Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown.Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values.P < 0.001), PFS  and OS  in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy . Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy.Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC.ClinicalTrials.gov identifier: NCT03668496.The online version contains supplementary material available at 10.1186/s12943-021-01479-4. Lung squamous cell carcinoma (LUSC) accounts for 25%-30% of non-small-cell lung cancer (NSCLC) . It remaTumor mutation burden (TMB) serves as a candidate biomarker for the efficacy of ICI monotherapy in various solid tumors –15. HoweClinicalTrials.gov identifier: NCT03668496) to evaluate the efficacy and safety of camrelizumab  plus chemotherapy as first-line treatment for patients with advanced LUSC. The results showed that camrelizumab plus chemotherapy significantly improved PFS and OS compared to placebo plus chemotherapy as first-line treatment in advanced LUSC [CameL-sq is randomized, double-blind, phase III trial conducted in 53 medical centers in China (ced LUSC . This st2) for 4-6 cycles at investigator’s discretion, followed by maintenance therapy with camrelizumab or placebo until disease progression (PD), or intolerable toxicity. The stratification factors were smoking history (≥400 cigarettes-year vs <400 cigarettes-year vs never), presence of liver or brain metastases (both sites vs one site vs none), and sex . Patients in the placebo plus chemotherapy group with independent review committee (IRC)-assessed PD were allowed to cross over to receive camrelizumab monotherapy. The maximum exposure during of camrelizumab was two years. The primary endpoint was IRC-assessed PFS, defined as time from randomization to the first RECIST version 1.1-defined PD or death from any cause, whichever occurred first. OS and investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR) and duration of response were prespecified secondary endpoints. Complete response (CR), partial response (PR) or stable disease (SD) was required to be confirmed with a subsequent scan at least four weeks after the initial documentation. Survival was followed up every three months after treatment discontinuation. PD-L1 tumor proportion score (TPS) was centrally assessed by using a PD-L1 immunohistochemistry kit . The clinical protocol was approved by the respective institutional review boards and ethics committees. All participants provided written informed consent.Patients with previously untreated, pathologically confirmed stage IIIB-IV LUSC without sensitizing EGFR or ALK genomic aberration were randomized (1:1) to receive camrelizumab (200 mg) or placebo in combination with carboplatin (area under the curve 5 mg/mL*min) plus paclitaxel (175 mg/mFresh (from core needle biopsy) or formalin-fixed paraffin-embedded (FFPE) baseline samples were collected before the protocol-defined treatments. Fresh biopsy samples were snap-frozen in liquid nitrogen within 30 minutes. Pretreatment and on-treatment peripheral blood samples  were collected.DNA was extracted from tumor tissues using GeneRead DNA FFPE Kit  and from peripheral blood lymphocyte with TGuide S32 Magnetic Blood Genomic DNA Kit (TIANGEN DP601-T5C China) according to the manufacturer’s recommended protocol. Cell free DNA (cfDNA) was extracted using MagMAX Cell-Free DNA Isolation kit . DNA samples were quantified with the Qubit dsDNA HS Assay kit  following the manufacturer’s instructions. Genomic DNA was sheared into 150-200 base pairs (bp) fragments through Covaris LE220 using the recommended settings for NGS library preparation. KAPA Hyper Prep Kit  was used for fragmented DNAs construction according to the manufacturer’s instruction. All fragmented gDNA or cfDNA (10 to 50 ng) was end-repaired, sequencing adaptor-ligated, and PCR amplified before purification with 0.8X Agencourt AMPure XP beads . The concentration and quality of the library was determined using the Qubit 3.0 system and Bioanalyzer 2100 .A fraction of each library was hybridized to a predesigned panel covering 1.6 Megabase of genomic regions covering 543 cancer-related genes using HyperCap Target Enrichment Kit . After hybridization and washing according to the manufacturer’s protocol, the KAPA HiFi HotStart ReadyMix  was used for the amplification of captured libraries. Then, the capture libraries were purified with 1X AMPure, quantified, and pooled for sequencing on Illumina Novaseq 6000 with Paired end 150 bp mode.After filtering the low quality reads by Trimmomatic version 0.36 , clean rNonsynonymous mutations (including SNVs and InDELs) in the coding regions were selected for the following analysis of bTMB, while driver gene mutations and hotspot mutations included in the dbSNP138/COSMIC database were removed. Mutations that met a certain sequencing depth (100X for tissue samples and 500X for plasma samples) and VAF (5% for tissue samples and 0.7% for plasma samples) were chose as candidate mutations for bTMB analysis. Subsequently, bTMB was calculated based on the candidate mutations according to the following formula:The on-treatment bTMB for each patient was defined as the bTMB detected at the on-treatment timepoint. The ∆bTMB (bTMB dynamics) was calculated per patient as the on-treatment bTMB level minus the pretreatment bTMB level.P < 0.05 was considered statistically significant.Correlations between high and low bTMB groups were analyzed using the chi-squared or Fisher’s exact test for categorical variables. The continuous variables were analyzed by ANOVA and Tukey’s multiple comparison tests. Mann-Whitney U tests or Kruskal-Wallis rank sum tests were used for comparisons of continuous variables across multiple groups. The Kaplan-Meier curves were used to estimate the median survival time of PFS and OS, with the 95% CIs estimated using the Brookmeyer and Crowley method. Between-group comparison in PFS and OS were assessed using a stratified log-rank test. Hazard ratios (HRs) and associated 95% confidence intervals (CIs) were calculated based on a stratified Cox proportional-hazards model. ORR and DCR were analyzed and the corresponding 95% CIs were estimated using the Clopper-Pearson method; between-group comparisons were assessed using the stratified Cochran-Mantel-Haenszel method. All statistical analyses were conducted using GraphPad PRISM 6.0 and the SPSS statistical software, version 22.0 . Two-side A total of 389 patients with previously untreated, stage IIIB-IV LUSC were enrolled and randomized to receive camrelizumab plus chemotherapy N=193) or placebo plus chemotherapy (N=196). In total, pretreatment tissue and blood samples from 270 patients (134 from camrelizumab plus chemotherapy and 136 from placebo plus chemotherapy group) were collected for this biomarker analysis . Whereas baseline bTMB did not correlate with baseline ctDNA concentration, the sum of the diameters of the target lesions, age, sex, smoking history, disease stage, number of distant metastases, liver and brain metastasis, and PD-L1 expression . ctDNA and bTMB were detected in the pretreatment samples of 132 of 134 (98.5%) in camrelizumab plus chemotherapy group and 135 of 136 (99.3%) in chemotherapy group. The median tTMB was 7.6 Mutations/Megabase  in camrelizumab plus chemotherapy group and 7.8 Muts/Mb (range 1.3–33.0) in chemotherapy group. The median bTMB was 7.7 Muts/Mb (range 0.0–47.3) in camrelizumab plus chemotherapy group and 6.4 Muts/Mb (range 0.0–36.1) in chemotherapy group. The baseline bTMB correlated well with the matched tTMB Figure  and patiP = 0.032, Figure P < 0.001, Figure P < 0.001, Figure To investigate the predictive and prognostic value of pretreatment bTMB and tTMB, we defined the high-bTMB or tTMB group as that with a TMB value ≥75% level and the low-bTMB/tTMB group as that with a TMB value below 75% level. Although this definition for TMB cutoff is not popular in the research setting, it is more helpful for us to clarify the relevant investigations due to its briefness and shows the optimal predictive significance Figure . As showP = 0.010, Figure P = 0.005, Figure P = 0.031, Figure S5F). Of note, patients with high on-treatment bTMB had marginally statistically longer sum of the diameters of the target lesions after two cycles treatment  and OS  remained after the adjustments of clinical characteristics, pretreatment tTMB and bTMB  treated with ICI monotherapy –30. WhetMB Table .Table 1BP < 0.001; Figure P = 0.201; Figure P < 0.001, Figure rSpearman= 0.849, P < 0.001, Figure P < 0.001; Figure Next, we surveyed the association between bTMB dynamics (∆bTMB) and survival benefit. Patients with an increase or unchanged level in bTMB from pretreatment (defined as ∆bTMB ≥0) had obviously shorter PFS  and on-treatment VAF showed complementary correlates of prolonged survival in almost 1,000 patients treated with ICIs . These rDetermining whether a patient with initially radiologic SD could achieve long-term benefit from immunotherapy is still a challenge in clinical setting . ActuallThere are several limitations in this study. First, the BEC population accounted for approximately 70% of the ITT population. Despite of the analogous baseline characteristics and clinical outcomes between these two groups, selection bias could be inevitable. Second, given the limited sample size, we did not further divide the BEC population into a training and validation set. Therefore, our findings still need additional independent dataset validation. Third, we defined the cutoff of high-bTMB/tTMB as TMB level ≥75%. Although it is not popular in the research setting, it is more helpful for us to clarify the relevant investigations due to its briefness. In fact, we have used different bTMB level as the cutoff and found that bTMB≥75% was the optimal cutoff with best predictive value. Forth, given the difficulty to obtain adequate high-quality tumor tissue samples, we cannot systemically evaluate the immune activation, T cell response or myeloid cell response via transcriptomic or T cell receptor repertoire analysis in the responders versus non-responders or between the different treatment groups at different time points. Last but not least, whether PD-L1 expression could show complementary value for predicting immunotherapy plus chemotherapy benefit warrant future investigations.In summary, our data firstly reported that on-treatment bTMB, instead of tTMB and pretreatment bTMB was predictive of benefit from camrelizumab plus chemotherapy in advanced LUSC. On-treatment bTMB dynamics showed complementary, nonredundant value for predicting camrelizumab plus chemotherapy benefit. On-treatment bTMB could also adjudicate long-term benefit among patients with initially radiological SD. Our analysis extended the understanding of the predictive value of bTMB in advanced LUSC treated with immunotherapy plus chemotherapy.Additional file 1.


Introduction: Growing evidence suggests disparities in the prevalence, management, progression, and outcomes of chronic, nonmalignant pain-related conditions, especially for African American patients.Objective: The purpose of this review is to explore studied causative factors that influence the management of chronic pain among African Americans, including factors that result in disparate care that may contribute to unfavorable outcomes.Methods: This narrative review is based on available literature published on this topic published within the last 10 years.Results: Assessment of chronic pain is multifaceted, often complicated by patient medical comorbidities and a complex set of biopsychosocial/spiritual/financial and legal determinants. These complexities are further exacerbated by a patient's race, by provider bias, and by structural barriers—all intersecting and culminating in disparate outcomes.Conclusions: A comprehensive analysis is needed to identify quality improvement interventions and to mitigate major barriers contributing to disparities in the management of chronic pain in the African American population. CNMP represents a public health challenge affecting more than 116 million residents in the United States per year and has an estimated $600 billion annual impact on the U.S. economy.4 The Patient Protection and Affordable Care Act is in an ideal position to address these disparities in health care.5 Almost 10 years ago, the Institute of Medicine (IOM) report, “Unequal Treatment,” laid out a broad theoretical framework to address the root causes of health care disparities within three categories: the patient, the health process, and the health system.6 The authors contend that many of these discrepancies result from the interplay of a range of overlapping factors—found in Green's theoretical framework—such as barriers to trust in the doctor/patient relationship (related to communication), crosscultural awareness, compassion, empathy, sensitivity, and competence.There is growing evidence to suggest disparities in the prevalence, management, progression, and outcomes of CNMP-related conditions, especially for African American patients.6 It is important to expose the underlying mechanisms that prevent eliminating the disparities in the chronic pain experience and in the overall health and wellbeing of the African American population. This article highlights the biological, psychological, and social factors that contribute to racial and ethnic disparities in chronic pain care and outlines a plan to reverse the current trend and provide all patients with high-quality care for chronic pain.In an ideal situation, treatment decisions are informed by evidence, unbiased by characteristics such as sex, race, socioeconomic status, education level, and other factors .This literature review focuses predominantly on recent significant articles evaluating the main drivers of disparities in chronic pain management in African Americans. The review was conducted using the following search terms: “pain” and “ethnic or ethnicity or cultural or race or sociocultural or disparity or social determinants” in PubMed and Google. Only articles published in the past 10 years were included in the review. Recent literature was accessed through The University of Chicago's Crerar library; abstracts were evaluated to determine relevance for inclusion in the review. Also included is literature focused on the patient, the provider, structural influences on communication, and access to multimodal chronic pain care. A summary of key articles is included in 7 Pain, therefore, is largely subjective, highly individualized, and often defined by “what the patient says it is.” Physiologically, pain results from a nociceptive afferent impulse relayed from the periphery to the somatosensory cortex, which triggers the sensation of pain. This same impulse relays to limbic structures resulting in an emotional response.8 Racial differences in pain perception and responses are documented in experimental models. The results indicate significantly lower levels of pain tolerance or thresholds among African American subjects resulting in more intense pain and unpleasantness compared with non-Hispanic white subjects.9 This suggests that pain disparity may be related to racial and ethnic differences in pain processing and modulation caused by genetic polymorphisms. These biological differences likely contribute to the difficulties in managing pain across racial and ethnic groups.Pain is a biopsychosocial phenomenon. Simply put, one's pain perception, affective response to pain, and ultimate pain behavior is influenced by a complex set of biological, psychosocial, and cultural interactions.3 Consider, for example, Mukherjee's formula: phenotype (what we are)=genotype (gene)+environment+triggers+chance.10 Also, emerging evidence on the nature versus nurture debate reveals that psychosocial factors such as mood, rumination, and catastrophizing can significantly influence the pain experience.11 Therefore, a thorough assessment of CNMP requires consideration of the impact of nonbiological factors on racial and ethnic groups.Environmental, social triggers, and resultant allostatic load also have an impact on pain. Specifically, they influence gene transcription through gene methylation and epigenetics, suggesting that health outcomes may be less dictated by genes and more by environmental and social triggers.3 For example, determining how bias—either implicit or explicit—influences one's perception of pain and response to pain is important in analyzing pain levels. Hoffman et al., in two independent studies, set out to examine the influence of racial biases on responses to pain, specifically as they relate to false beliefs about biological differences between blacks and whites and vice versa—essentially, biology influencing responses to pain.12 In the first study, the authors surveyed white laypeople, posing various false stereotypes to determine their baseline levels of bias. Survey participants who strongly endorsed false beliefs about biological differences reported lower pain ratings for black subjects versus white subjects.12 In the second study, the authors surveyed white medical students and residents, half of whom expressed the same false beliefs. The result was lower pain ratings and ultimately suboptimal treatment recommendations for black patients versus white patients.12 Study participants who did not endorse these beliefs rated black patients' pain levels higher than white patients’, and showed no bias in treatment recommendations.12 The authors' conclusion: Lay people and individuals with limited medical training might hold false beliefs about biological differences between black and white patients. When such false beliefs inform management decisions it may contribute to racial disparities in pain evaluation and management.12Doctor/patient communications and trust may also be a significant factor in pain analyses.13 Racial priming was then used to identify the ways in which automatic (implicit) and deliberate (explicit) racial biases might influence their treatment.13 Before reading the case reports, half of the students were implicitly primed through a 100-millisecond flash image of an African American or European American; the remaining students were explicitly primed through a 7-sec flash of the same image.13 The study found that implicitly primed participants tended to perceive and respond more to European American patients than to African American patients when the effect of patient race was presumably below the level of conscious control or regulation.13 The opposite effect was observed when the patient's race was presented explicitly, such that participants perceived and responded more to the pain of African American patients than to European American patients.13 This finding is likely the result of participants' conscious efforts to respond without prejudice or bias.In another study, Mathur et al. evaluated 120 self-identified African American medical students and 204 European American medical students. Study participants were read 10 case reports describing pain severity and symptoms.14 set out to examine the role of provider bias and contextual ambiguity in the care of white and black patients suffering from acute pain. Medical residents and fellows recruited from across the country were asked to make clinical decisions on 12 unique patient-simulated cases, evaluating each patient's pain level and the likelihood of using different analgesics. The findings suggest that clinical ambiguity—that is, discordance between patient complaints and physical exams—influenced providers' decisions to treat pain for white patients but not for black patients.14 The study authors provided two potential interpretations of this finding: (1) black patients received care that was less responsive to contextual information, and (2) black patients received more consistent care while white patients received variable care and in some instances were overtreated.14These results suggest that stereotypes, rather than general racial biases, may be responsible for the observed race-based differences in pain perception and response. The study findings present two new questions: How pervasive are these implicit racial biases or stereotypes? And what else might be at play in assessing pain disparities? To answer these questions, Hirsh et al.The Hirsh study highlights the complexity of patient, provider, and contextual factors on pain management decisions, and specifically on provider/patient communications. Furthermore, while implicit bias seems to influence first impressions, if the case presented is clear and unambiguous then these initial impressions seem to play a lesser role. Therefore, the quality of patient/provider interactions appears to be an important factor in assessing and addressing disparities in chronic pain management.15 The differences were largely determined by observation—that black patients were significantly less talkative than white patients during their examinations and provided less information in both the psychosocial and biomedical domains.15 This concept of ambiguity and engagement of black patients during examinations is confirmed in a study by Anderson et al.16 Anderson et al. found that inadequate pain assessment and staff members' limited knowledge of pain management in cancer patients is a significant barrier to physicians' and nurses' ability to manage cancer pain in low-income minority patients.16Furthermore, a study comparing patient/provider communications among black and white HIV-infected patients found that providers were more dominant in conversations with black patients compared with white patients.17 They found that while patients may rank their pain severity the same, in situations with race concordance, patients are more likely to exhibit more distressing pain behaviors.17 These findings suggest that interpersonal and sociocultural behaviors between patient and provider are crucial to determining true pain levels, with implicit bias likely to occur on both sides of the relationship.How do provider/patient interactions differ when provider and patient are the same race? To answer this question, Hsieh et al. evaluated patients' reporting of pain using severity ratings, measurement of affects, and nonverbal pain behaviors. Hsieh et al. compared the differences when provider and patient race were concordant and when they were not.18 Identifying techniques to encourage provider/patient interactions may help reduce disparities. Engaging patients in their own care, particularly those with chronic diseases, is essential to reaching optimal outcomes.19 What is clear is that the assessment of chronic pain is complicated, primarily because pain is inherently subjective, and a lack of objective data or diagnostic concordance complicates comprehensive assessments. The primary means to assess pain remains dependent on patient self-reports and providers with the clinical acumen and communication skills to establish rapport and build trust with their patients. Not surprisingly, provider/patient interactions are highly susceptible to provider bias and variations in quality.Additionally, health illiteracy may contribute to the overall effectiveness of provider/patient interactions, especially when considering that only 12% of Americans have proficient levels of health literacy.20 They found that just 22% of physicians provide care for 80% of African Americans in the United States and that these physicians report limited access to health care resources, such as specialists and diagnostic imaging.20 Bach et al. found that physicians caring for black patients are less likely to be board certified and more likely to report an inability to provide high-quality care to all of their patients.20 Varkey and colleagues took the Bach et al.20 study one step further, evaluating the workplace characteristics of primary care clinics, in which at least 30% of patients are underrepresented racial or ethnic minorities.21 They found that these clinics have less access to medical supplies, fewer examination rooms per physician, and refer fewer patients to specialists.21 These patients are more likely to be covered by Medicaid, report symptoms of depression (within the previous 2 weeks), and convey lower levels of health literacy.21 Also, physicians at these clinics tend to perceive their patients as speaking little or no English, having more chronic pain and substance use disorders, and being more medically and psychologically complex.21 Furthermore, clinics with at least 30% underrepresented minority patients are generally more chaotic. Physicians at these clinics report less control over their work environments, lower job satisfaction levels, and higher rates of burnout.21 The study authors' conclusions: “The combination of time pressure, insufficient resources, and complex patients is likely to constitute a ‘perfect storm’ of challenges that physicians face in providing quality care to large proportions of minority patients.”21In addition to inadequate provider/patient communications, other health system-related factors such as access to care may be driving disparities in pain management. Bach et al. investigated the role that access to care plays in driving disparities.22 The authors observed that patients with limited or no insurance had significantly higher pain scores and tended to be young, single, non-white, and often on opioids.22 These findings reinforce the barriers to access that hinder optimal chronic pain management, including lack of a well-trained and culturally competent workforce.A study by Azhar et al. evaluated access and referrals to specialty pain and palliative care services for patients with advanced cancers.23 The team observed that 63% of residents in low-nSES areas were more likely to receive opioid-only therapy and not receive referrals for physical therapy. In contrast, patients in high-nSes areas tend to receive both opioid and physical therapy.23 This finding is in sharp contrast to that of Joynt et al., which notes a significant decrease in opioids prescribed for moderate-to-severe pain.24 However, this study is based on emergency room approaches to care, which are vastly different from primary care approaches. Gebauer et al., suggest that the low nSES and increased opioid prescriptions might be attributed to patients' lower education levels and a certain unwillingness to accept nonpharmacologic or non-narcotic treatment modalities.23 However, limited access to comprehensive pain care—including rehabilitative medicine, integrative medicine, and pain specialty consultations—and minimal patient/provider communications also contributes to the “non-guideline, quick-fix” approach. Additionally, insufficient neighborhood resources often lead to physical and social isolation and increased stress that often proves detrimental to the chronic pain experience.25Neighborhood socioeconomic status (nSES) is another factor that can significantly influence the quality of care delivered to patients in pain. In a study by Gebauer et al., the influence of nSES was evaluated based on the type of treatment patients with new back pain receive in primary care clinics.26 Another study observed that in outpatient nonemergency settings, white children are more likely to receive opioids while minorities are more likely to receive nonopioid analgesics.27 Recent evidence suggests three main drivers of high-risk opioid prescribing to Medicaid enrollees—white race, rural residence, and depression.28 Also, based on the reviewed evidence, blacks are less likely to receive an opioid for acute pain (nonguideline based), more likely to receive an opioid for chronic pain (nonguideline based), and less likely to receive a high-risk opioid prescription (unless depressed), due to concern over misuse. The bias around African Americans and opioid use disorders or addictions is not supported by the national demographics of opioid users.Differences in pain management also appear to be age independent. For example, in the Emergency Department (ED), black children with appendicitis are less likely to receive pain medication for moderate pain or opioids for severe pain compared with white children.29 Om makes an interesting point, stating that the present national attention on the opioid epidemic might be in part because of past failures in the treatment of addictions. However, it is also plausible that the reaction to the opioid epidemic is yet another example of the disparate attention given to diseases based on the demographics they affect.30Historical patterns of opioid use from 1993 to 2009 show a disparity between the rate of prescription opiates prescribed to white Americans  and the rate prescribed to African Americans . These values directly correlate with opioid overdose rates for white Americans  and African Americans .31 Heroin rates are currently increasing at 31%  per year for whites and 34% per year for blacks (95% CI: 30% to 40%), respectively.32 Concurrently, synthetic opioids are increasing at 79% (95% CI: 50% to 112%) for whites and 107% (95CI: −15% to 404%) for blacks.32Additionally, more recent statistics suggest that opioid-related mortality is affecting whites and blacks equally. This is mainly driven by heroin and synthetic opioids (often laced with heroin), with blacks experiencing the largest relative increase (25.2%) in opioid-involved deaths.33 Additionally, some minority patients face structural barriers and limited availability of opioids in their neighborhood pharmacies due to “medication deserts.”34 Altogether, these factors illustrate that disparities in access may be driving the current opioid epidemic.Historically, prescription opioid drugs have been the gateway to heroin use. This might suggest that heroin use among African Americans results from shortfalls in pain evaluation and management, affordability, and easier access to heroin than to prescription opioids.In this article, we explored the patient-, provider-, and system-level drivers of racial disparities. These disparities represent an ethical dilemma as well as practical barriers that further perpetuate racial differences. The problems are both broad and complex. As health care providers, it is our professional responsibility to equitably deliver evidence-based management that is individualized and patient concordant. Because race has both practical and societal implications, we must address all barriers that prevent us from achieving optimal chronic pain management. Furthermore, it is a mistake to focus on genetic contributions to racial disparities. Doing so minimizes the impact of environmental, structural, and societal factors on managing chronic pain. More importantly, racial bias can lead to stereotyping that detracts from employing objective clinical decision making to treat chronic pain.14 Focusing on provider/patient communications will require more comprehensive cultural competency training to overcome this disparity gap.19 A number of structural barriers exist to prevent standard multimodality pain management in minority patients—including access to specialists , diagnostic imaging, supplies, integrative medicine, psychosocial counseling , and the full array of pharmaceuticals. Both neighborhood and clinic-specific dynamics create time-constrained and chaotic care environments that perpetuate implicit racial disparities and result in low-quality or nonguideline pain management.Racial bias plays a role in some provider tendencies to minimize the pain suffered by African Americans , assuming little ambiguity in the case.35 Furthermore, chronic pain can become increasingly more complex over time resulting in treatment-refractory disease—thus making a timely referral and implementing an early multimodal management plan critical.35 Taken together, these data support a quality improvement initiative to focus more resources on managing chronic pain in the African American population and to confer a patient and societal benefit.35African Americans are not as directly impacted by the overprescribing of prescription opioids, because of the limitations we have addressed so far. However, recent data suggest that African Americans die from heroin and synthetic opioids at a similar rate as their Caucasian counterparts die from prescription opioids. As with other chronic conditions, chronic pain when managed poorly has adverse long-term sequelae such as: impaired sleep, cognitive processes, and brain function; mood/health; cardiovascular health; sexual function; and overall quality of life.36 One way to overcome this mistrust is to partner with community organizations to bring more value to these communities. Community instability or neighborhood social environment has been demonstrated to significantly influence the degree of mistrust in the health care system among the African American community.36 By developing shared goals and building alliances with African American communities, we have an opportunity to increase trust with our neighbors.While experimental models have demonstrated biological and physiological difference in pain perceptions between Black and white patients the etiology is not well described (9), it is also unclear whether this experimental difference has applicability to clinical practice and the allocation of therapeutic interventions for the treatment of acute and chronic pain. Therefore, recruiting more African Americans into clinical research studies will help clarify these variables. Yet, already, our recruitment efforts are compromised by the general mistrust minorities have for the medical establishment.37 This lack of empathy, or at least the appearance of such, highlights a known concern about inadequate training in pain assessment that may focus more attention on pain-related dysfunction in general.38 The data on pain-assessment skills emphasize a need for empathy and, potentially, deeper cultural training for all health care professionals. As patients become more diverse, cultural competence and freedom from bias become crucial professional responsibilities. A related issue is the mismatch between the diversity of health care professionals and patients, as minorities make up 25% of the U.S. population and only 10% of the health care profession.38 A more diverse workforce will enhance cultural sensitivity and the quality of patient interactions while also strengthening the medical research agenda. Culturally focused quality improvements will inform a more enlightened health care system.39Empathy has been shown to have a positive impact on the quality of patient/provider interactions. Yet many primary care providers appear to lack empathy, especially when evaluating patients with chronic pain.40 Health care organizations that exemplify these 10 attributes are better able to help patients access and benefit from a range of health care services necessary for comprehensive CNMP.40 One study found that black or African American patients who received an opioid prescription in the past year not only had higher depressive symptoms but were also associated with increased health care utilization, including visiting low-income clinics for help with chronic pain.41 Based on these findings, the authors suggested that focusing on patients' psychosocial factors would likely confer a larger benefit on CNMP outcomes for patients receiving care at low-income clinics.41 Unfortunately, as published by Varkey, the challenging work environments at low-income clinics contribute to treatment and resource disparities. Burdened by time pressures to see patients and demands to increase relative value units, providers are hampered in their ability to accurately assess the presenting symptoms of under-represented minority patients, especially when there are cultural or language barriers. While these pressures exist in many clinics, low income or not, when added to other resource limitations, providers suffer from stress, fatigue, and burn out that can further trigger a lack of empathy and lead to implicit bias.The spectrum of health literacy affects the care being delivered and warrants a comprehensive educational campaign. In 2012, the IOM published “Ten Attributes of Health Literate Health Care Organizations,” to help people navigate, understand, and use available information and services to take control of their own health.42 The team composition consists of physicians, advanced practice nurses, physician assistants, and nurses.42Clearly, the work environment has a role to play in health disparities, particularly in chronic pain management. One solution is to employ targeted interventions designed to address clinic chaos, work controls, and physician burnout. This is even more relevant today as the U.S. faces a primary care physician shortage. The solution may reside in full implementation of a team-based approach to care—delegating tasks to team members—thus addressing the primary care shortage without adding new physicians.43 Research demonstrates that pharmacists with advanced clinical training perform at least as well as physicians in managing chronic disease states, measured by intermediate outcomes such as glycemic controls and blood pressure.44 Clinical pharmacists who support the management of complex pain patients can reduce burdens on physicians and better guide concordant opioid-based pain care.45Pharmacists are also an important part of the team-based approach to chronic pain management. Most already have relationships with patients in the community, are crucial members of medication management teams, and have the required expertise to review medications and educate patients.The 7 Habits of Highly Effective People, author Steven Covey recounts how people see the world, … “not as it is, but… as we are conditioned to see it.”46 Paradigms are the sources of our attitudes, behaviors, and relationships with others.46 If we want major changes, we must transform the way we look at things, and part of what defines a paradigm shift is learning new habits.46 “Reducing racially or culturally based inequities in medical care is a moral imperative,” explains Geiger.47 As health care professionals, we must lead by example. We must encourage societal change by taking the first important step of honest self-reflection—not only acknowledging the need for change but also providing the solutions. We can start with implicit bias, which is likely the most common form of bias among health care providers and contributor to observed patterns of inequities in the receipt of high-quality care.48–50 Implicit bias is universal, often subconscious, and even the most well-meaning clinicians harbor deep-seated biases, which affect medical decision making and the quality of communication and nonverbal behavior.50In 51 More research is needed to demonstrate that changes in implicit bias are linked with reduction in discriminatory behaviors and improvement in health equity. There is also a need to recognize the ways in which policies and procedures in medical and social institutions sustain racial inequality. While awaiting both the dismantling of institutional legacies of implicit bias and the corroborating research on individual implicit bias reduction, we propose a course of action to begin to mitigate their effects.There is emerging evidence that a variety of social psychological interventions may reduce implicit bias. In one study, implicit biases were viewed as deeply engrained habits that can be replaced by specific behavioral strategies, including stereotype replacement, counter-stereotype imaging, individuation, perspective taking, and increasing interracial contact.(1)Acknowledge the pervasive presence and pernicious effects of implicit bias.(2)Avoid stereotypes; deploy targeted strategies such as stereotype replacement using a consciously adjusted response or counter-stereotypic imaging in which the patient is framed as the stereotypic opposite.(3)Adopt an “individuation” approach with focus on each patient's unique personal history and context for their care.(4)Empathize with each patient—incorporate cognitive empathy of “putting yourself in your patient's shoes” and affective empathy of sharing in the experience of their illness and pain.(5)Establish meaningful partnerships in which the patient/provider exchange is a collaboration between equals and forms the basis of shared decision making.(6)Engage in ongoing critique of our behaviors, attitudes, and biases through patient feedback and self-reflection.It is time for our paradigm shift.


Forty-four patients were randomly distributed into the two arms of the study (robot vs. control). A physician filled the Oswestry disability index (ODI) before starting the treatment and at the end of it, in a blind fashion. In addition, patients filled a visual analogue scale (VAS) after each of the 10 treatment sessions. The ODI and the VAS were analyzed as the primary and secondary outcome measures. Both treatments (robot and control) resulted in a significantly lower ODI (p < 0.05). On the other hand, robot-treated patients significantly reduced their VAS levels (p = 0.0001) whereas control treatment did not reach statistical significance. Patients of both sexes obtained similar benefits from either treatment. Overweight patients (body mass index ≥ 25kg/m2) in the robot arm benefited more from the treatment (p = 0.008) than patients with normal weight. In conclusion, the ADAMO robot is, at least, as efficient as regular treatment in reducing low back pain, and may be more beneficial for specific patients, such as those with excessive weight.Non-specific low back pain (NSLBP) affects many people and represents a high cost for health care. Manual pressure release of myofascial trigger points is used to treat NSLBP and is very effective but difficult to standardize since it is provided by different therapists, which also suffer musculoskeletal complications from this highly repetitive activity. A robot designed for this purpose may help in reducing these problems. Here, we present data from a two-arm, single-blinded, randomized controlled clinical trial evaluating the efficiency of a therapeutic massage robot (ADAMO) in reducing NSLBP ( Low back pain is defined as a musculoskeletal syndrome, or group of symptoms, whose main characteristic is the pain, which is focalized in the lumbar area of the spine. The diagnosis is rather easy since symptoms are very evident. When this pain cannot be attributed to a known cause , it is called non-specific low back pain (NSLBP)  and the Oswestry disability index (ODI) , produced and distributed by Future Sense, Inc (Spain). ADAMO bases its operation on a computer program that controls the manipulator robot, which, by means of cameras installed at the end of its arm, must find in each session the points of treatment in the patient previously defined by the health professional and apply the necessary pressure. This pressure is generated by means of a compressed air nozzle integrated in a handpiece installed at the end of the robot arm . The study follows all tenets of the Declaration of Helsinki and was conducted at the Rehabilitation Service, High Resolution Center San Millán, in Logroño (Spain) between October 2020 and February 2021.This was a two-arm, single-blinded, randomized controlled trial. The study was approved by the local ethics committee  and registered at Patients of both sexes that arrived to the Rehabilitation Service seeking treatment for NSLBP were included in the trial if they were suffering from NSLBP, had between 18 and 60 years of age, and they signed the informed consent form. Participants were excluded if they fulfilled any of the following criteria: pregnancy, impossibility of staying in a prone position, previous pathologies , allergies and/or skin affectations.Sample size was calculated based on data published by Patti et al. . In thathttps://pinetools.com/es/aleatorizar-lista).For each patient, the intervention period lasted for five weeks, with one-h exercise sessions twice a week (10 sessions). Before starting treatment, clinical characteristics of the patient were collected . Then, patients were assessed with an ODI questionnaire and were randomly allocated to one of the two arms of the study: robot and control . Allocathttps://adamorobot.com/)  . Then, tIn the control arm, patients were laid down on the robot platform. Physiotherapists identified the trigger points and the robot was connected, providing the expected background noise and vibration, but the air pressure was not applied. Thermotherapy and rehabilitation exercises were also applied.At the end of each session, the physiotherapist applied the VAS questionnaire (not blinded). At the end of the 10 sessions, the patient went back to the physician's office to complete the second and final ODI questionnaire (the physician was blinded to the treatment).The primary outcome for this study was pain-related disability as tested by the Oswestry disability index (ODI). This is a questionnaire which gives a subjective percentage score of level of function (disability) in activities of daily living in those rehabilitating from low back pain. Possible scores go from 0 to 50, being 0 no pain and 50 the highest possible pain  and two other candidates declined to participate. At the end, 44 patients were randomized into the two arms of the study, and one patient from each arm was lost during the trial. Finally, we obtained complete data from 21 patients in each arm .2. At the beginning of the trial, they presented a median score of 15 in the ODI and 6 in the VAS. After allocation into the two arms of the study, the baseline characteristics of both populations were similar  of 27 kg/m similar .p = 0.009). In the robot treatment group, patients went from 15 (11–20.5) to 11 (5.5–15.5) (p = 0.036). No significant differences were found between the groups in their final ODI (p = 0.58). When analyzing pain perception through the VAS questionnaire, patients in the control treatment arm did not express a significant relief of their symptoms (p = 0.13). On the other hand, patients treated by the robot experienced a significant relief after their 10th session (p = 0.0001), going from an initial VAS of 6 (6–7.5) to 3.6 (2–4). There was no significant difference in VAS final values between both treatments (p = 0.94)  .p = 0.038) and in the robot (p = 0.005) arms. Among men, the control treatment did not reach statistical significance (p = 0.36) but men treated with the robot experienced a very significant relief (p = 0.008), going from 6 (6–8) to 2 (1–4)  .2 are considered overweight. Clinical characteristics of these patients are summarized in p = 0.001), going from 6 (6–8) to 4 (2–5).Another variable we wanted to measure was the influence of the patient's body composition, as measured by the body mass index (BMI). According to metabolic guidelines , reducing disability symptoms. On the other hand, only the robot was able to reduce perceived pain, as measured by the VAS. Interestingly, overweight patients experienced more significant relief than patients of normal weight, and this difference was more striking in the patients treated by the robot.Obesity is a leading preventable cause of death and disease worldwide. The prevalence of obesity was 42.4% in the US in 2018. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer CDC, . The medThe use of robotic devices to perform therapeutic massages has been previously reported  in all patients. Nevertheless, larger effects could be expected from this technology. First, in this study, the air pressure that was applied by the robot arm was always constant. Perhaps patients would benefit from different pressures depending on their specific pathology or body type. Also, a single patient may receive different pressures in specific trigger points, depending on their thickness. Second, in this study, a trained therapist identified the trigger points. We are working on a routine that would allow the robot to identify the trigger points by itself, thus liberating a lot of extra time for the therapist. Of course, the efficiency of the robot in locating the trigger points will need to be validated with a clinical trial.There is evidence that, despite receiving proper training in therapy postures and self-care, a high proportion of massage therapists suffer from upper extremity pain and discomfort as a result of delivering therapy treatments. The most affected areas are the wrist and the thumb, followed by the low back, neck, and shoulders , grant number: 2018-I-IDD-00039.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chronic pain (CP) is a common and debilitating symptom in patients with knee osteoarthritis (KOA). Massage has been supported as a non-pharmacological intervention for the individual symptom relief of CP. However, relevant evidence of using massage for CP in patients with KOA has been lacking.A systematic search will be performed in the following electronic databases for randomized controlled trials to evaluate the effectiveness and safety of massage for CP of KOA: China National Knowledge Infrastructure (CNKI), Wan Fang, PubMed, EMBASE, PsycINFO, and the Cochrane Library databases from their inception to December 2021. The entire process will include study selection, data extraction, risk of bias assessment and meta-analysis.This proposed study will evaluate the effectiveness and safety of massage for CP in patients with KOA. Changes in pain relief and adverse effect will be included in our outcomes.This systematic review will provide evidence for assessing the credibility of massage for CP in patients with KOA.The results of this review will be disseminated through peer-reviewed publication. This review does not require ethical approval because all of the data used in this systematic review and meta-analysis have already been published. Furthermore, all of these data will be analyzed anonymously during the review process. It is reported that 30% to 50% of people over the age of 60 suffer from KOA. Such a high incidence leads to a huge personal and socio-economic burden. The patient's ability to move is limited by CP, which further leads to the aggravation of pain symptoms. CP is one of the most common symptoms in patients with KOA. 25% of KOA patients suffer from severe joint pain. CP is defined as pain that lasts more than 3 to 6 months.–12 Patients with CP are more likely to suffer from depression, anxiety, and insomnia.–16Knee osteoarthritis (KOA) is a common and disabling condition that typically manifests as attacks of pain around the joints, and it is a typical disease which can develop chronic pain (CP).,18 Current trials show that massage therapy is an effective nondrug intervention, which is possible to be more flexible in dealing with different clinical manifestations of CP in patient with KOA. There is evidence that massage has a positive effect on the treatment of KOA symptoms, such as pain without a specified course, stiffness and dysfunction. Massage does not have any major risks or side effects, and has the characteristics of high security, low cost, and convenient operation, and it has certain advantages for patients with drug allergy. This systematic review will attempt to provide a basis for evaluating the credibility of massage therapy in patients with CP caused by KOA.Nondrug therapies is one of the treatments recommended by various guidelines for KOA.Meta-analysis is a powerful statistical technique and is widely accepted as an important tool of evidence-based medicine. So far, there is no evidence for massage to be used for CP in patients with KOA for more than 6 months. Therefore, we perform this protocol to comprehensively assess the effect of massage for CP in patients with KOA, which will attempt to provide a basis for evaluating the credibility.22.1This protocol was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) on December 19, 2021 (registration number: INPLASY2021120087). We will strictly perform this protocol by following the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocol statement guideline.2.2We will conduct a comprehensive search of China National Knowledge Infrastructure (CNKI), WanFang, PubMed, EMBASE, PsycINFO, and the Cochrane Library databases from their inception to December 2021.The inclusion criteria are as follows:Only randomized controlled trials (RCTs) about massage for CP by KOA will be included, with language restrictions in English or Chinese. Case report, experience report, and laboratory studies will not be included.All patients with CP over 6 months will be included without limitation of age, race, gender, economic level, and severity.The interventions of experimental group will only consist of massage therapies, mainly including general massage, acupressure, Chinese massage, relaxation, manual lymphatic drainage and so on. There will be no limitation on the methods, duration, and frequency of massage.The interventions of control group will involve any therapy other than massage .2.3Primary outcomes: Western Ontario McMaster Osteoarthritis Index pain subscore.Additional outcomes:WOMAC Stiffness subscore, Physical Function subscore and global score.Visual analogue scale.A 12-item Short-Form Health Survey (SF-12).Pressure pain threshold.Numerical rating scale of soreness intensity.Adverse events.Frequency of delayed onset of muscle soreness.2.4We will perform a comprehensive search in PubMed, the Cochrane Library, EMBASE and 4 Chinese databases  for articles published before December, 2021. Only RCTs that used massage as the main treatment for adults with athletic injuries will be included. The Chinese and English search strategies in PubMed database are shown in Table 2.5All the search results will be imported into NoteExpress v3.5.0.9054 for management. Two reviewers (JX and YF) will independently screen all potentially eligible studies. Titles and abstracts will be screened first to exclude irrelevant citations. Full text of all the articles with potentially relevant abstracts will be retrieved and screened according to the study eligibility criteria. Disagreements will be resolved by consensus or discussion with a third reviewer (GG). The research flow chart is shown in Figure 2.6Two reviewers will extract data from the included literature through Microsoft Excel 2010 , mainly including the following information  will evaluate the consistency of all the extracted data and quality ratings. Disagreements will be resolved by discussion with a third reviewer (GG).Study quality will be assessed in RevMan V5.4.1  using the Cochrane risk of bias tool.2.9P > .1 or I2 < 50%). If there is a significant heterogeneity (P > .1 or I2 < 50%), we will conduct subgroup analysis or sensitivity analysis to identify possible causes of heterogeneity among populations.Revman 5.4 software will be used to perform statistical analysis. For discontinuous variables, the risk ratio with 95% confidence interval (CI) will be selected. For continuous variables, the weighted mean difference with 95% CI will be selected when the measuring instruments are the same, and the standardized mean difference with 95% CI will be selected when the measuring instruments are different. We will use the fixed-effect model if there is no significant heterogeneity .2.11To identify the robustness of the meta-analysis, low-quality trials, with high risks of bias or outcomes that are seriously distant from the rest of the data, will be excluded.2.12Ethical approval will not be in need because the data used in this systematic review will not be individual patient data, and there will be no concerns regarding privacy.3 The mechanism of CP in KOA is complex and the degree of pain may be inconsistent with the local abnormal pathological manifestations of the knee. At molecular level, an animal model study shows that inflammation contributes to the evolution of joint tissue degradation and remodeling as well as joint pain.,28 On the structural image, CP can cause more bad experiences and induce changes in brain structure and brain function related to emotion. The reorganization of functional brain network structures such as thalamus, periaqueductal gray (PAG), anterior cingulate cortex (ACC) and prefrontal cortex (PFC) is closely related to KOA-related CP.–34 Emotion can in turn aggravate the pain experience. At biomechanical aspect, a study compared the walking gait biomechanics of patients with KOA after intensive intervention of lower extremities. Fifty-three patients with KOA had slight changes in their knee flexion angle (KFA) due to the enhancement of lower limb muscle strength 10 times in 28 days.Quality of life of a large number of patients with KOA is reduced by CP. The efficacy of massage in the treatment of KOA has been confirmed by some RCT.,38 A study found that massage can change the expression of RANTES and MCP-1 and improve the symptoms of KOA, The latest research also points out that massage can not only remove neutrophils from seriously injured muscle tissue, but also eliminate inflammatory factors released during the process, thus promoting the regeneration of muscle fibers. It can also adjust the changes of pain-related brain function network.,34,40 A study of 72 KOA patients shows that 36 times massage in 12 weeks can improve the soft tissue tension, adjust the structural relationship of the knee joint, make the tibial angle tend to normal range to balance local mechanics, reduce the degree of varus deformity and reduce the pain of patients. A study of 18 female patients with KOA shows that 6 weeks of massage plus exercise is more beneficial to blood circulation, muscle tension, and flexibility than only exercise, thus improving patients’ mood and quality of life. An increasing number of studies have demonstrated that massage has beneficial effects on symptom management in patients with KOA,42; however, almost all the studies focused on pain without time limit. And there is a widespread lack of identification of the most effective massage treatment for CP.Massage in the treatment of KOA has a history of thousands of years in China.Therefore, this online meta-analysis will provide a detailed summary and analysis of the latest evidence, with a focus on the available massage methods. We hope that our findings will help patients, clinicians and health care policy makers make better treatment choices for CP.JX, YF, and BW conceived the study. SX, HZ, GW, and GG provided general guidance to the drafting of the protocol. JX and BW drafted the protocol. GW and SX designed the search strategy. GG, BW, and JX drafted the manuscript. SX, HZ, BW, GW, YF, JX, and GG reviewed and revised the manuscript. All authors have read and approved the final version of the manuscript.Conceptualization: Guangxin Guo.Funding acquisition: Guangxin Guo.Writing – original draft: Jianghan Xu, Boyi Wu, Shengji Xie, Guanghui Wu, Heng Zhang, Yangyang Fu, Guangxin Guo.Writing – review & editing: Jianghan Xu, Boyi Wu, Shengji Xie, Guanghui Wu, Heng Zhang, Yangyang Fu, Guangxin Guo.


The purpose of this study was to outline the feasibility of continuous epidural analgesia in the treatment of failed back surgery syndrome (FBSS) or spinal stenosis.We queried our prospective collected institutional database to include all consecutive patients, who underwent continuous epidural analgesia with accompanying intensive physiotherapeutic exercise within a timeframe of 4 years. Patients suffered from FBSS or spinal stenosis; protocolled continuous epidural analgesia was planned for 4 days within the framework of an inpatient multimodal pain therapy concept. The instillation technique of the epidural catheter, the capability to attend in accompanying physiotherapy, and the peri-interventional complications were evaluated.p = 0.007).153 patients with an average age of 57.4 years (± 11.9) were enrolled in this study. 105 patients suffered from FBSS and 48 patients had spinal stenosis. Overall, 148 patients (96.7%) reported the pain reduction and were able to perform daily intensified physiotherapeutic exercise. There were no serious adverse events, neither infection nor bleeding, no cardiopulmonary complication or permanent neurological deficits. The most common side effect was neurological impairment, such as numbness, dysesthesia, or weakness of the lower limbs with complete regression after flow rate adjustment. Patients with FBSS were more likely to develop dysesthesia (Continuous epidural analgesia is feasible in patients with FBSS or spinal stenosis. This treatment enables extensive physiotherapeutic treatment even in patients with severe pain conditions and can be considered as an alternative to epidural injections. An increased complication rate in comparison to short-term perioperative or perinatal application was not observed. There has been an increasing rate of surgery for degenerative spinal diseases within the last 30 years due to wider availability of radiological imaging for the broader public and improvement of surgical techniques toward novel minimal invasive and reconstructive procedures . NeverthLocal instillation of anesthesia yields promising results in patients suffering from FBSS or spinal stenosis , 4. Due Is it feasible to routinely place epidural catheters in patients with spinal pathologies, such as FBSS or spinal stenosis?Does continuous epidural analgesia enable the patients to undergo intensified physiotherapeutic treatment, which was not possible before the catheter placement due to chronic low back pain? Overall, is it feasible to undergo physiotherapy with a placed epidural catheter?What is the complication rate in this special cohort of patients in comparison to perioperative or perinatal application reported in the literature? Do serious adverse events occur and what are the main complications and problems following epidural catheter placement in these degenerative and post-operative spinal conditions?No study has been published yet that investigates the feasibility of continuous epidural analgesia for pain management in patients with FBSS or spinal stenosis. According to that, our study aims to evaluate the feasibility of continuous epidural analgesia in the treatment of patients with FBSS or spinal stenosis regarding three main questions:This retrospective study was conducted after approval by the ethics committee of the medical university center of Frankfurt / Main, Germany. A prospectively collected institutional database was reviewed retrospectively. All patients with chronic low back pain due to FBSS or spinal stenosis who received continuous epidural analgesia as part of an inpatient multidisciplinary biopsychosocial rehabilitation program within a timeframe of 4 years were enrolled in this study. Chronic low back pain was defined as pain which is localized between the costal margin and the inferior gluteal folds with or without radiculopathy for at least 3 months. In addition, FBSS is defined as a collective of patients with symptomatic recurrent lumbar disk herniation, insufficient pain relief, or pain recurrence after mono- or bi-segmental decompression of the lumbar spine or after mono- or bi-segmental lumbar interbody fusion. Spinal stenosis is defined as an abnormal narrowing of the lumbar spinal canal with a limitation of the pain-free walking distance due to pain or motorical dysfunction in both legs.(a) Severe impairment of quality of life or ability to work;(b) Failure of previous monomodal pain therapy;(c) Opioid addiction or misuse;(d) Accompanying psychological diseases.Inclusion criteria for this therapy were chronic low back pain due to FBSS or spinal stenosis that could not be managed by outpatient treatment and the patient’s wish for extended conservative therapy. None of the patients was able to participate in physiotherapy on a regular basis despite the existing pain medication and additionally fulfilled at least two of the following characteristics:All patients included in this therapy concept received continuous epidural analgesia. Single or repetitive epidural injections were not performed. Physiotherapeutic treatment included structured and repetitive exercise interventions, such as exercises for muscle strengthening, core stability, coordination and stretching muscles. Passive interventions, such as manual therapy, massage, or electrotherapy, were reduced to a minimum. Physiotherapeutic treatment was performed in individual training or in group training sessions for at least 45 to 60 min each session and at least twice a day. Exclusion criteria included (sub-) acute fractures, pregnancy, active malignoma, infections, and patients receiving full anticoagulation treatment.After patient information and obtained written consent, epidural catheter placement was performed by a senior anesthesiologist at the interspace closest to the clinical level of pathology or one segment higher or lower. For patients with FBSS the catheter was inserted above or below the surgical scar. All patients were placed in a sitting position. After disinfection of the puncture site, the Tuohy needle was placed according to the landmarks with ultrasound assistance. Using the saline loss-of-resistance technique, an epidural catheter was inserted through an 18-gauge Tuohy needle  and advanced 3 cm beyond the needle tip. Correct position of the catheter was confirmed by a test dose of 2 ml of 0.2% ropivacaine, followed by a patient-controlled epidural analgesia (PCEA) with a background infusion of 1.5 ml/h 0.2% ropivacaine and a 3 ml bolus with a lockout time of 120 min. The flow rate was adjusted based on the pain reduction of the patient in steps of 0.1 to 0.2 ml/h until the pain reduction enabled a sufficient mobilization. In case of the occurrence of neurologic deficits, the flow rate was stopped until the patients showed a complete symptom relief. The flow rate was then restarted at 1.0 ml/h. The catheter was fixated with adhesive bandage. First mobilization was carried out under medical supervision. Complication assessment was carried out on a daily base and the flow rate adjusted if necessary. Before catheter removal triamcinolone 40 mg was applied. In case of persistent lower extremity neurologic deficits after adjusting the flow rate for more than two times or if there were signs of superficial infection or other serious side effects or in case of patient dissatisfaction the catheter was removed immediately and without corticosteroid application.t test was used for normally distributed data, the Wilcoxon and Mann–Whitney U test for non-normally distributed data and the Fisher two-sided exact test for dichotomous data and small sample sizes. A p value ≤ 0.05 was considered statistically significant. Statistical analysis was done using “BiAS for Windows” (version 11.09.).Demographic and descriptive data, such as gender, age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, comorbidities, duration of catheter insertion, and peri-interventional complications, were collected. In case of premature termination of the epidural catheter treatment or if physical exercise was not performed, the underlying reasons were noted. For numerical data, mean values and standard deviations or medians and quartiles are calculated depending on distribution. Categorical data are presented as absolute and relative frequencies. The parameters were compared between the two groups. The student’s 2 (± 6.0). 17 patients (11.1%) had an ASA-score of I, 100 patients (65.4%) were ASA II, and 36 patients (23.5%) were ASA III. The most common observed secondary diagnosis was hypertension , followed by depression  and neurological deficit of the lower extremity . Patients with spinal stenosis were older (61.0 years (± 12.5) vs. 52.6 (± 10.9), p value < 0.001), had a higher BMI (32.0 kg/m2 (± 6.5) vs. 28.5 kg/m2 (± 5.8), p value: 0.001), and were more likely to suffer from hypertension .Patient characteristics and pre-existing conditions are shown in Tables p value: 0.280, for detailed information see Table Patients with FBSS or spinal stenosis did not differ significantly in terms of oral pain medication according to the WHO level scheme  slipped during physiotherapy. They did not suffer from sensorimotor deficits. In no case epidural catheter treatment caused an extended inpatient stay, need for medication or for surgical intervention Table .Table 4Ap value: 0.007). Overall, the rate of temporary lower extremity neurological impairment did not differ significantly . A dysregulation of the autonomic nervous system including nausea, dizziness, or headache, was rarely observed . All these symptoms completely disappeared after adjustment of the flow rate. Eleven patients (7.2%) developed temporary local pain. 19 patients (12.4%) had prolonged bleeding at the puncture site.The most common side effect was temporary neurological impairment in 91 patients (59.5%). This included numbness in 70 patients (45.8%), dysesthesia in 22 patients (14.4%), and motor deficits in 15 patients (9.8%). Patients with FBSS were more likely to develop dysesthesia  underwent physiotherapeutic treatment. Only in five patients (3.3%), the epidural catheter treatment did not provide pain relief or was followed by recurrent lower extremity neurologic deficit leading to no participation in physiotherapy.In chronic low back pain, non-pharmacological approaches, such as physiotherapeutic and psychological treatment modalities, are recommended as a first-line therapy . NeverthEpidural catheters are widely used for peripartal and perioperative pain management, but there are only few reports with small case numbers and uncommon methodological approaches assessing the use of continuous epidural analgesia in patients with chronic low back pain –17. DoliFor decades, there has been an ongoing discussion on the possibility of degenerative changes of the lumbar spine such as spinal stenosis to worsen or to cause neuraxial injuries following lumbar epidural analgesia . There aHowever, catheter positioning in patients with known FBSS or spinal stenosis is challenging due to a reduced spinal canal cross-sectional area, distorted anatomy, and possible scar tissue. Thus, epidural catheter placement should only be performed by experienced anesthesiologists. Because of the retrospective nature of this study, it was not possible to document the concrete number of patients who have not received continuous epidural analgesia due to technical difficulties. Nevertheless, in our experience it is possible to routinely place epidural catheters in patients with FBSS or spinal stenosis that technically could also be treated with epidural injections.In our study’s cohort, serious adverse events were not observed . IrritatTwo patients accidentally slipped during physiotherapy. This was not secondary to sensorimotor deficits. The approximated probability of accidental falling in general population over 65 years is estimated at 0.1% per day and is further increased in patients with spinal degeneration , 26. HowThis study was limited due to its retrospective study design. There was no randomization and no further comparison with a placebo group. It would certainly be desirable to investigate the advantages and disadvantages of epidural catheter treatment compared to single or multiple epidural injections. It should also be investigated whether epidural catheter treatment can be used as an alternative to percutaneous adhesiolysis which is effective in FBSS after the failure of conservative treatment, including epidural injections , 27, 28.This is the first study to investigate the feasibility of continuous epidural analgesia as part of an inpatient treatment program. Continuous epidural analgesia is feasible in patients with FBSS or spinal stenosis and enables enhanced physiotherapeutic treatment even in patients with severe pain conditions. Despite the degenerative or postoperative changes of the lumbar spinal canal, an increased complication rate in comparison to perioperative or perinatal application as reported in the literature was not observed. This treatment can be considered as an alternative to conventional epidural injections and should be established in studies for different lumbar pain conditions, especially in the management of acute lumbar disk herniation prior to microdiscectomy.


Resilience represents a fundamental element in the experience of pain, as it allows adaptation to suffering and increases psychological social well‐being and quality of life (QoL). We investigated resilience in patients affected by urologic chronic pelvic pain (UCPP) and the relationships with pain severity and distribution, catastrophizing and psychological distress.Forty‐eight consecutive UCPP patients were classified on a pain body map as being affected by pelvic pain only or widespread pain (WP), and underwent the evaluation of resilience with the 14‐item Resilience Scale (RS‐14), with higher scores indicating high resilience levels; scores < 56 denote very poor resilience. Pelvic and nonpelvic pain intensity and the bother of urinary symptoms on QoL were measured by means of Pain Numerical Rating Scale (PNRS) and Visual Analog Scale (VAS). Pain Catastrophizing Scale (PCS) and Depression Anxiety Stress Scales (DASS‐21) investigated catastrophizing and psychological conditions.SD total score was 50.2 ± 12.5 in patients with pelvic pain only and 40.2 ± 10.2 in those with WP. Significant relationships were observed between low resilience levels and high scores of pelvic and nonpelvic PNRS, VAS, pain catastrophizing scale and depression and anxiety, stress scale . Significantly lower RS‐14 scores were detected in females and in patients with WP.Overall, RS‐14 mean ± A very poor resilience has been identified in UCPP patients, particularly in those with greater catastrophizing and mood alterations. WP and female gender were mostly affected. In UCPP patients, low resilience appears as a crucial factor in pain experience. Diagnosis of IC/BPS and CP/CPP was previously performed according to the European Society for the study of IC, with the exclusion of confusable diseases and to the Consensus Definition and Classification of Prostatitis from the National Institute of Health.Sociodemographic characteristics  and clinical data were collected in a clinical setting by in‐person interviews at the three out‐patient urology clinic departments. Collected information were then sent to our data management site for the final analysis. Patients were classified with a pain body map as being affected by pelvic pain only (PP only), pelvic pain and beyond the pelvis, and widespread pain (WP).RS‐14 is a measure of resilience, with intrinsic properties highlighting individuals' positive psychological prerogatives rather than deficiencies, it includes a 7‐point rating  with scores ranging from 14 to 98.2.1t test and the Mann–Whitney U test were used to compare continuous parametric and nonparametric variables. χ2 test with Yates' continuity correction or Fisher's exact test were used to test associations between categorical variables. The Pearson correlation assessed the relationships between variables. A two‐sided p < 0.05 was considered significant. All values are expressed as mean ± SD. Calculations were performed with IBM‐SPSS version 25.0 (IBM Corp).The Student 3SD age between patients with PP only and those with WP , while patients with WP had a trend to a significant longer disease duration as compared to those with PP only .From June to September 2020, 61 UCPP patients were prospectively observed and included in the study; 48 cases  completed all the questionnaires and underwent the evaluation. All patients were under a multimodal treatment regimen based on the UPOINT system,On the pelvic pain site map, 10/48 patients 20.8%) presented with PP only, two with PP and beyond (4.1%) and 34/48 (70.9%) with WP . Among patients with WP, women presented with significantly higher scores as compared to men  . Table p < 0.000). RS‐14 items indicative of “authenticity” and “perseverance” were significantly lower in males and females with WP presenting with higher stress scores . Other significant relationships were observed among RS‐14 and marital status and employment, with lower RS‐14 scores being detected in patients who were single and not engaged in work activity . Finally, no significant relationship was detected between RS‐14 scores and duration of disease.Overall, we could detect significant relationships between lower RS‐14 scores and higher pelvic and nonpelvic PNRS (4The present study investigated resilience profile in a group of UCPP patients and assessed the relationships with pain intensity and distribution, catastrophizing, and general distress. We found very low resilience levels in UCPP patients, particularly in those presenting with WP and COPCs and, overall, in female gender. To our knowledge this the first study investigating resilience in patients with UCPP. In our study, patients with very poor resilience scores showed also high levels of catastrophizing, stress, and mood disorders.While it is known that UCPP patients demonstrate catastrophizing beliefs about pain, especially when they show multiple comorbid conditions, and high rates of mood disorders and general distress,Resilience is a multidimensional entity determined by the interplay among hereditary, biological, emotional, intellectual, and external factors and it ascribes to the process of adapting well in the face of adversity, and eventually return to preadversity status.Indeed, resilience is not only a personality' trait but it involves specific neurobiological changes, such as modifications in the cerebral content of neurotransmitters,All our UCPP patients presented with a very poor resilience, which was particularly affected in cases with WP and multiple COPCs. There is no consensus on the causes of WP and COPCs, but it is generally retained they can be the result of central sensitization, with consequent, abnormal plasticity in several brain regions.Another notable finding was the gender difference in resilience we observed in the present study, with the three domains being more impaired in women and particularly in those with widespread pain. This is in contrast with the original validation study,The finding in our study of a poor resilience profile particularly in patients living alone and not engaged in work activity is in line with previous observations showing that emotional and social relationships improve resilience and well‐being.Resilience in our study was measured with the Italian version of RS‐14, which has been validated in a homogeneous group of young, unmarried females, with resultant scores appearing difficult to compare to those in the current study. Indeed, the validation study of the original RS‐14 was performed in middle aged and older adults.Limitations in our study were the small UCPP population included, and the higher number of females and cases with WP. Longitudinal data are needed to further elucidate resilience profile in UCPP patients, with deeper investigations about possible links between resilience, pain, and other psychological aspects. Worth of noting, all the patients we studied were under a phenotyping‐based, multimodal treatment strategy with beneficial effects on pain as compared to before treatment. Nevertheless, the results in our study induce us to state that we are still far from controlling all the pathological aspects of UCPP, specifically poor resilience, impaired mood, and catastrophizing beliefs, all making the experience of pain really a source of suffering, and requiring also resilience‐oriented interventions.5Patients affected by UCPP with greater catastrophizing, mood alterations, and severe general distress present with very low resilience levels. A common pathogenetic process could underpin the co‐occurrence of chronic pain, mood disorders, and low resilience.Antonella Giannantoni: conception and design of the study, data collection, drafting the article, critical revision of the article and final approval of the version to be published. Marilena Gubbiotti: data collection, data analysis and interpretation. Matteo Balzarro: data collection, data analysis and interpretation. Emanuele Rubilotta: data collection, critical revision of the manuscript, final approval of the version to be published.The authors declare that there are no conflict of interests.


To evaluate the effect of corticosteroid injections in the painful temporomandibular joint (TMJ) of patients with rheumatoid arthritis (RA) in relation to systemic inflammatory activity.Examination of 35 patients  included maximum mouth opening capacity, degree of anterior open bite (AOB), TMJ pain intensity at rest, and crepitus. Serum levels of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serotonin, and plasma levels of interleukine-1β (IL-1β) were determined. Out of the 70 examined joints, 53 joints received a corticosteroid (methylprednisolone) injection after the clinical examination at baseline (T0). The examination was repeated for all patients at T1 (median 3.1 weeks after T0), and for 21 patients at T2 (median 6.3 weeks after T1), of whom 20 patients received a second injection at T1.Maximum mouth opening capacity significantly increased, and TMJ pain intensity significantly decreased between T0 and T1, but these improvements were no longer present at T2. No differences were found in AOB between the time points. Of the joints that received an injection at T0, 19 joints had pretreatment crepitus, which resolved in eight joints at T1. No correlations were found between the change in mouth opening capacity or TMJ pain intensity and ESR, CRP, serotonin, or IL-1β.Methylprednisolone injections in the TMJ alleviate pain and improve mouth opening capacity for approximately 3 weeks, allowing patients to perform jaw exercises during this timeframe of temporary relief. It thus seems useful for the short-term management of TMJ involvement in RA. Rheumatoid arthritis (RA) is an auto-immune disease affecting the synovial joints . RA sympAs recommended by the European League Against Rheumatism (EULAR), standard management of RA consists of systemic pharmacological treatment with disease-modifying antirheumatic drugs (DMARDs) . OccasioIn people with arthrogenous TMJ pain, corticosteroid injections were shown to be an effective method for pain reduction . In patiTherefore, the aim of the current study was to evaluate the clinical effect of corticosteroid injections in the painful TMJ of patients with RA, which were performed as a part of routine care, in relation to systemic inflammatory activity. We hypothesize improvement of pain and, consequently, improvement of function after treatment with corticosteroid injections. Furthermore, we hypothesize that lower pretreatment systemic inflammatory activity, as assessed by CRP and ESR, and lower pretreatment levels of serotonin and interleukin-1β result in better treatment effects on TMJ pain and function.A total of 35 patients, 31 woman and 4 men, with RA according to the 1987 classification criteria of the American College of Rheumatology , were inThis project has a prospective cohort study design, and was approved by the regional ethical committee at Karolinska Institutet, Stockholm, Sweden  according to the Declaration of Helsinki. Written informed consent was obtained from all study participants.The clinical examination included the assessment of several variables, further described below. All clinical examinations were performed by two experienced examiners , and the two examiners were calibrated regularly throughout the years, both theoretically and clinically, in order to prevent drift.The maximum voluntary mouth opening was measured in millimeters between the right central incisors, with the vertical overbite added.The degree of anterior open bite (AOB) was assessed by recording of the occlusal contacts upon hard biting on a double occlusal foil in intercuspid position . Both the left side and the right side were assessed, and the following scores were used: 0 = occlusal contacts including the canine, 1 = no contacts anterior to the first premolar, 2 = no contacts anterior to the second premolar, 3 = no contacts anterior to the first molar, 4 = no contacts anterior to the second molar, and 5 = no occlusal contact. The sum of the scores of both sides was used in the analyses as an estimation of the degree of AOB. None of the patients in this study was edentulous, and the possible score thus ranged from 0 to 9. Score 9 (4 + 5) means that only one contact between two opposing posterior molars exists on one side.Local TMJ pain intensity at rest was assessed using either a 10-cm visual analogue scale  or a numerical rating scale  with the end points “no pain” (score 0) and “worst pain ever experienced” (score 10). Despite the use of two types of scales throughout the years of examinations, minimal influence on the results is expected due to the high correspondence between the two types of scales .Besides maximum voluntary mouth opening, participants were asked to perform maximum protrusion and maximum laterotrusion to both sides. Crepitus was recorded as present if crepitus was palpable or audible during at least one of these movements.Probable clinical arthritis was defined according to Alstergren et al. , where “Venous blood was collected at the start of the first visit and immediately before the clinical examination, to determine serum levels of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serotonin, as well as plasma levels of interleukine-1β (IL-1β). Rheumatoid factor titers below 15 IE/mL and C-reactive protein levels below 10 mg/L were considered as zero values according to the standard procedures of the accredited laboratory at the Department of Clinical Chemistry at Karolinska University Hospital, Huddinge, Sweden.After the clinical examination at the first visit (T0), painful TMJs received an injection with glucocorticoid methylprednisolone (40 mg/mL) with lidocaine (10 mg/mL) added . A volume of 0.7–0.8 mL was injected in the upper joint compartment of the TMJ. All injections were administered by a dentist with a specialization in orofacial pain and dysfunction, several years of experience in the use of TMJ corticosteroid injections, and more than 2500 synovial fluid samplings (SK or PA), without the use of imaging guidance. Participants also received individualized care with self-care instructions, including jaw exercises.For all patients, the clinical examination was repeated (T1) after a median  interval of 3.1 (2.1–9.0) weeks. Based on the clinicians’ decision on desired follow-up within the clinical care setting, for 21 patients, the clinical examination was repeated again (T2) after a median (IQR) interval of 6.3 (4.3–17.9) weeks between T1 and T2.th/75th percentiles are presented. Differences in maximum voluntary mouth opening, anterior open bite, and pain intensity between time points were tested with the Wilcoxon signed-ranks test. To assess the correlation between clinical effect of the corticosteroid injections and systemic variables, the changes in maximum voluntary mouth opening and pain intensity between T0 and T1 were used as the clinical variables. The significance of correlations was tested with the Spearman’s ranked correlation test. A probability level of p < 0.05 was considered as significant.Non-parametric statistics were used throughout the study due to the characteristics of most measured variables. For descriptive statistics, median values and 25Data were collected for 70 joints in 35 RA patients. Table p = 0.004). For the 21 patients that had a third visit, the median maximum mouth opening capacity slightly increased between T1 and T2, but this change was not significant , and there also was no significant difference between T0 and T2 , and also not between T1 and T2 , nor between T0 and T2  for patients that had three visits.The AOB did not differ significantly between T0 and T1  for the joints that received an injection at T0. For patients that had a third visit, no further difference was found between T1 and T2 , nor between T0 and T2 . For the joints that did not receive an injection at T0, no differences in TMJ-pain intensity over time were found , CRP , and serotonin , nor to plasma levels of IL-1β .The change in maximum voluntary mouth opening between T0 and T1 did not correlate to pretreatment serum levels of ESR , CRP , and serotonin , nor to plasma levels of IL-1β .The change in pain intensity between T0 and T1 also did not correlate to pretreatment serum levels of ESR  patients, adverse joint findings such as accelerated OA progression have been observed . HoweverIn this study, the change in maximum mouth opening and pain intensity was not related to pretreatment systemic inflammatory activity. However, in a population of patients with various rheumatic diseases, Fredriksson et al.  found anNo significant changes in the degree of anterior open bite (AOB) were found over time. AOB can be used as a coarse clinical sign of tissue destruction, and may develop over time in RA patients with TMJ involvement . The durThe limitations of the current study that may influence the generalizability of the conclusions, further discussed below, include the lack of a control group, the lack of information on individualized care regarding the TMJ, the use of the 1987 classification criteria for RA, the lack of detailed information on systemic pharmacological treatment, and that the medication profiles presumably do not fully correspond to current guidelines.In studies that measure the effect of a certain treatment, it is preferable to have a non-treatment control group. On the other hand, one of the main aims of this study was to relate treatment effects to systemic inflammatory activity. In the current study, 17 joints did not receive treatment with a corticosteroid injection and showed no change in pain intensity over time. However, these joints cannot be considered as pure controls because the decision to inject was based on baseline pain intensity. In these joints, pain intensity was very low to absent throughout the duration of the study, and they are thus difficult to compare to the joints that did receive an injection. In addition, anti-inflammatory treatment in one joint may influence the contralateral joint through systemic or central mechanisms.In addition to the corticosteroid injections, participants within this study received individualized care with self-care instructions, including jaw exercises. However, specific information was not available to take into account during the analysis of the results. Furthermore, the clinical relevance of the decrease in pain intensity and increase in maximum mouth opening capacity were not measured on a subjective level. In future research, the combination of corticosteroid injections and other treatment modalities, and the subjective effect of the injections—for example, as measured by possible changes in oral health-related quality of life—deserve further attention.Since patients were included between 1990 and 2006, RA was diagnosed according to the 1987 classification criteria of the American College of Rheumatology (ACR). In 2010, the ACR and the European League Against Rheumatism (EULAR) published revised classification criteria . These 2Specific data on the pharmacological treatment of patients were not available and could thus not be analyzed as a possible confounding factor. The medication profiles presumably do not fully correspond to current guidelines, since the period of data collection was mostly before the introduction of biologics, which means that results can only be generalized to RA patients that are not on biologic therapy. However, it may also be considered an advantage as previously mentioned. Furthermore, although developments in the treatment of RA have substantially changed the course of the disease, nowadays frequently resulting in remission , 25, recThis study indicates that corticosteroid injections with methylprednisolone in the TMJ alleviate pain and improve mouth opening capacity for approximately 3 weeks. The temporary relief achieved with an injection can facilitate patients to perform jaw exercises, without being limited by pain. Corticosteroid injections thus seem useful for the short-term management of TMJ involvement in RA.