Ennov Clinical® software  with an embedded IWRS (Interactive Web Response System) randomization system. Patients will be stratified by the type of surgery  and type of anesthesia . The configuration of the randomization and the implementation of the randomization list in the software were made by the statistician who is not involved in the process of patient inclusion and randomization. The list was created with variable block size using nQuery Advisor®, 7.0 . No one, except the statistician, has access to the randomization list.The result of randomization will be available after obtaining the patient’s consent, and before study group assignment, using an online, central randomization service IRWS. Allocation concealment will be ensured, because the IRWS will not issue the group assignment until the patient has been recruited into the trial.Recruiting physician will use IRWS of the Ennov Clinical® software to receive allocation instructions and will give the information about allocation to the patient.There will be no other changes in anesthesia protocol or postoperative care protocol, the same standard at-home analgesics prescription is provided for all patients at discharge by surgeons.Due to the nature of the intervention, the allocation cannot be masked neither for participants nor for physicians or data managersNot applicable, no blinding.A dedicated electronic case report form (e-CRF) within Ennov Clinical® software was created and managed by Clinical Research Department, Hospices Civils de Lyon. The following data are collected upon inclusion: demographics, type of surgery, type of anesthesia, assessment of neuropathic pain with DN4, and assessment of the sleep quality with PSQI. After the discharge, patients fill in the dedicated diary. The prevalence of severe pain (which patients deem to be important) (binary), pain relief (continuous), painkiller administration (binary), and side effects from painkiller (binary) are collected in a time-dependent manner with 30 min grid over 24 h. On day 30, patients fill in the assessment of neuropathic pain with DN4, assessment of the sleep quality with PSQI, and the International Pain Outcome questionnaire . After the diary completion, patients were asked to send the collected data to the investigators.After the inclusion and discharge from the hospital, patients receive a short text message and/or e-mail reminders to complete the follow-up on days 0, 1, 2, 3, 4, 5, 10, 20, and 30 post-discharge. A postal stationery envelope (prepayment of postage) with the printed investigator’s return address is given to each patient along with the diary. Patients are invited to return their diary via the post service, or they may bring it to the hospital. Two weeks following the end of study, if there is no diary return, the patient is contacted by the associate research coordinator and invited to send the diary to the investigator.Upon each diary reception, all data are transcribed to the e-CRF by a dedicated Clinical Research Associates from Clinical Research Department, Hospices Civils de Lyon. The quality of collected data is verified upon monitoring visits. After the study completion, all data will undergo the quality check by the Data Manager. All collected data are confidential and anonymized. Only the principal investigator has access to the de-anonymization tables.Ennov, controlled by our institution. The access to both systems is controlled. All study-related data are pseudo-anonymized, and the deanonymization list is encrypted, stored separately, and available only for investigators.All study-related information is stored in the secured institutional Electronic Health Record system and electronic Clinical Research Form system Not applicable; no biological sampling nor laboratory investigation is planned for this study.p value will indicate statistical significance. Statistical analyses will be performed using R software .Analyses will be performed on an intention-to-treat basis. All data will be checked for normal distribution, and variables will be presented as mean ± standard deviation (SD) or as the median and interquartile range [IQR] accordingly. Categorical variables will be presented as the number and percentage of the total. To compare the two groups, we will use Fisher’s exact test for qualitative data and the non-parametric Mann-Whitney tests for quantitative variables. A comparison of the two groups at randomization will identify potential bias due to unequal allocation. A multivariate logistic regression analysis will be performed to study conditions independently associated with the response to the intervention and to control potential confounding factors. A 0.05 We do not plan to perform an interim analysis.No additional analyses are planned.No missing data will be accepted for the primary end-point. If there are no measures of pain relief after the postoperative day three registered, but the diary is completed, the TOTPAR will be considered as 100% starting from the next blank page. In a case of missing data for the first three days post-discharge, patients will be replaced by new patients, recruited up to 186-target accrual. Missing data for the secondary endpoints will be examined and the decision guided by a principal investigator and statistician will determine whether these data will be excluded or imputed. In that case, a Multiple Imputation by Chained Equations (MICE) will be performed. A R-software implemented algorithm imputes missing data through an iterative series of predictive models using the other existing variables in the dataset.The full protocol (French version) is available upon request to the authors. No participant-level data will be shared.This study is promoted and coordinated by the Direction of Clinical Research and Innovation (DRCI) of Hospices Civils de Lyon, France. This structure includes dedicated Clinical Research Associates, who will monitor the study upon EudraLex practice guidelines.The data monitoring committee is a part of the institutional Research Department, and is independent from the sponsor; it has no competing interests regarding the study.The nature of the study (education intervention) is not intended to produce any harm. However, at the last visit, any potential adverse effect will be collected by the responsible surgeon.At least 10 monitoring sessions are scheduled—before the first inclusion, every 50 inclusions, and after the last inclusion.A formal amendment to the protocol will be made for any changes to the protocol that may affect the study . These changes will be reported to relevant parties .The results of the trial will be disseminated through international scientific conferences and submitted to highly ranked peer-reviewed journals for publication. The findings will also be shared through regional, national, and international scientific and practical meetings.PELOPS is a randomized controlled trial comparing a structured educational intervention to a control group that receives standard information on pain self-management at home after discharge from orthopedic outpatient surgery. The primary outcome measurement is focused on the time-dependent variable—TOTPAR score as the most sensible, and not on summarizing pain intensity assessment , with a Current evidence does not demonstrate a clear effect of preoperative patient education on outpatient pain control. Paucity and methodology weakness  of published studies preclude the inference , 13. AltRising popularity of minimally invasive surgeries, thorough selection of patients, and availability of high-quality short-acting anesthesia has led to a dramatic decrease in hospital stay for numerous procedures. The low-risk complications and benefits associated with reduced cost and less hospital stay have driven the growth of the market. Arthroplasty, spine fusion, colorectal resection, and open prostatectomy—procedures associated with important potential for postoperative pain—are more and more performed in ambulatory settings (49). Our study will contribute to the growing evidence base for non-pharmacological pain treatment optimization, as we do not modify surgical analgesics prescriptions. If the study hypothesis is supported, the findings will provide the evidence and the base for educational intervention development in other than orthopedics specialties. As our intervention is not specialist-based, a wide range of clinicians can provide it, individually or in groups, before surgery.At the date of the manuscript revision, the protocol version 4 from 29/12/2020 was effective. A total of 256 patients were recruited.Additional file 1: Appendix 1. Comprehensive Anchoring Scale for Outpatient Orthopedic Surgery. Appendix 2. Scandalized script for educational intervention to be used with the scale (Additional file Additional file 2: Appendix 3. PELOPS Carnet Patients 02Additional file 3: Appendix 4. PELOPS Carnet Patients 01