Background and Objectives: Pain is a multidimensional phenomenon with a wide range regarding the location, intensity and quality. Patients with chronic pain, in particular those suffering from mixed pain, often present a special challenge. The PainDETECT questionnaire (PD-Q) is a screening instrument designed to classify whether a patient has neuropathic pain (NP), often rated as more distressing compared to nociceptive pain. The objective of this study was to investigate whether the PD-Q score correlates with pain intensity, measured with the numeric rating scale (NRS), in chronic pain patients in an outpatient setting. Materials and Methods: A questionnaire-based study was conducted to identify the associations between the unidimensional NRS scale for pain intensity and the PD-Q score for screening of an NP component in an outpatient setting. Participants were asked to fill in the questionnaire themselves. Results: One hundred seventy-six participants completed the PD-Q questionnaire and rated pain on the NRS scale at the baseline visit. The PD-Q and NRS scores significantly correlated at the baseline visit and the 1-month follow-up visit in chronic pain patients. The identification of a neuropathic component in chronic pain may permit more targeted and effective pain management. Conclusions: The findings of our questionnaire suggest that a significant proportion of chronic pain patients had manifested features of NP at the first visit to the outpatient clinic. The PD-Q is a useful screening tool to alert clinicians of NP that may need further diagnostic evaluation or therapeutic intervention and may also help to predict treatment response. Further research is needed to investigate if a correlation is predictive of treatment response when pain therapy targets NP. Pain represents a major clinical, social and economic problem. Chronic pain is a multidimensional phenomenon with a wide range regarding the location, intensity and quality. In particular, the group of patients suffering from chronic pain often present a special challenge for physicians specialized in the field of pain management.Epidemiological surveys reported that a large proportion of chronic pain patients, particularly ones with neuropathic symptoms, is not treated appropriately ,2,3. ThiNeuropathic pain (NP), often underdiagnosed and undertreated, is a frequent condition affecting 7–10% of the general population . It is cIt should be noted that not all patients affected by neural disorders or lesions develop neuropathic sensations . Indeed,The common definition of the term “mixed pain” is a pain with an overlap of nociceptive and neuropathic symptoms ,11. It iTherefore, to identify chronic pain patients with potential mixed pain, validated screening tools such as the PainDETECT questionnaire (PD-Q) may be advantageous in the evaluation and management of complex pain.The PainDETECT screening questionnaire (PD-Q) was designed to measure neuropathic components in pain. It has an easy-to-use paper and pencil version that can be performed in less than 5 min . StudiesUsing the PD-Q to screen a patient with chronic pain, particularly one suffering from pain with both nociceptive and neuropathic components, allows the physicians to use targeted treatment according to the evaluation scores.This study was designed to investigate whether the PD-Q score correlates with the corresponding numeric rating scale (NRS) score in chronic pain patients with mixed diagnoses in painful conditions in an outpatient setting.Study subjects were recruited from outpatients diagnosed with chronic pain at the Division of Special Anesthesia and Pain Medicine at the Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University Vienna between September 2010 and June 2011. Patients were selected according to the following inclusion criteria: age ≥18 years and painful disease lasting for more than 6 months. Exclusion criteria were inability to perform PD-Q questionnaire; history of neurological or psychiatric diseases or disorders; abuse of medication, alcohol or drugs; or an existing therapy with WHO III analgesics. The study protocol was approved by the local Ethics Committee of the Medical University of Vienna. Informed consent was obtained from each participant.Participants completed a validated self-administered questionnaire (PD-Q) and rated their pain on a numeric rating scale (NRS) at baseline visit and at the 1-month follow-up.The PD-Q is a symptom-based assessment tool performed by clinicians to specify the subjective neuropathic pain experience of patients. With the score, pain can be classified into neuropathic, unclear or nociceptive pain groups. It was developed for the identification of a neuropathic component. It evaluates pain intensity, pain pattern and pain quality, with a sensitivity and specificity of over 80% . The ovePain intensity was observed using the 11-point numeric rating scale . Participants were asked about their pain experienced at the moment of testing (current pain), the average pain during the last 4 weeks and the maximum pain during the last 4 weeks. The NRS score was evaluated at baseline visit and re-evaluated at the 1-month follow-up.t-test for independent samples and the Kruskal–Wallis test were used. The chi-squared test was used to screen for correlations between gender and the distribution into the subgroups. Participants were divided post hoc into subgroups based on PD-Q score  and anti-neuropathic therapy . We calculated descriptive statistics  to describe the findings of both the PD-Q and the three NRS scores at the two points in time and for all subgroups defined according to the PD-Q score and anti-neuropathic medication intake. Spearman’s rank correlation coefficient was used to search for correlations between the PD-Q scores and the individual NRS scores in both the overall study population and subgroups defined by PD-Q score and anti-neuropathic therapy. Correlations were calculated for baseline and follow-up visit. To test for a difference in PD-Q score and NRS between the groups with and without anti-neuropathic medication, we used the Mann–Whitney U test for independent samples at baseline and follow-up visit.Data were analyzed using IBM SPSS Statistics 27.0 . Age and gender were analyzed using the appropriate descriptive statistics in the overall study population and all subgroups. To test for statistical differences in age between the subgroups, a In total, 176 patients filled in the PD-Q on the first outpatient visit (baseline). All subjects had a history of chronic pain sensations of at least 6 months.The included patients had various underlying diagnoses, which for convenience and simplicity were allocated into 12 groups following the ICD-10 code. ICD-10 groups and the number of patients with the respective diagnoses are listed in The average age of participants at baseline visit was 57.6 years, with the oldest patient being 92 years old and the youngest being 27 years old. One hundred fifteen participants (65.3%) were women and 61 (34.7%) were men.The mean ages were 54.5 years , 59.4 years  and 59.3 years  in the groups of patients with likely, uncertain and unlikely NP, respectively. There was no statistically significant difference in age between the three groups.According to the PD-Q score, at the baseline visit NP was likely (score ≥ 19) in 62 (35.2%), possible (score ≥ 13 to ≤18) in 55 (31.3%), and unlikely (score ≤ 12) in 59 (33.5%) patients. Of the group of patients with likely NP, 46 (74.2%) were women and 16 (25.8%) were men. Of the group with uncertain NP, 35 (63.6%) were women and 20 (36.4%) were men. Of the 59 patients with unlikely NP, 34 (57.6%) were women and 25 (42.4%) were men. There was no statistically significant correlation between the gender of the patients and the distribution into the three groups.The mean PD-Q score at the baseline visit was 15.69 . The mean NRS score at baseline visit was 6.86 , the mean NRS of the most severe pain during the last 4 weeks was 8.15  and the mean NRS of average pain during the last 4 weeks was 6.74 .p = 0.007), NRS of most severe pain during the last 4 weeks  and NRS of average pain in the last 4 weeks . When testing the three different groups of patients defined by likely, uncertain and unlikely NP, for a correlation between the PD-Q score and the three NRS scores, we found a significant positive correlation  between the NRS of average pain in the last 4 weeks and the PD-Q score at the baseline visit in the group of patients with likely NP.There was a significant positive correlation between the PD-Q score at the baseline visit and the current NRS score  were prescribed anti-neuropathic medication (new onset or ongoing). The mean age of the participants who were prescribed anti-neuropathic medication was 58.46 years . These 79 patients were divided into 48 (60.8%) women and 31 (39.2%) men. Of these, 30 were in the group with likely, 30 in the group with uncertain and 19 were in the group with unlikely NP.In the group of patients under anti-neuropathic therapy, we found no significant correlation between the three NRS subgroup scores and the PD-Q score at the baseline visit.p = 0.039), NRS of most severe pain during the last 4 weeks  and NRS of average pain in the last 4 weeks  at baseline.Of the 97 patients without anti-neuropathic therapy, 32 had likely, 25 had uncertain and 40 had unlikely NP. The mean age in this group was 56.98 years . Of the 97 patients in this group, 67 (69.1%) were women and 30 (30.9%) were men. A positive correlation was found in this group of patients between the PD-Q score and the current NRS score , the mean NRS at the baseline visit was 7.01 , the mean NRS of average pain during the last 4 weeks was 6.77  and the NRS of the highest pain in the last 4 weeks was 8.05 .In the group without anti-neuropathic medication, the mean PD-Q score at baseline was 14.75 , the mean NRS at baseline was 6.74 , the mean NRS of average pain during the last 4 weeks was 6.71  and the NRS of the highest pain in the last 4 weeks was 8.24 .p = 0.021) in the group with anti-neuropathic medication than in the group without anti-neuropathic medication. The PD-Q score was significantly higher  were female and 22 (35.5%) were male. The mean age in this group was 59.1 years . Following the PD-Q score, NP was likely in 20 (32.3%), uncertain in 22 (35.5%) and unlikely in 20 (32.3%) patients at the 1-month follow-up. In the group with likely NP, 12 patients (60%) were women and 8 patients (40%) were men. Of the 20 patients with uncertain NP, 11 (57.9%) were women and 8 (42.1%) were men. Seventeen patients (73.9%) with unlikely NP were women and 6 patients (26.1%) with unlikely NP were men. Gender had no statistically significant impact on the distribution into the three groups. The mean ages were 59.52 years , 55.87 years  and 61.63 years  in the groups with likely, uncertain and unlikely NP, respectively. The was no statistically significant difference in age between the three groups. The mean follow-up PD-Q score was 15.9 .At the follow-up visit, the mean NRS was 5.0 , the mean NRS of the most severe pain during the last 4 weeks was 7.16  and the mean NRS of average pain during the last 4 weeks was 5.55 .p = 0.019), NRS of most severe pain during the last 4 weeks  and NRS of average pain in the last 4 weeks .When we tested for a correlation between the PD-Q score and the NRS at the follow-up visit, we found a positive correlation with the PD-Q score for the current NRS score  and the current NRS at the time of the follow-up . In the group with uncertain NP, we found no correlation between PD-Q and NRS. In the group with unlikely NP, there was a positive correlation  between the average NRS in the last 4 weeks and the PD-Q score.Equally to the statistical analysis at the baseline visit, we split the follow-up patients into PD-Q subgroups defined by likely, uncertain and unlikely NP and tested groups for correlations between PD-Q score and the NRS. In the likely NP group, we found a positive correlation with the PD-Q score for both the average NRS in the last 4 weeks  correlation between gender and whether the patients were treated with anti-neuropathic medication or not at the follow-up visit. A subanalysis showed that 14 of the 34 patients with anti-neuropathic medication had likely NP, 14 had uncertain NP and 6 had unlikely NP.Of the 62 patients at the follow-up visit, 34 (54.8%) were treated with anti-neuropathic medication. The mean age in this group of patients was 60.56 years . The mean age in the patients without anti-neuropathic medication was 57.05 years . There was no statistically significant difference in age between these two groups. Of the 62 patients treated with anti-neuropathic medication, 17 (50%) were women and 17  were women and 5 patients (17.9%) were men. We found a statistically significant (p = 0.039), NRS of most severe pain during the last 4 weeks  and NRS of average pain in the last 4 weeks  and the PD-Q score at the follow-up visit.Considering only the patients with anti-neuropathic medication, we found a positive correlation between the current NRS score , the mean NRS at the follow-up visit was 5.07 , the mean NRS of average pain during the last 4 weeks was 5.97  and the NRS of the highest pain in the last 4 weeks was 7.36 .In the group without anti-neuropathic medication, the mean PD-Q score was 13.75 , the mean NRS at the follow-up visit was 4.92 , the mean NRS of average pain during the last 4 weeks was 5.05  and the NRS of the highest pain in the last 4 weeks was 6.93 .There was no significant difference in the PD-Q score between the patients with and without anti-neuropathic medication at the follow-up visit. Pain, particularly chronic pain, represents a major clinical, social and economic problem. Most patients with chronic pain receive multimodal treatment, partly dependent on whether pain manifests itself in a dominant neuropathic or nociceptive way. The majority of chronic pain states present as mixed ones, with a strong interindividual variability. Frequently, the diagnosis of NP is made too late or is too unspecific, leading to a delayed or inadequate pain therapy, which possibly promotes the chronification of NP. Adequate assessment by using validated tools plays an essential role in successful pain therapy.Unidimensional pain scales such as the numeric rating scale (NRS), verbal rating scale (VRS) or visual analog scale (VAS) are useful for the measurement of pain intensity, while multidimensional scales consider multiple characteristics of chronic pain and can categorize pain more accurately. Performing the PD-Q in addition to the routine NRS scoring in an outpatient setting can help to correctly categorize the pain and thereby prevent an unnecessary delay at the beginning of a targeted anti-NP treatment if indicated.The PD-Q was developed and validated in patients with low back pain, but it has been performed and used to estimate the prevalence of NP in several studies concerning diabetic neuropathy, postherpetic neuralgia or knee osteoarthritis ,17.Further studies considering NP therapy demonstrated that pain with a neuropathic component is often described in painful conditions that are not typically associated with neural lesions ,9. ThirtFurthermore, the results of our study showed, according to the baseline PD-Q scores, that 66.5% of the investigated outpatients had an NP component (PD-Q score 13–38) at baseline. We demonstrated that that at the first visit to the outpatient clinic, patients were experiencing high levels of pain (NRS 6.86) accompanied with an NP component, represented in the PD-Q scores. These results suggest that a large number of chronic pain patients have poor pain control with standard analgesic regimens prior to visiting the outpatient clinic. Filtering out these patients as a distinct subgroup would allow physicians to improve their pain treatment by using anti-neuropathic analgesics with central activity. Furthermore, the PD-Q may also be a useful diagnostic tool for general physicians to screen for NP in private practice. Depending on the results of the questionnaire, and if clinically indicated, the pain therapy can be adapted immediately, or the patient can be referred to a pain specialist.When treating chronic pain, it must be clear, that besides intensity, the type and quality of pain can change and vary over time. Therefore, repeated performance of a questionnaire, including items concerning neuropathic symptoms and intensity of pain, may be helpful to monitor the course of the overall pain and its components. An initial baseline screening followed by repeated re-evaluations of the NP component, using the PD-Q, may help physicians to guide complex pain therapy regimes.In a study by Velluci et al. on the heterogeneity of chronic pain, it is recommended that the pain management approaches are tailored to each patient, with adequate assessment of pain by using validated tools and prompt administration of analgesics that are appropriate to the individual pain intensity .However, it may be of crucial importance that in the special cohort of chronic pain patients, both the evaluation of pain intensity using the NRS score and the screening for a neuropathic component using the PD-Q are repeated at regular time intervals, regardless of whether patients have received anti-NP therapy. The PD-Q, designed primarily as a screening tool, may thus also be a helpful, easy and time-saving tool to evaluate a therapeutic outcome.The results of our study showed a positive correlation between PD-Q scores and NRS scores measured at baseline and follow up visit. At baseline visit in patients with a PD-Q score indicating likely NP, a significant positive correlation between the NRS of average pain in the last 4 weeks and the PD-Q score was detected. At the follow-up, the correlation between PD-Q and average NRS in the last 4 weeks followed the same pattern. Analyzing the two subgroups of patients with and without an anti-NP therapy, the correlations between PD-Q and NRS scores changed in opposite directions to each other at both points in time. In the anti-NP therapy group, there was no correlation at baseline visit but there was a correlation at follow-up between PD-Q and NRS, and vice versa in the subgroup of patients without anti-NP therapy. Furthermore, there was a significant difference in the PD-Q score between the patients with and without anti-neuropathic medication at baseline visit but none at the follow-up visit.However, based on these results, it can be assumed that the partly controversial trend in the subgroups is due to the anti-NP therapy. This trend is reinforced by the results showing that the correlations in the PD-Q subgroups of likely NP and unlikely NP change with similar tendency, which may be attributed to the anti-neuropathic therapy. Further, our results indicate that a large number of chronic pain patients have likely or possible NP at their first visit to the outpatient pain clinic. The implementation and re-evaluation of a simple NP questionnaire like the PD-Q in routine clinical practice would contribute to early recognition and appropriate treatment of these patients. All these study findings point out that the relevant factor in this context is the anti-neuropathic medication. A potential limitation of this study was the relatively small number of patients in the follow-up and in the subgroups of patients with and without anti-NP therapy; therefore, further studies concerning this special topic with longer follow-up intervals are warranted. They should contribute in determining whether improvement over time is observed in subjects with anti-neuropathic therapy and PD-Q scores indicating likely NP.The results of this study show a significant correlation between PD-Q score and NRS score at baseline and 1-month follow-up visit. These results demonstrate that the neuropathic component is closely related to the experience of intense pain sensations, represented in both the PD-Q and NRS scores. However, this study highlights the importance of implementing a validated questionnaire like the PD-Q in the daily routine of pain therapy to screen for a neuropathic component in a wide range of chronic pain diseases.


Breast cancer is one of the most commonly diagnosed cancers among women in the United States and pain is the most common side effect of breast cancer and its treatment. Yet, the relationships between social determinants of pain and pain experience/intensity remain under-investigated. We examined the associations between social determinants of pain both at the individual level and the neighborhood level to understand how social conditions are associated with pain perception among early stage breast cancer patients.We conducted integrated statistical analysis of 1,191 women with early stage breast cancer treated at a large cancer center in Memphis, Tennessee. Combining electronic health records, patient-reported data and census data regarding residential address at the time of first diagnosis, we evaluated the relationships between social determinants and pain perception. Pain responses were self-reported by a patient as a numerical rating scale score at the patient’s initial diagnosis and follow-up clinical visits. We implemented two sets of statistical analyses of the zero-inflated Poisson model and estimated the associations between neighborhood poverty prevalence and breast cancer pain intensity. After adjustment for demographic characteristics, cancer stage, and chemotherapy, pain perception was significantly associated with poverty and blight level of the neighborhood.Among women living in the highest-poverty areas, the odds of reporting pain were 2.48 times higher than those in the lowest-poverty area. Women living in the highest-blight area had 5.43 times higher odds of reporting pain than those in the lowest-blight area. Neighborhood-level social determinants were significantly associated with pain intensity among women diagnosed with early-stage breast cancer.Distressed neighborhood conditions are significantly associated with higher pain perception. Breast cancer patients living in socio-economically disadvantaged neighborhoods and in poor environmental conditions reported higher pain severity compared to patients from less distressed neighborhoods. Therefore, post-diagnosis pain treatment design needs to be tailored to the social determinants of the breast cancer patients. Breast cancer is one of the most commonly diagnosed cancers among women in the United States. Pain is one of the common side effects of breast cancer and its treatment –3. AdequAbundant evidence has emphasized the importance of social conditions of breast cancer patients , 25–28. We merged the clinical data from electronic health records, patient-reported pain, and socio-economic information about the neighborhood of 1,191 women with breast cancer. By integrating multiple sources of data, we had an opportunity to explore and unveil the complexity of social embeddedness and perceived pain among breast cancer patients.We examined pain reported by female patients diagnosed with early stage (I-III) hormone receptor-positive breast cancer at the West Cancer Center and Research Institute . The PCM is an electronic, tablet-based patient engagement platform used to collect information on patient-reported treatment side effects, physical and emotional symptoms, and functional status at the point of care. Patient responses are included in their electronic health record. Summary reports of patient PCM responses highlight significant changes as well as elevated symptom severity that may require further evaluation and treatment during the clinical visit . WCCRI hWe included female patients diagnosed with early stage (I-III) hormone receptor-positive breast cancer between 2007 and 2015 at the WCCRI. We merged the breast cancer patient data from the WCCRI and the 2010 census data including patients’ residential addresses at the time of their first diagnosis . According to the 2010 census, the overall population density in Tennessee was 162.9 residents per square mile and the Shelby County population density was 1,215.5 people per square mile . To mainDescriptive statistics are shown in To overcome the high noise and complexity in the outcome variable, we computed the average pain score for each patient during the observation period . Immediate pain  within , 39 and Social determinants were measured both at the individual level and at the neighborhood level. Neighborhood-level social conditions have been suggested as key factors to study how social inequalities are engraved into health inequalities , 40–44. We estimated the associations between social determinants and pain with the final models adjusted for multiple individual-level covariates including biomarkers  and demographic attributes (age and race). To examine the association between social determinants and pain, we conducted group difference tests to examine the significance of differences among different categories of independent variables. We also investigated the impact of these variables on pain intensity in an adjusted as well as unadjusted regression framework. In the unadjusted models, we analyzed pairwise regression of pain intensity against each of the covariates, revealing partial relationships. The adjusted model included all available regressors selected by model selection.P<0.001). To deal with the excess zero counts, we applied the zero-inflated Poisson (ZIP) model, which fit the zero count component using a logit model and the count component using a Poisson model (P<0.001)]. We additionally tested and confirmed that the assumptions of the ZIP model were valid based on comprehensive model diagnostic tests including linearity, link function, response variable distribution, outliers, and multicollinearity. The results from the ZIP model were reported separately for each component. The outputs from the Poisson count data component were reported using the estimated incidence rates  and the outputs from the zero-inflation component were reported using the estimated odds ratios.A large proportion of patients reported no perceived pain, resulting in a considerable number of zero counts in the response variable. Altogether, 452 patients (39.5%) reported pain. Considering a standard Poisson model, there were significantly more number of zero counts than expected  and the pscl package was used to fit the zero-inflated model. All of the methods were performed in accordance with the Declaration of Helsinki and the relevant guidelines.P<0.001) and unemployed patients (5.8%) perceived higher pain intensity than employed patients (38.9%) and retired patients (5.5%) (P=0.016). Medicaid beneficiaries (24.3%) reported significantly higher pain intensity than patients with other types of insurance (44.7%) (P=0.047). Higher pain perception was associated with higher cancer stage at diagnosis (P<0.001) and patients treated with chemotherapy reported higher pain perception (P<0.001). We also observed higher pain perception among African American patients compare to white patients (P<0.001).Applying the inclusion criteria described above, a total of 1,191 women with breast cancer aged 22 to 95 years participated (791 patients with low age (age < 65) [66.4%]; 634 Whites [53.2%], 510 African Americans [42.8%]; 667 stage I [56%], 390 stage II [32.7%], 134 stage III [11.3%]). The averages for neighborhood-level social determinants of pain from 33 zip code areas were 21.56 for poverty and 13.85 for blight levels. For individual-level social determinants of pain, 38.9% of participants were employed , 34.7% were married , and 44.7% had commercial insurance (Medicaid [24.3%]). Mean values of pain intensity, by individual and neighborhood-level characteristics, are presented in P<0.001). With progression in the cancer stage, patients were more likely to suffer from pain. Moreover, patients who did not undergo chemotherapy had a lower probability of reporting any pain compared to patients treated with chemotherapy (P<0.001).We found significant association between no pain and three social determinant- poverty, blight, and insurance types. In the unadjusted model, the ORs of the estimated probabilities of pain occurrence and no pain were 1.015 for every 1-unit increase in poverty  and 1.033 for every 1-unit increase in the blight level . These results suggest that the odds of perceiving pain in the highest-poverty area and in the highest-blight area were expected to increase by about 140% and 600%, respectively, when compared with the lowest-poverty area and the lowest-blight area. The estimated odds of the presence of pain in the Medicaid group were 1.78 times higher . The estimated probabilities of zero pain in the commercial insurance group and in the Medicaid group at fixed levels of other covariates  were 0.39  and 0.26 , respectively, demonstrating a considerable inequality.Among the individual social context variables, employment and marital status were significantly associated with lower pain intensity. In the unadjusted models, unemployed patients showed 35.5% greater pain perception than the employed group . Single patients showed 32% greater pain than the married group . The adjusted model exhibited similar results with a slightly lower IR of 1.204 .We observed that markers of lower socio-economic status were associated with higher self-reported pain perception among breast cancer patients in Memphis, Tennessee. After adjustment for demographic characteristics, cancer stage, chemotherapy, and individual-level social determinants, patients living in areas with higher levels of poverty or blight were more likely to report any pain and higher pain severity. We also observed a strong association between individual-level social determinants and pain experience. Marital status and employment status showed significant associations with pain severity. Insurance type showed significant association with pain perception.The importance of social embeddedness with respect to mortality and quality of life in breast cancer is widely known , 25–28. Neighborhoods are important in influencing individual health outcomes , 17. ConThe study has some limitations. All the participants were from a single location . The generalizability of the findings might depend on the local setting. The high prevalence of poverty and the unique demographics (52.1% African American and 40.6% Caucasian) in Shelby County, Tennessee should be considered while applying our findings to other states. Our residential address linking procedure had its own limitations. We did not have information regarding residence before the diagnosis. Thus, we could not determine if the patients lived in the neighborhood long enough to be influenced by its local condition. We merged the data sets at the time of the first diagnosis. Due to the lack of data availability, we could not control the prior residential history. Additionally, we do not have medication data, which would have been helpful to further understanding of the mechanism of pain disparities. Future studies should include pharmaceutical data, which can offer a better care plan those paints living in disadvantaged neighborhoods.Despite the limitations, the findings strongly suggest that breast cancer patients living in socio-economically disadvantaged neighborhoods exhibited higher intensity of pain when compared with patients living in less distressed neighborhoods. We observed that the disparities in pain experience depended on the neighborhood-level social conditions. During post-diagnosis pain management in breast cancer patients, the patient care plan should be consider not only to the pathological factors but also the social conditions of patients for better-tailored pain and disease management.https://github.com/hyochoi/BreastCancerPainStudy). Requests to access these datasets should be directed to Ilana Graetz, ilana.graetz@emory.edu.The data analyzed in this study is subject to the following licenses/restrictions: Although electronic health record data will not be available due to patient privacy, the R codes that support the findings of this study are available on Github. .ES conceptualized, designed the study. HC and ES analyzed the data, wrote the original draft. LS, GV, and IG provided the data. IG curated and cleaned the data. All authors revised the manuscript and approved this version.This research was supported in part by NCI Health Grant (R21CA208161) and Korea University Future Research Grant (K2007651). Funders did not have any role in the study design; collection, analysis, or interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication.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.


Propofol injection pain (PIP) is a common condition in anesthesia practice and can be detrimental for patients. In this study, we aimed to investigate the effects of preoperative anxiety, depression levels, and D-type personality trait on PIP and to determine predictive factors.Sixty-eight patients who underwent elective septorhinoplasty under general anesthesia were analyzed. The effects of various factors  on the incidence of PIP were assessed. To identify risk factors associated with PIP, multivariate logistic regression analysis was performed.The incidence of PIP was significantly higher in patients who had preoperative anxiety and venous cannulation pain and who are Type D personality and female. Preoperative anxiety , Type D personality  and venous cannulation pain  were identified as independent risk factors for development of PIP. Depression, general anesthesia history, marital status, smoking, education status, and age were not significant as risk factors for the PIP.In addition to the physical factors that can predict PIP in anesthesia application, we believe that the presence of preoperative anxiety, Type D personality, and venous cannulation pain is significant, and it will be useful to apply preventive treatments for injection pain. Propofol is the most commonly used intravenous (IV) anesthetic agent for anesthesia induction and maintenance during surgeries [urgeries . Howeverurgeries , 2. AccoStudies have stated that there are many factors responsible for PIP, but the specific mechanism has not been revealed yet. It has been claimed that propofol-related PIP has two basic mechanisms. First, the phenol groups contained in the propofol directly irritate the skin, mucous membranes, and venous wall intimacy, and stimulate the nociceptors and free nerve endings, and the second; activates the quinine-calicrine system by indirectly affecting the endothelium of the propofol –5. FactoPsychogenic problems such as anxiety, depression, somatoform disorders, and fear of pain are frequently observed in patients undergoing elective surgery. Among these, preoperative anxiety and pain sensitivity has been the most interesting factors . PreoperPain sensation is specific to the individual’s personal experience is due to psychological factors , 12. TheThere is no published data on the effects of preoperative anxiety levels and D type personality trait on PIP. The primary aim of our study is to examine the effects of preoperative anxiety, depression levels and D-type personality trait on PIP. Our secondary goal is to identify predictive factors for PIP.This prospective observational study was carried out between February 1 and April 15, 2020 in the Medical Faculty Hospital of Yozgat Bozok University. Ethics committee approval of this study was given by the Clinical Research Ethics Committee of Yozgat Bozok University (Reference number: KAEK-189_2020.01.22_04).Sixty-eight patients, aged 18 to 55, American Society of Anesthesiologists Physical Status (ASA) I–II, who gave written informed consents and underwent elective septorhinoplasty surgery with propofol induction were included in the study. Exclusion criteria were poor understanding or communication difficulty, mental illness, hypersensitivity to study drugs, history of chronic pain or those taking regular analgesics preoperatively, those who had applied more than once IV cannulation, those with a known psychiatric illness and drug use.•Propofol injection pain (PIP) is a common condition in anesthesia practice.•Preoperatif anxiety, Type D personality and venous cannulation pain were identified as independent risk factors for development of PIP.•Evaluation of this factors that can predict PIP is important for the application of preventive treatments for PIP.-1 propofol dose  was given IV during 10 seconds after 3 min preoxygenation. The patients were asked to evaluate their injection site pain by using the VRS . In our study, pain was classified as presence of significant pain (VRS score ≥2) and absence of pain (VRS score <2) according to severity. The remaining dose of propofol was administered after initial evaluation. Prior to tracheal intubation, 1 μg/kg of fentanyl and 0.6 mg/kg rocuronium was administered to all patients. Anesthesia was continued with sevoflurane in 50% oxygen/nitrogen oxide. When the patients were referred to the anesthesia outpatient clinic, type-D personality scale was used to assess the personality trait, and the Hospital Anxiety and Depression Scale (HADS) was used to determine the level of anxiety and depression 1 hour before the operation. During the preoperative visit, patients signed the informed consent, and were informed about the visual analogue score (VAS) and verbal rating scale (VRS) for pain scoring. We used VRS since there would be loss of consciousness after propofol administration. None of the patients received premedication. When patients were brought to the operating room, nurses who did not participate in the study placed the 20-gauge IV cannula in a vein in the dorsum of the hand and the normal saline infusion was started. Patients were asked to estimate the maximum intensity of pain associated with this procedure on a horizontal VAS scale (0–10). Patients were then divided into two according to VAS levels of <3 or ≥3. Those with VAS ≥3 were considered as the group with venous cannulation pain . All stuHospital Anxiety and Depression Scale (HADS) was developed by Zigmond and Snaith (1983)  and its Type-D personality scale (DS14) was developed by Denollet (2005)  for use IBM SPSS for Windows, version 23.0 package program  was used for statistical analysis. Descriptive values were given as mean and frequency. Relationships between the incidence of PIP and risk factors such as anxiety, depression and D-type personality traits, gender, general anesthesia history, marital status, smoking, educational status, age, and venous cannulation pain, was examined by Chi-Square test or Fisher’s exact test. The variables found important in univariate analyzes were analyzed with the multivariate binary logistic regression (BLR) backward Wald model, and variables found to be statistically significant were shown in the table. In the regression analysis, the fit of the model was examined by Omnibus Tests (p<0.05), goodness of fit by Hosmer and Lemeshow tests (p>0.05), and impact coefficient by Nagelkerke R square. Results for p<0.05 were considered statistically significant.The main point we examined was the relationship between PIP and preoperative anxiety level. Sample size estimation was based on the results of the study on pain sensitivity  by Kil et al.  We calcuA total of 68 patients  with a mean age of 36.98±1.26 years were included in this study . 2, 13.229; p=<0.001) in the univariate analysis (In the comparative univariate analysis of risk factors for PIP, preoperative anxiety, Type D personality, female gender and venous cannulation pain were statistically significant differences . These fanalysis , still ganalysis .The aim of this study was to determine the relationship between preoperative anxiety, depression, and D-type personality trait with propofol injection pain and to determine conditions that are risk factors for PIP. According to our results, we found preoperative anxiety, D-type personality, and venous cannulation pain as independent risk factors for PIP.Propofol is widely used in clinical practice, and pain due to injection is one of the most common side effects of this IV agent . VariousIn general, age and gender are believed to be predictors for postoperative pain and analgesic consumption. In the incidence of PIP, while some studies did not report gender differences  most stuThe fear of venous cannulation is one of the important anxiety situations in patients undergoing surgery and may cause severe pain in most patients. However, vascular puncture for venous cannulation is a necessary procedure for safe and effective anesthesia , 27. StuAlthough there are various studies that investigated the causes of PIP, studies investigating psychogenic factors are limited. Vaughn et al.  reportedAn older study reported that there was no reduction in the incidence of PIP due to premedication . HoweverType D personality has been reported as a psychosocial factor associated with negative clinical outcomes –38. StudWhen the relations of psychogenic factors with PIP were examined in our study, we found that preoperative anxiety was a strong predictor of PIP. These results supported the theory that the only predictor of postoperative pain is situational anxiety and that increased anxiety reduces the patient’s pain threshold . More stIn conclusion, pain perception is individual and is associated with psychogenic risk factors in addition to tissue damage. Our results showed that D-type personalities, patients with high venous cannulation pain and high preoperative anxiety levels were more susceptible to pain after IV propofol injection. We also found that depression was not associated with PIP. Thus, we believe that in clinical anesthesia practice, evaluation of preoperative anxiety and venous cannulation pain in addition to physical factors that can predict PIP is important for the application of preventive treatments for propofol injection pain.


Knee osteoarthritis (KOA) is a chronic progressive disease that can cause pain, functional impairment, and ultimately disability. A novel and promising therapeutic approach to KOA is the so-called regenerative medicine, a set of procedures designed to harness tissue regenerative capacity and optimize functional recovery. Increasing evidence points out that platelet-rich plasma (PRP) intra-articular injections can decrease pain and improve functional abilities in KOA patients. In the present case reports, we analyze two patients who were treated with PRP injections coupled with a posttreatment home-based rehabilitation program. The two patients were selected to represent two different populations: patient 1 was an 85-year-old with severe impairment of functional abilities, while patient 2 was a younger (59 years old) and more active patient. The protocol consisted in a series of exercise to be performed at home, during the five days following PRP injection for two consecutive weeks . The exercises were designed to reduce the inflammation after the injection, enhance the proprioceptive control of the treated lower limb, and strengthen hip and knee flexors and extensors, mainly by isometric work. Results were evaluated at two time points: before and 2 months after the first PRP injection. The outcomes considered were as follows: visual analog scale for pain, EuroQol 5 dimensions questionnaire, Tegner Activity Scale for functioning, and Knee Injury and Osteoarthritis Outcome Score (KOOS). Both patients did not report any side effects from the treatment. Improvement in patient 1 was drastic at the two months follow-up as far as pain and functional abilities are concerned. Patient 2’s improvement was less evident, probably due to the higher starting point in both pain and functionality. Overall, the developed program seemed safe and was tolerated by the patients analyzed in the study, who performed it with good compliance. Osteoarthritis (OA) is a chronic progressive disease that mainly affects the articular cartilage, causing pain, stiffness, and limitation of articular range of motion (ROM) . It consMultiple therapeutic approaches are currently available for KOA, including pharmacological treatments, rehabilitation , and surIn particular, blood-derived products are among the most used therapeutic options in regenerative medicine because of their efficacy together with ease of preparation and use. They consist of fluid phase plasma, with platelets, white cells, and red cells suspended in different concentrations, depending on the specific preparation protocol and indication of use . PlateleThe rationale of PRP use in patients with KOA is the high and easily accessible content of these critical growth factors and other signaling molecules, which are involved in both healing processes and immune- and inflammatory modulation, therefore potentially leading to the restoration of joint tissue homeostasis . Neverthth day, resolution after 2 weeks) and an increased release of MMP-3, MMP-13, IL-1b, IL-6, and TNF-α in rabbits treated with LR-PRP injections in patellar tendon (An important classification distinguishes between leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP) preparations, depending on a higher or lower concentration of leukocytes (neutrophils particularly) from the baseline . LR-PRP r tendon . On the r tendon . Althougr tendon .There is increasing evidence on the efficacy of intra-articular injections of blood-derived products in patients with KOA in terms of pain reduction and improvement of function and activities of daily living . RehabilCurrently, we are not aware of validated guidelines or trials on the association of a rehabilitation exercise-based program with PRP intra-articular injection for pain, function, and quality of life on human patients with KOA. Therefore, these case reports aim to check the feasibility and safety of a rehabilitation program following PRP intra-articular injection.During the first 48 h after PRP (PRGF) injection, activities of daily living were allowed. In case of pain, 1,000 mg acetaminophen were prescribed for max three times a day, and the local application of ice for 20 min, three times a day. Instructions were given both orally and in written on a pamphlet by the clinician performing the injection (Appendix n.1).− Isometric co-contractions of quadriceps and hamstrings in the supine position, maintaining knee extended: 5 repetitions lasting 10 s for three series, twice a day.− Straight leg raises (SLR) in the supine position: 10 repetitions for three series, twice a day.− “Alphabet,” in the supine position, maintaining hip flexed at about 45° and knee extended. In this exercise, the patient has to "draw" with his foot some letters of the alphabet, maintaining the lower limb's described position: ten letters for three series, twice a day.The rehabilitation program was designed to work in synergy with the injection. It aimed to reduce the inflammation after the injection, enhance the proprioceptive control of the treated lower limb, and strengthen hip and knee flexors and extensors, mainly by isometric work. The program included three exercises, which are as follows:After an accurate explanation, both patients performed the program during the 5 days following PRP injection for two consecutive weeks . We recommended not practicing sports for the entire duration of the rehabilitation program.We tested the program on two consecutive female patients recruited at RE.GA.IN  Centre of IRCCS Galeazzi, Milan, Italy, between January and March 2020. The following case report adheres to the CARE (CAse REporting) structure and reporting guidelines .A woman, 85 years old, with a BMI of 28.1, presented a diagnosis of left KOA, with pain onset around six months before. She had no knee traumas in the last year. She was a nonsmoker with hypertension and hypercholesterolemia, in treatment with NSAIDs, pain killers (including acetaminophen and opioid drugs), antithrombotics/antiplatelets, anticholesteremic agents, proton-pump inhibitors, and vitamin D plus calcium supplements. She already underwent a complete KOA rehabilitation program, intra-articular injections of corticosteroids and hyaluronic acid with no results.The PRGF-Endoret® was prepared using the method described by Sanchez et al.  and admiThe outcome measures were as follows: visual analog scale (VAS) for pain  ; EuroQolThe pain-related score showed improvement, in terms of VAS, EQ VAS, the pain-related domain of EQ-5D, and the KOOS pain domain . The TegA woman, 59 years old, with a BMI of 20.3, presented a diagnosed with right KOA, lasting for over a year before PRP injection. She had no knee traumas in the last year. She reported recent smoking cessation, hypertension, and consumption of antithrombotic/antiplatelet drugs and vitamin D plus calcium supplements. She previously received intra-articular injections of hyaluronic acid for the same knee with no results. She received two intra-articular injections of PRGF-Endoret® one week apart, following the same procedure as reported for patient 1. Likewise patient 1, she was evaluated by using VAS, EQ-5D, Tegner Activity Scale, and KOOS-ADL.All the pain-related scores did not change during the follow-up, with persisting mild-to-severe symptoms . ConcernInjections of blood-derived products are a widely diffused treatment for KOA, and increasing evidence shows their safety and efficacy . HoweverDue to the limited sample size, we can only evaluate the feasibility and safety of the program. However, the treatment of the two patients obtained the results we expected. The patients did not report any side effects due to the exercise program. The two cases studied were carefully selected in order to represent two different populations that can benefit from adding a short exercise program to PRP injections. While both patients suffered from KOA, patient 1 is an 85-year-old with severe KOA and reduced functional capabilities, as underlined by a baseline total KOOS score of 6.55, with a function sub-score of 5.88. On the other hand, patient 2 is a 59-year-old with better baseline functional performance with a total KOOS score of 60.12 and a function sub-score of 60.29. Indeed, the two patients represent two different populations that can potentially have different responses to therapy as well as different expectations. The difference in the results reflects the difference in baseline condition. Patient 1 dramatically improved at T2 in almost every outcome. It is interesting to notice that KOOS improved significantly. While exercises are often beneficial in KOA also for pain relief, especially in the long run, they are inherently linked to improving strength and proprioception needed to improve function and independence on ADL. Patient 2 showed less improvement. However, outcomes manifested a ceiling effect due to the relatively good clinical condition pretreatment. Furthermore, we prescribed the same set of exercises for both patients. However, the two patients had very different clinical conditions. It is possible that the intensity and degree of difficulty of exercises were enough to warrant a bettering in condition in a less performing patient such as patient 1, but were not enough for patient 2. Indeed, for future studies including young and active patients, functional tests with no ceiling effect, such as 6-minute walking test, 2-minute step-test, and 10-m walking test at maximum speed, should be implemented. Furthermore, exercise intensity should be tailored on functional capabilities of the individual patient.Our study limitation is represented by the short follow-up. Unfortunately, the patients were treated right before the first pandemic lockdown in our country, and it was impossible to reach them out for longer time points. Certainly, future patients will have to be monitored at least until 12 months from the treatment.Overall, the developed program seemed safe and was tolerated by the patients analyzed in the study, who performed it with good compliance. The results obtained motivated us to plan another study based on the same program, with the implementation of telemedicine and biomechanical evaluation to enhance compliance, efficacy, and outcomes that do not reach a ceiling effect in high-performance patients.


Chronic post-surgical pain (CPSP) has a negative impact on the recovery, quality of life, and physical functioning of elderly patients. This study aimed to test the superiority of parecoxib vs. placebo in preventing chronic post-hepatectomy pain in elderly patients under combined general-epidural anesthesia.A total of 105 elderly patients undergoing hepatectomy under combined general-epidural anesthesia were randomized into the parecoxib or placebo group. The primary outcome was the proportion of patients with CPSP 3 months postoperatively. The secondary outcomes included the Short-Form McGill Pain Questionnaire score in CPSP-positive responders, acute pain intensity, postoperative analgesic demand, inflammatory markers change, and postoperative complications within 28 days.P = 0.34). The average chronic pain visual analog scale in the parecoxib group was lower than that in the placebo group (P = 0.04). Significantly less moderate-to-severe acute pain at rest (P = 0.04) and with coughing (P < 0.001), less patient-controlled epidural analgesia (PCEA) consumption (P = 0.01), and less rescue analgesia (P < 0.001) were observed in the parecoxib group compared to the placebo group. Furthermore, no between-group difference was observed in inflammatory markers (P > 0.05) and postoperative complications (P = 0.65).The parecoxib group provided a non-significant absolute 9.1% reduction in the rate of CPSP compared to the placebo group  on August 3, 2020 .This study was retrospectively registered in the Chinese Clinical Trial Registry (URL: The online version contains supplementary material available at 10.1186/s40360-021-00501-1. In China, liver cancer is one of the most commonly diagnosed malignant tumors, mainly treated by surgical procedures. Although liver cancer incidence and mortality trends have been decreasing significantly in recent years , China aThe right subcostal incision is the most applicable method to open hepatectomy. After transection of abdominal muscles and nerves, the incision effectuates the release of inflammatory cytokines and massive initiate cellular reactions to severe tissue injury at the surgical sites , 9. PersTo test this hypothesis, we designed and conducted this prospective randomized controlled study enrolling elder patients over 65 undergoing hepatectomy at the Zhongshan Hospital affiliated with Fudan University. Next, we established a multimodal analgesia system by adding perioperative parecoxib to the routine practice of combined general-epidural anesthesia. Stringent criteria were set to select patients and avoid the potential adverse reactions due to parecoxib. Other potential risk factors for CPSP after hepatectomy were also evaluated in our cohort.This prospective, double-blind, random, placebo-controlled, single-centered trial of perioperative analgesia to prevent CPSP in elderly patients after hepatectomy. The objective of the study was to test the superiority of parecoxib vs. placebo in preventing chronic post-hepatectomy pain in elderly patients over 65 under combined general-epidural anesthesia.All patients, aged 65–80-years-old, with American Society of Anesthesiologists (ASA) physical status classification of I or II, scheduled to undergo elective open hepatectomy for hepatocellular carcinoma at the Zhongshan Hospital, Fudan University, were considered eligible for this study. We excluded patients who underwent hepatectomy previously, had a history of chronic pain, were treated with radiation or chemotherapy, were not suitable for epidural anesthesia , and had a history of psychology or mental illness. Given the potential adverse reactions of COX-2 inhibitors, patients were excluded if they fulfilled one of the following conditions: 1. allergy to parecoxib; 2. active gastrointestinal bleeding or ulceration; 3. history of congestive heart failure or ischemic cardiac diseases; 4. Child-Pugh score > 6 points or resection of more than three hepatic segments; 5. disease of peripheral arteries or cerebral vessels; 6. estimated glomerular filtration rate of < 60 mL/min.All participating patients provided written informed consent for this clinical trial, approved by the Ethics Committee of Zhongshan Hospital, Fudan University. A trial registration number (ChiCTR2000035198) was obtained from the Chinese Clinical Trial Registry.A computer-generated randomization sequence was used to recruit and enroll patients consecutively. Only the statistician and the pharmacists were aware of the concealed allocation schedule. The participants were randomly assigned to one of the following treatment groups in a 1:1 ratio.Parecoxib sodium of 40 mg diluted with normal saline to 4 mL was administered intravenously, starting from 10 min before incision and once every 12 h until the sixth dose.A volume of 4 mL normal saline was administered intravenously, starting from 10 min before incision and once every 12 h until the sixth dose.Based on the allocation schedule, the unblinded pharmacist prepared the parecoxib sodium or placebo with an identical appearance in the same type of syringe. The nurse  followed the study protocol and administered the medication according to the sequence. To reduce the bias, the patients, anesthesiologists, surgeons, nursing staff, postoperative follow-up group, and data processors were blinded to patient grouping until all the data were collected.All patients completed a questionnaire of the Hospital Anxiety and Depression Scale (HADS)  on the n2 partial pressure were recorded. 5) Anesthesia was maintained by 0.7 minimum alveolar concentration sevoflurane and continuous epidural anesthesia. Intraoperative fentanyl and muscle relaxants were administered on demand.All surgical operations were performed through a right subcostal incision by senior physicians with surgical experience of > 5 years. Our institute developed a routine practice of combined general-epidural anesthesia, followed by patient-controlled epidural analgesia (PCEA) in liver surgery. After the patient entered the operating room, a standardized protocol was followed to achieve general anesthesia combined with an epidural block: 1) A central venous catheter was placed through the internal jugular vein to guide intraoperative fluid therapy. 2) An epidural catheter was placed properly at the T8-T9 interval, and the anesthesia plane was tested by 2% lidocaine in a volume of 3 mL. 3) General anesthesia was induced with fentanyl 3 μg/kg, propofol plasma target controlled infusion, and rocuronium 0.6 mg/kg. 4) Intraoperative monitoring was carried out via an electrocardiogram (lead II and lead V5); also, oxygen saturation, arterial blood pressure, central venous pressure, and end-tidal COPCEA pump was applied to each patient after emergence from anesthesia, with the formulation of 0.12% ropivacaine and 2 μg/mL fentanyl. The infusion rate was 2 mL/h, bolus volume was 4 mL, and lock time was 10 min. The patients received parecoxib sodium or placebo intravenously, starting from 10 min before the incision and once every 12 h till the sixth dose. In addition, non-NSAIDs rescue analgesia, according to the surgeon’s preference for postoperative breakthrough pain.Venous blood was collected separately for each patient before surgery (D0) and on the day1 (D1) and day 3 (D3) after surgery to measure levels of the following items: leukocyte count (WBC), neutrophil count (N), lymphocyte count (L), prothrombin time (PT), activated partial thrombin time (APTT), highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, and IL-10.Pain intensity was evaluated using a visual analog scale (VAS) from 0 cm as no pain to 10 cm as the worst pain imaginable. Patients were assessed for pain intensity separately at rest and coughing at 2, 4, 8, 24, 48, and 72 h post-surgery. The consuming volume and press times of the PCEA pump, the suspicious analgesic-associated adverse reactions, and any postoperative complications within 28 days were recorded.The patients participating in the clinical trials were requested to complete a questionnaire via telephone 3 months after the surgery. They were questioned about CPSP, and if the answer was positive, the state of CPSP was assessed using the Short-form McGill Pain Questionnaire (SF-MPQ).The primary outcome was the proportion of patients with CPSP at 3 months after hepatectomy. The diagnostic criteria of CPSP were referred to the International Association for The Study of Pain (IASP) definition [The observational data unpublished from patients after liver surgery revealed a CPSP prevalence of 48.6%. Previous studies , 17 wereThe database was established, a two-pass verification was performed using EpiData , and data were analyzed using IBM SPSS Statistics . Continuous variables were reported as mean ± standard deviation (SD), and categorical variables were reported as the number (percentage) of patients. The primary outcomes were analyzed based on an intention-to-treat basis according to the previous randomization categories. The proportion of patients developing CPSP between groups was compared using Pearson’s chi-square test. The relative risk (RR) value and its 95% confidence interval (CI) of CPSP were calculated for the parecoxib group. To analyze the sensitivity of the results, the worst-case scenario and per-protocol analysis were operated. For the baseline characteristics and secondary outcomes, normally distributed continuous data were compared using t-test. Non-normally distributed continuous data were compared using the Mann–Whitney U test. The categorical variables were compared using Pearson’s chi-square test or Fisher’s exact test. For repeated measurement, such as inflammation index and VAS within 72 h, an analysis of variance (ANOVA) was employed to assess the between-group difference. To compare the difference in SF-MPQ score between the two groups, we used Mann–Whitney U test. No imputation was performed for missing data for the secondary outcomes.To investigate other potential risk factors for CPSP after hepatectomy, logistic regression was performed with respect to gender, ASA status, coexisting hypertension, the neutron-lymphocyte ratio (NLR) at baseline, and intervention. The multivariate logistic regression model was constructed after the removal of collinear variables. A type 1 error of 0.05 was used for all analyses.P = 0.03). Since the cutoff of depression score of the HADS was 8 points, the depression status of the between-group was similar.A total of 525 patients were screened, and 105 patients were recruited and assigned to receive intervention from November 2018 to July 2020 . The sensitivity analyses, including both worst-case scenario and per-protocol analysis, did not reveal any significant change.The overall incidence of CPSP at 3 months was 40.0% 42/105) in this cohort. As stated in Table /105 in tP = 0.32) and the present pain intensity .Among the respondents experiencing CPSP at 3 months, no difference was detected in the pain rating index  and needed more rescue analgesia  and activated partial thrombin time (P = 0.250).The perioperative changes in inflammatory indexes are illustrated in Fig. Post-hoc analysis using logistic regression for gender, ASA status, coexisting hypertension, the NLR at baseline, and group intervention was summarized in Table In the current study, the overall prevalence of CPSP at 3 months after hepatectomy was 40% (42/105), and moderate-to-severe pain accounted for 3.8% (4/105). This finding was consistent with a single-center observational study reporting a CPSP prevalence of 50% in patients 3 months after liver transplantation . The difAccording to the current results, parecoxib could not significantly reduce the prevalence of CPSP, despite an absolute decrease of 9.1%. This difference was less than the 30% difference anticipated while estimating the sample size. These findings were consistent with the previous results in both the worst-case scenario and per-protocol analysis. Helmond et al. reached a similar conclusion for patients after breast cancer surgery . ConversIn order to guide the use of parecoxib in clinical practice, the knowledge of pharmacokinetics is essential. Parecoxib is rapidly hydrolyzed by enzymes in the liver after a single intravenous injection and converted into the active metabolite valdecoxib ; perceivBased on the analysis of a series of peripheral inflammatory indexes, we deduced the following facts: 1) concentrations of hs-CRP and IL-6 increase gradually over time, the trend coincided with the postoperative pain intensity; 2) peripheral leukocyte count, NLR, and IL-10 increase and reach the peak on day 1 postoperatively, followed by a decrease on day 3; 3) No connection was established between parecoxib and inflammatory changes in peripheral blood. Peng et al. found in aged rats that parecoxib inhibits hepatectomy-induced IL-1β and TNF-α expression in the hippocampus through the downregulation of the COX-2/PGE2 pathway . BjurstrSurprisingly, we found that females had a reduced risk of developing CPSP in elderly patients after hepatectomy. The association between sex and pain has been studied widely. Sorge et al.  revealedThe application of NSAIDs in elderly patients has been controversial due to the concerns of severe adverse reactions. NSAIDs-related adverse reactions include myocardial infarction, acute kidney failure, severe gastrointestinal ulceration, anaphylaxis, and coagulopathy. Currently, no significant difference has been detected between the two groups in postoperative complications and coagulation change in our study. Moreover, none of the above side effects were reported. One patient in parecoxib withdrew from the trial because of severe anaphylaxis on day 1 post-surgery. However, given our small sample size, the power to evaluate those side effects is limited. Thus, the safety of parecoxib use in elderly patients requires further verification.Nevertheless, the present study has several limitations. It was a single-center RCT based on a small sample size. The lack of statistical significance could be attributed to low statistical power due to the small sample size. Due to the potential adverse reactions associated with COX-2 inhibitors, we used stringent inclusion criteria. It inevitably reduced the sample size and affected the generalization of our results. The sample size in this study was smaller than that in Kehlet et al.  but simiIn conclusion, parecoxib reduced the prevalence of CPSP in elderly patients after hepatectomy under epidural analgesia from 44.4 to 35.3%, with no statistical significance. In addition, parecoxib markedly reduced CPSP intensity and was used to optimize postoperative acute pain management. Thus, prudent but individualized use of parecoxib in healthy elderly patients undergoing liver resection is recommended.Additional file 1.


Our aim was to investigate the alterations of the dynamics in de novo dPD, 34 de novo patients with PD without depression (ndPD), and 43 healthy controls (HCs). Group independent component analysis, a sliding window approach, followed by k-means clustering were conducted to assess functional connectivity states (which represented highly structured connectivity patterns reoccurring over time) and temporal properties for comparison between groups. We further performed dynamic graph-theoretical analysis to examine the variability of topological metrics.We performed dFC analysis on the data of resting-state functional MRI from 21 via dFC analysis. Compared to patients with ndPD and HCs, patients with dPD showed increased fractional time and mean dwell time in state 2, characterized by default mode network (DMN)-dominated and cognitive executive network (CEN)-disconnected patterns. Besides, compared to HCs, patients with dPD and patients with ndPD both showed weaker dynamic connectivity within the sensorimotor network (SMN) in state 4, a regionally densely connected state. We additionally observed that patients with dPD presented less variability in the local efficiency of the network.Four distinct functional connectivity states were clustered Our study demonstrated that altered network connection over time, mainly involving the DMN and CEN, with abnormal dynamic graph properties, may contribute to the presence of depression in patients with PD. Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder . NowadayResting-state functional MRI (rsfMRI) is a novel, non-invasive method, widely used in investigating neuroimaging substrates of PD with depression (dPD). Previous studies employing the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) approaches revealed that aberrant regional brain activity in several specific areas of prefrontal and cingulate cortices was associated with depressive symptoms in PD . FunctioIn fact, the strength and directionality of FC can substantially change at fast time scales of seconds to minutes . NowadayAdditionally, considering that prior studies have proven that levodopa and antidepressants could affect the dynamic functional measures , we focude novo patients with PD and 43 HCs. All the participants completed the clinical assessments and MRI scans during the baseline visit.The study was approved by the Medical Ethics Committee of the Affiliated Brain Hospital of Nanjing Medical University. Written informed consent was obtained from all participants after a full explanation of the whole procedure. Patients were recruited from the Movement Disorder Clinic at the Department of Neurology of Brain Hospital Affiliated with Nanjing Medical University. PD was diagnosed by an experienced neurologist according to the UK Parkinson’s Disease Society Brain Bank diagnostic criteria . PatientPatients with dPD were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria by an experienced psychiatrist. The severity of depression was quantified with the 17-item Hamilton Depression Rating Scale (HAMD-17). A HAMD-17 score higher than 14 was required for a more accurate diagnosis of dPD . Twenty-Magnetic resonance (MR) images were required using a 3T MRI scanner . All participants laid supine with their heads fixed by foam pads with a standard birdcage head coil to minimize head movement. The participants were instructed to remain as still as possible and to close their eyes while remaining awake without thinking of anything. Axial anatomical images were acquired using a T1 fluid-attenuated inversion recovery sequence with the following parameters: repetition time (TR) = 2,530 ms; echo time (TE) = 3.34 ms; field of view (FOV) = 256 mm × 256 mm; matrix = 256 × 192; slice thickness/gap = 1.33/0.5 mm; flip angle (FA) = 7 degrees; bandwidth = 180 HZ/PX; 128 slices covered the whole brain, for image registration and functional localization. Functional images were subsequently collected in the same slice orientation with a gradient-recalled echo-planar imaging pulse sequence. A total of 240 volumes were obtained .1  using tissue probability maps derived from the T1 images, normalized into the standard Montreal Neurological Institute space using diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL), resliced as a 3 mm × 3 mm × 3 mm voxel size, and spatially smoothed with a 6 mm full-width at half-maximum (FWHM) Gaussian kernel. Aiming to further minimize the potential effects of head motion, we excluded patients with a mean framewise displacement (FD) > 0.5 mm or whose head motion exceeded a maximum translation of 3 mm or rotation of 3° from the further analysis , referring to a previous study (P = 0.12). Additionally, considering the possible deleterious influence of head motion, we added a scrubbing step in the preprocessing procedures and repeated the following analyses for further verification  data was carried out using data processing assistant for resting-state fMRI (DPARSF)1  based onus study . There wfication . we founfication .3. Subject-specific data were reduced to 120 independent components (ICs) with the principal component analysis (PCA), and further decomposed into 100 ICs using the expectation-maximization algorithm at the group level as previously done  implemented in the Group ICA of the fMRI Toolbox (GIFT v4.0b)sly done . The Infsly done  was repesly done . Subjectsly done .Out of the 100 independent components, 37 ICs were identified as meaningful according to the following criteria by via Fisher’s z-transformation using the post-processed time courses , which were repeated 100 times  for multiple comparisons. The threshold for statistical significance was set at P < 0.05.In order to explore the temporal properties of dynamic functional connectivity states, we calculated three different indices for each subject, including: (1) fraction time, defined as the percentage of total time one subject spent in a given state; (2) mean dwell time, defined as the time a subject remained in a certain state; and (3) number of transitions, defined as the number of translations between states. The differences among groups  were investigated using a one-way ANOVA test, followed by post hoc two-sample t-tests .Additionally, the subject-specific connectivity pattern of each state was represented by the median value of all functional connectivity matrices assigned to that state. Group differences among patients with HCs, ndPD, and dPD in dynamic functional connectivity pairs (666 pairings) within each state were calculated using one-way ANOVA, followed by 4. Thirty-seven ICs were defined as nodes and the functional connectivity between each two ICs was constructed as edges for each time window. The resulting 208 functional connectivity matrices per subject were binarized with respect to a fixed sparsity threshold (the existing number of edges divided by the maximum possible number of edges), set as 0.1 to 0.34 in 0.01 increments based on prior studies (t-tests (or Mann–Whitney U test) and ANOVA test  were respectively conducted to assess whether there were differences in topological variability between PD and HCs groups or among the HCs, ndPD, and dPD groups (P < 0.05).We applied a graph theory approach to analyze the dynamics of graph characteristics of the network using GRETNA software studies . Only pot-test or Mann–Whitney U test was applied to compare two groups. One-way ANOVA or Kruskal–Wallis test was performed to compare the HCs, ndPD, and dPD groups. A chi-squared test was used to compare categorical variables such as gender. Spearman’s correlation analyses were conducted to assess the correlations between the detected temporal properties and HAMD-17 scores. P-values were corrected for multiple comparisons and P < 0.05 was set as a threshold for statistical significance.Statistical analyses were calculated using SPSS Statistic 24.0 . A two-sample P = 0.963, P = 0.780, P = 0.150, P = 0.056). No significant differences between patients with dPD and ndPD were found in disease duration, H&Y stage, UPDRS-III scores . In addition, the HAMD-17 score of the patients with dPD was significantly higher than that of patients with ndPD or HC (P < 0.001)  .Spatial maps of all 37 independent components defined by using group ICA are illustrated in Through the k-means clustering analysis, a total of four highly structured functional connectivity states were identified by the elbow criterion. We displayed the 5% of the functional connectivity network with the strongest positive or negative connections to observe the different patterns of each state . CombineP = 0.004; mean dwell time: P = 0.048, FDR-corrected). Post hoc t-tests demonstrated that patients with dPD had a significantly higher fraction time in state 2 than that of patients with ndPD (P = 0.030 FDR-corrected) and healthy controls . Additionally, patients with dPD spent significantly more dwell time in state 2. This is consistent with fraction time when compared to patients with ndPD  and HC . We found that fraction time  and mean dwell time  in state 2 were slightly correlated with HAMD scores in all participants when regressing out a group as a covariate. No differences were found in the number of state transitions or temporal properties in other states between the three groups   .Validation analyses showed that the main results of temporal properties in state 2 were consistent for different window sizes . BesidesP < 0.001, FDR-corrected) showed a significant overall difference between the HC, patients with ndPD, and patients with dPD. Post hoc t-tests indicated that patients with dPD and patients with ndPD both had significantly decreased connection within the SMN  in state 4 compared to healthy controls . In contrast, no differences were found between the ndPD and dPD groups (P = 0.58) (We subsequently examined between-group differences in the strength of connections for each state. ANOVA results ( = 0.58) .P = 0.755) nor HCs group and PD sub-groups  differed significantly in this aspect. No significant differences were found between the HCs and PD groups  or between the dPD, ndPD, and HCs groups  with respect to betweenness centrality. In terms of the local efficiency of the network, there were significant differences between the dPD, ndPD, and HCs groups . Post hoc t-tests revealed that the dPD group exhibited smaller variance than the HCs group did (P = 0.010), but no significant differences were found between the dPD and ndPD groups (P = 0.143) or between the ndPD and HCs groups (P = 0.319). There was a trend for less variability in the PD group than in the HCs group . Further, the analysis of small-worldness variability demonstrated that the PD group was less variable than the HC group , and there may be a trend of differences between the dPD, ndPD, and HC groups , consistent with the results of clustering coefficient   .The present study investigated the characteristics of dynamic functional connectivity and dynamic topological properties in drug-naïve PD patients with depression, thereby excluding the confounding effects of dopaminergic therapy and long-term disease duration. Four distinct connectivity states were found across the entire participants. Importantly, we observed that in contrast to patients with ndPD and the healthy population, patients with dPD showed increased fractional time and mean dwell time in state 2, characterized by DMN-dominated and CEN-disconnected patterns. This indicated that patients with dPD preferred to spend more time in a dysfunctional connectivity state. Additionally, the above dynamic metrics exhibited a slight correlation with the severity of depression. Our results suggested that the occurrence of depression in PD may be attributed to the temporal fluctuations of functional network connectivity.State 2 was characterized by strong connections mostly within the DMN or between DMN and several other networks. Accordingly, the DMN may play a central role in the development of depression in PD. The DMN is a highly integrated network that is active during wakeful rest state and deactivated during externally directed processes , involveFurther, we observed that the ndPD group and dPD group relative to healthy controls showed weaker dynamic connectivity within the SMN in state 4, mainly located between the left postcentral cortex and right precentral cortex. PD was proposed as a disconnection syndrome . DecreasGlobal efficiency is a measure of parallel information transfer efficiency across the entire brain network , and dynThere still exists a few limitations in the present study that should be considered. First, only 21 patients with dPD were included in the current study. We did not observe a significant correlation between dynamic properties and HAMD scores when specifically considering the dPD group. This can be attributed to the small sample size, although we ruled out the effects of dopaminergic or antidepressant medication. Studies with larger sample sizes should be performed for further validation. Second, the participants in our study underwent single resting-state scanning, while a prior study suggested multiple sessions could improve the detection power especially under the circumstance of applying the sliding window approach . Third, de novo patients with PD and depression. Our study demonstrated that altered network connections over time, mainly involving the DMN and CEN, with less variable graph properties, could play important roles in the presence of depression in PD. Decreased time-varying FC within the SMN may facilitate the emergence of PD. Dynamic functional connectivity analysis could provide new insights into the pathophysiology of depression in patients with PD.In summary, the present study is the first study to explore the characteristics of dynamic functional connectivity in The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Medical Research Ethics Committee of the Affiliated Brain Hospital of Nanjing Medical University. The patients/participants provided their written informed consent to participate in this study.WL designed and organized the research. JX, YL, LL, JR, and CP collected the imaging and assessment scale data. JX, MY, and HW were responsible for formal analysis. JX drafted the manuscript. WL and MY made important revisions to the manuscript. All authors contributed to the article and approved the submitted version.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.


Percutaneous cementoplasty is a minimally invasive procedure that can provide immediate pain relief and improve range of motion in patients with metastatic bone pain. Conventionally, this procedure is guided by computed tomography (CT). However, to minimize exposure to radiation, we performed percutaneous cementoplasty under the guidance of a navigation system.A 60-year-old man presented with left hip pain for several months due to bone metastasis in the left ilium.The patient was diagnosed with lung cancer and multiple bone metastases including ileum.The puncture needle was placed under the guidance of a navigation system with pre-procedure CT images, and bone cement was injected into the osteolytic lesion in the left ilium.Bone cement placement was confirmed by post-procedure radiography, and its distribution was satisfactory. The patient's Karnofsky Performance Scale and Brief Pain Inventory scores showed improvement in pain and mobility without complications.Percutaneous cementoplasty guided by a navigation system is a safer and more effective method with less radiation compared with conventional CT-guided methods. These metastases frequently affect the pelvic bone and cause significant pain and disability. Surgical treatment is an option to treat bone metastases, but in patients with extensive lytic lesions, this option could be technically difficult. Palliative radiotherapy could be helpful, but some patients do not respond, and bone strengthening may be delayed for patients with lytic lesions. Percutaneous cementoplasty is a minimally invasive procedure that can immediately relieve pain and restore mechanical stability. Conventionally, computed tomography (CT) has been used to guide percutaneous cementoplasty. However, cancer patients who undergo radiotherapy for primary tumors are concerned about radiation exposure associated with the procedure. Thus, navigation can be a good alternative for CT in guiding percutaneous cementoplasty. Here, we present a case of lytic metastasis in the left pelvis originating from the lungs. The lesion was treated by navigation-guided percutaneous cementoplasty. The application on ilium is unprecedented.Bone metastasis is a common complication in cancer patients, especially lung cancer patients.1.1This Paper was approved by the institutional review board of Daegu catholic university hospital, Daegu, Republic of Korea (CR-21-031). The patient has provided informed consent for publication of this case.22.1In April 2020, a 60-year-old man visited the orthopedic out-patient department of our institution for a chronic left hip pain. Pelvic radiography was performed, and it revealed an osteolytic lesion in both the ilium and left acetabulum Fig. . In ordeChemotherapy was initiated to treat the lung cancer. However, the patient persistently complained of left hip pain. Palliative radiotherapy to the left pelvic bone was performed twice without pain relief.In October 2020, the patient was referred to a pain clinic for the persistent left hip pain. He was unable to walk or stand because of this pain. The anesthesiologist performed a femoral nerve block and targeted the muscle around the left ilium. This procedure relieved the pain for several days but not for long, and it did not improve his disability. We suggested percutaneous cementoplasty of the left ilium, which could relieve the pain by stabilizing the osteolytic lesion. Conventionally, percutaneous cementoplasty is performed under the guidance of 3-Dimensional (3-D) fluoroscopy-based CT. However, the patient was concerned about radiation exposure since he had previously been treated with radiation twice and was subjected to repetitive radiation imaging to track cancer progression. Therefore, we devised a plan to perform percutaneous cementoplasty guided by navigation in order to minimize radiation exposure.2.2To confirm the size of the lytic lesion and perform navigation-guided cementoplasty, thin-section CT of the left pelvis was performed, with CT images sliced to 1 in. sections Fig. .Based on the pre-procedure CT images, we assumed the osteolytic lesion to be spherical with a radius of 1.3 cm. The volume of the sphere was calculated using Thin-section CT images were uploaded to the navigation system  using a USB device. The probe that was required for navigation was attached to the left flank to minimize interference with the procedure and movement. Then, the antenna of the navigation system was placed where both the treatment area and probe could be sensed. A pointer was used to touch the treatment area gently for registration, and by altering the pointer's projection depth and direction, the target point for cementoplasty could be confirmed Fig. . After nAfter the procedure, C-arm radiography was used to obtain anteroposterior (AP) and oblique views of the left pelvis using in the operating room to confirm the location of the cement Fig. .Radiographs of the pelvic AP and pelvic outlet view were taken after the patient was removed from the operating room; these showed a more accurate view of the pelvis Fig. .2.3 score was 40 and the worst pain score on the Brief Pain Inventory (BPI) was 8 on a scale of 0 to 10 in the left pelvis. The general activity, mood, mechanical ability, normal work, human relations, sleep, and enjoyment of life affected by pain on the BPI were at a score of 7 on a scale of 0 to 10. To control pain, the patient was administered oxycodone 10 mg twice daily.Before the procedure, the patient's Karnofsky Performance Scale (KCP)After the procedure, the patient's KCP score, worst pain score in BPI, and functional interference score on the BPI showed little improvement. However, on day 2, he felt dramatically better, and his KCP score improved to 60 and worst pain score on the BPI to 6. One week after the procedure, his KCP score was 70, worst pain score on the BPI was 4, and functional interference score in improved to 4 on a scale of 10. However, at 2 weeks post-procedure, the KCP and functional interference scores on the BPI returned to the pre-procedure levels because of dyspnea aggravation and newly emerged right hip pain due to right pelvic bone metastasis. Nevertheless, the worst pain score on the BPI remained constant at 4 on a scale of 10.3 However, these are often insufficient for metastatic cancer patients. Cementoplasty of the pelvic bone can significantly reduce pain, and by stabilizing the weakened lesion, it can improve functional movement in the treated area.Bone metastasis in the pelvis not only causes pain but also affects the mobility and other functional abilities of the patient. Traditional treatments for pain due to bone metastasis include conservative treatments such as pain medication, physiotherapy, and local anesthetic injection.,12 The navigation system is a useful tool to avoid these clinical complications because it shows the position of the puncture needle perfectly on axial, coronal, and sagittal CT images.,13Pain relief and increased functional ability are important targets of a treatment; however, it is also important to minimize complications because they could potentially be life-threatening or cause iatrogenic pain. Serious complications of cementoplasty include cement leakage, eccentric distribution of cement, and bone cement embolism. These complications are usually associated with disposition of the puncture needle, repeated insertion of the needle, cement viscosity, and volume of the bone cement.Furthermore, the navigation guidance technique involves less radiation exposure compared with that with conventional method (3-D fluoroscopy-based CT guidance). Most patients undergoing this procedure are patients with advanced cancer and have been exposed to a lot of radiation before the procedure owing to radiotherapy and follow-up imaging for progress tracking. They choose to undergo the procedure because of severe pain and immobility. However, many patients are afraid of radiation exposure from the conventional method. Navigation-guided cementoplasty is not entirely free from radiation because a few C-arm images are acquired to confirm the needle and cement position after the procedure and prevent complications such as disposition of the needle or cement leakage. However, compared with that of 3-D fluoroscopy-based CT-guided cementoplasty, radiation exposure is greatly reduced. This is beneficial to both the patients and operator.,14 With a navigation system, radiation exposure can also be minimized. Since cementoplasty is usually used for terminal cancer patients as a palliative therapy, guidance methods that are less invasive and involve limited radiation exposure should be chosen. Therefore, we recommend navigation-guided percutaneous cementoplasty as the optimal treatment choice for metastatic bone pain.In summary, percutaneous cementoplasty is an efficient method for treating metastatic bone pain by stabilizing osteolytic lesions. In addition, this procedure is a minimally invasive and could be more beneficial compared with other surgical procedures because it has a short recovery time and provides immediate pain relief with fewer complications.Conceptualization: So Young Lee, Jin Yong Jung.Data curation: Ji Hyeon Lee, In Young Kim, Young Don Kim.Formal analysis: Ji Hyeon Lee.Investigation: Ji Hyeon Lee, In Young Kim, Young Don Kim, So Young Lee, Jin Yong Jung.Methodology: Young Don Kim, Jin Yong Jung.Resources: Jin Yong Jung.Software: Young Don Kim.Supervision: Jin Yong Jung.Validation: Ji Hyeon Lee, In Young Kim, Jin Yong Jung.Visualization: Ji Hyeon Lee, In Young Kim.Writing – review & editing: Jin Yong Jung, Ji Hyeon Lee.