Neuroimaging studies have documented brain structural alterations induced by chronic pain, particularly in gray matter volume. However, the effects of trigeminal neuralgia (TN), a severe paroxysmal pain disorder, on cortical morphology are not yet known. In this study, we recruited 30 TN patients and 30 age-, and gender-matched healthy controls (HCs). Using Computational Anatomy Toolbox (CAT12), we calculated and compared group differences in cortical thickness, gyrification, and sulcal depth with two-sample t tests . Relationships between altered cortical characteristics and pain intensity were investigated with correlation analysis. Compared to HCs, TN patients exhibited significantly decreased cortical thickness in the left inferior frontal, and left medial orbitofrontal cortex; decreased gyrification in the left superior frontal cortex; and decreased sulcal depth in the bilateral superior frontal (extending to anterior cingulate) cortex. In addition, we found significantly negative correlations between the mean cortical thickness in left medial orbitofrontal cortex and pain intensity, and between the mean gyrification in left superior frontal cortex and pain intensity. Chronic pain may be associated with abnormal cortical thickness, gyrification and sulcal depth in trigeminal neuralgia. These morphological changes might contribute to understand the underlying neurobiological mechanism of trigeminal neuralgia. TN is mainly manifested as recurrent electric shock-like attacks in the distribution of one or more trigeminal nerve branches4. These attacks can be commonly evoked by subtle, harmless stimuli or occur spontaneously.Trigeminal neuralgia (TN) is a common paroxysmal facial pain disorder with annual incidence of approximately 4.3–27 per 100,000 people9. For example, based on the voxel-based morphometry (VBM), Obermann et al.7 found decreased gray matter volume in TN patients, which were mainly located in the dorsolateral prefrontal cortex, anterior cingulate cortex (ACC), primary/secondary somatosensory and orbitofrontal cortices, thalamus, insula, and cerebellum compared with controls. Wang et al.8 reported that patients with classic TN displayed gray matter volume reductions and negatively correlations between gray matter volume of left inferior temporal gyrus and pain intensity or disease duration in patients. Tsai et al.6 investigated the left and right TN patients respectively, and found gray matter volume reductions in the inferior frontal gyrus, precentral gyrus, cerebellum, thalamus, ventral striatum, and putamen among left TN patients and in the prefrontal cortex, precentral gyrus, cerebellar tonsil, thalamus, hypothalamus, and nucleus accumbens among right TN patient. However, the effects of TN on cortical morphology remain enigmatic.Although neurobiological mechanisms of TN are not fully understood, neuroimaging studies have supported that chronic pain is associated with brain morphological changes, particularly in gray matter volume10, and cortical morphological analyses are widely used to investigate the neuroplastic changes associated with aging12, cognitive performance13, and pathophysiological changes15. Based on the surface-based morphometry (SBM), previous studies have investigated alterations of cortical thickness in TN18. For example, DaSilva et al.16 chose cortical regions based on sensory, motor, and emotional processing of pain as ROIs, and found abnormal cortical thickness in sensorimotor regions and emotional regions. Parise et al.17 used SBM and reported cortical thickness reductions in the left cuneus and left fusiform in the TN patients. In contrast, the study of DeSouza et al.18 showed that the TN patients had cortical thickening in the contralateral primary somatosensory cortex and frontal pole, while thinning in the pregenual anterior cingulate cortex, the insula and the orbitofrontal cortex compared to controls. Although previous studies have found cortical abnormalities in TN patients, these studies have not produced consistent results and these differences may be the result of differences in the precise patient samples studied or methods used. Furthermore, gyrification and sulcal depth, another two morphological characteristics, that are thought to be parallel to cortical thickness20, have fewer been investigated in TN patients, except one study of Wang et al.21, which reported significant reductions of local gyrification index in the left insular cortex. Sulcal depth is sensitive to cortical atrophy and development24, and the spatial distribution of deep sulcal regions is relatively robust26. Cortical gyrification adapts the cortical surface area to the skull, which promotes the development of neural circuits27. Thus, the exploration of cortical morphology might provide more accurate and reliable information about underling neurophysiological mechanisms related to chronic pain.Cortical characteristics, including cortical thickness, gyrification index and sulcal depth in the present study, have been indicated to reflect the regulation of intermediate progenitor cells genesis and amplification7. In addition, we also hypothesized that the cortical characteristics in significant regions observed in TN may be correlated with the pain duration or intensity.Therefore, the aim of present study was to perform a comprehensive analysis on alterations of cortical morphology in TN patients and explore the relationships between cortical characteristic’s changes and pain duration or intensity in the TN patients. Given the findings of previous neuroimaging studies of chronic pain, we hypothesized that cortical characteristics would be altered in some brain regions in the TN patients4 to diagnose of TN and assess the intensity and frequency of the symptoms using visual-analog scales (VAS). Most of the patients were treated with carbamazepine and five were treated with gabapentin due to allergies  were recruited from the Guangdong Second Provincial General Hospital. All TN patients were screened according to the International Classification of Headache Disorders version III criteriaThis study was approved by the Ethics Committee of Guangdong Second Provincial General Hospital. Written informed consent was obtained from each subject. The study was carried out in accordance with the relevant guidelines and regulations.2, flip angle (FA) = 8°, slice thickness = 1.0 mm, and 185 sagittal slices.Imaging data were obtained on a 3.0 T Philips Ingenia MR scanner using a 32-channel head coil at the department of Medical Imaging in Guangdong Second Provincial General Hospital. High resolution T1-weighted 3D images were collected using a fast field echo (FFE) pulse sequence with repetition time (TR) = 7.9 ms, echo time (TE) = 3.6 ms, acquisition matrix = 256 × 256, field of view (FOV) = 256 mmhttp://dbm.neuro.uni-jena.de/cat/), which is an automated approach based on a projection-based thickness (PBT) method to estimate the thickness of cortex and reconstruct the hemispheric central surface28. The procedures have been described in our previous study29. In brief, the processing pipeline included brain segmentation into gray matter, white matter and cerebrospinal fluid, affine registration to MNI template space, and subsequent nonlinear deformation. The cortical thickness was measured as follows: we used segmentation to estimate white matter distances and then project local maxima to other gray matter voxels using neighborhood relationships. We also extracted two additional measured surfaces, gyrification and sulcal depth. Based on the absolute mean curvature, gyrification index was calculated as a ratio of the external brain surface with the outer surface excluding the sulci30. The sulcus depth with square root function transformation, making the data more normally distributed, was defined as the Euclidean distance between the central surface and the convex hull. The square root function transformation was used to make the data more normally distributed. The newly generated images were smoothed using a Gaussian kernel with a full-width-half-maximum (FWHM) of 15 mm for cortical thickness and 20 mm for gyrification and sulcal depth, respectively.The surface-based analysis was performed using the Computational anatomy toolbox (CAT12)  method, with a cluster threshold of p < 0.05, uncorrected).In addition, based on the results of the surface-based morphometry, we estimated the partial correlation between the mean cortical characteristics and the duration of TN, pain intensity, age of pain onset, while taking age, gender, and education as covariates  regions in the TN group compared to the HCs . There was also a significant negative correlation between the mean gyrification index of the left prefrontal cortex and pain intensity   in cortical thickness in the frontal region of TN patients. Desouza et al.18 found that the anterior cingulate cortex and orbitofrontal cortex were thinner in TN patients. A study of Schmidt-Wilcke et al.39 about chronic facial pain have shown a decrease in gray matter volume in the anterior cingulate region and demonstrated that the anterior cingulate connects the prefrontal cortex to the limbic system, which is associated with pain regulation. Thus, the observed decrease in cortical morphology in the prefrontal and anterior cingulate regions may reflect a highly pain-related response to chronic pain, including TN. Considering the functional correlation between the two regions, the interregional connections between the prefrontal cortex and the anterior cingulate cortex appear to form part of the central pain processing system, responsible for pain regulation and perception.We found that, compared to the control group, the cortical characteristics of TN patients, including decreased cortical thickness, gyrification index, and sulcal depth, were mainly located in the frontal region Fig. . The sup40. Hayes and Northoff41 previously reported that painful stimuli could activate the motor cortex. One previous study of Peck et al.42 has proposed and refined a new "Integrated Pain Adaptation Model", which stated that pain could induce a new recruitment strategy to change muscle activity to minimize pain. For TN patients, simple and painless exercise can also lead to trigeminal neuralgia attacks43. Therefore, TN patients would like to limit facial movement to reduce pain. Therefore, we hypothesized that inhibition of the pain response of the trigeminal nerve to relieve pain might result in plastic changes in the primary motor cortex.In addition, it was found that compared to the HC group, the cortical thickness decreased in the left precentral gyrus of TN patients. As a part of the primary motor cortex, the precentral gyrus is responsible for reflecting sensory pain response, maxillary motor inhibition, and facial muscle tension38. Therefore, the correlations between the cortical morphology of the frontal cortex and the intensity of pain may indicate that the intensity of pain is a key factor responsible for the morphological changes of TN patients.The correlations between cortical morphology and pain intensity may indicate the effect of pain intensity on changes of the cerebral cortex. Our study found that there was a significant negative correlation between the mean cortical thickness of the left orbitofrontal cortex and pain intensity, and a significant negative correlation between the mean gyrification of the left superior frontal cortex and pain intensity. In other words, the higher the level of pain, the thinner the thickness of the cortex and the lower the gyrification index. This is similar to the results of previous study of chronic pain, which analyzed the changes in the volume of gray matter in the patients with back pain and found a negatively correlation between the decreased gray matter volume in the prefrontal cortex with pain intensity27, which are sensitive to cortical development24. Thus, our finding of altered sulcal depth and gyrification may also provide the evidence of pain-related cortical morphological changes.In this study, we first reported the abnormal changes in the sulcal depth and gyrification. Previous studies have indicated that sulcal depth and gyrification reflects a measure of cortical folding and complexity30. In terms of spatial smoothing, cortical thickness was normalizing the cortical surface with a 15 mm Gaussian kernel, while sulcal depth and gyrification was used a 20 mm Gaussian kernel. The second possible interpretation is that three measures might be sensitive to different underlying neurobiological effects. Cortical thickness could reflect the structure of the cerebral column10. Sulcal depth might be related to genetic control and cytoarchitectonic areas44. Cortical gyrification allows a larger cortical surface area to fit in the skull, facilitating the development of compact neural circuits27. Generally speaking, the SBM analysis might provide a comprehensive perspective to the findings in TN.Unfortunately, we noticed lack of overlap in our findings when comparing the results among three cortical characteristics Table . This ap47, which was partly consistent with our findings. For example, Mao et al.46 studied patients with chronic low back pain and found reported decreased gray matter volume in the bilateral superior frontal gyrus, right frontal pole, left insular cortex, left middle and inferior temporal gyrus. Blankstein et al.47 reported cortical thinning in the anterior midcingulate cortex in irritable bowel syndrome. The possible explanation for consistent findings is that different types of pain may have common pain mechanisms, as well as specific mechanisms associated with pain. However, as to the TN patients, limited studies on cortical morphology have not found consistent results21. For example, Parise et al.17 found reduced cortical thickness in the left cuneus and left fusiform in the TN patients. In contrast, the study of DeSouza et al.18 showed both cortical thickening and thinning compared to controls. Wang et al.21, reported significant reductions of local gyrification index in the left insular cortex. And our study found that TN patients exhibited significantly reduced cortical thickness in the left inferior frontal, and left medial orbitofrontal cortex; reduced gyrification in the left superior frontal cortex; and reduced sulcal depth in the bilateral superior frontal cortex. The reason for these inconsistent results in the cortical morphometry may be multifaceted, such as the precise patient samples studied or the methods used, and need to be further investigated.Compared with other neuropathic pain, we noticed decreased cluster in the cingulate, insula and thalamus, frontal, temporal and postcentral gyrusThe study has some limitations. Firstly, we adopted a cross-sectional design, and detected reductions in cortical morphological indicators in patients with TN. However, we cannot elucidate the causal relationship between alterations of cortical characteristics and TN development. Secondly, all TN patients in this study were treated with analgesics, therefore, we cannot rule out the possible confounding effect of drugs in cortical morphological analysis. Thirdly, the inhomogeneous distribution of affected sides (8 left/22 right) in the included subjects may be responsible for the left-lateralization of cortical morphometry, which may indicate possible compensatory effects or neuroadaptation. Fourthly, in the correlation analyses, the uncorrected results were presented, which may provide the possible correlation between cortical characteristics and pain intensity in TN. Future studies should expand the sample size and report the corrected results to increase the statistical efficiency of correlation analysis.In conclusion, this is the first comprehensive analysis of cortical thickness, gyrification index, and sulcal depth in patients with trigeminal neuralgia. We found that patients with trigeminal neuralgia had cortical morphological changes in prefrontal cortex, anterior cingulate and precentral gyrus, which are mainly involved in pain management and perception. This study also found a correlation between reduced cortical morphological indicators and increased pain intensity. These results may provide important information about the neurophysiological mechanisms associated with pain.


Background: Punctal/intracanalicular plugs on the market nowadays are all designed before clinical use in treating dry eye disease (DED). To provide an individualized lacrimal drainage system occlusion method and reduce the complications, we developed a “liquid plug” strategy by intracanalicular injection of hydroxybutyl chitosan (HBC) solution, a thermosensitive, phase-changing biomaterial. This study evaluated the efficacy and safety of the HBC plug in treating dry eye disease by comparing it with the VisiPlug absorbable intracanalicular plug.Methods: A monocenter, randomized, controlled clinical trial was performed. Fifty patients with DED were randomized 1:1 to undergo either the HBC injection treatment or the VisiPlug treatment. Ocular Surface Disease Index (OSDI) questionnaire, tear break-up time (TBUT), corneal fluorescence staining (CFS), tear meniscus height (TMH), and phenol red thread test were evaluated at Day 0  and Weeks 1, 4, and 12.Results: The two groups had a balanced baseline of age, gender, and DED-related characteristics. Both occlusion methods could relieve the symptoms and signs of DED. Significant improvement was found in OSDI, phenol red thread test, and tear meniscus height (P < 0.05 compared to baseline) but not in corneal fluorescence staining and tear break-up time (P > 0.05). There is no statistically significant difference between HBC injection and VisiPlug at Weeks 1 and 4 (P > 0.05). However, at week 12, the HBC injection was not as effective as the VisiPlug in maintaining phenol red thread test  and tear meniscus height . The numbers of ocular adverse events were relatively low in both groups.Conclusions: The HBC injection showed similar efficacy and safety compared to VisiPlug. The intracanalicular injection of HBC solution proves to be a promising, individualizing method to treat DED.Clinical Trial Registration: This study is registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn/enindex.aspx), Identifier: ChiCTR1800016603. Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles . DED canLacrimal drainage system occlusion is commonly undertaken using punctal/intracanalicular plugs, including absorbable and non-absorbable plugs. Though featuring numerous materials –9, plugsRecently, we have designed a novel type of “liquid plugs” using hydroxybutyl chitosan (HBC), a thermosensitive and dissolving material with good biocompatibility . When inA monocenter, randomized, controlled clinical trial was performed to evaluate the difference of safety and efficacy between the intracanalicular injection of HBC solution  and the absorbable intracanalicular plug, VisiPlug , in DED patients. The study was performed in the Eye & ENT Hospital of Fudan University, was registered in the Chinese Clinical Trial Registry (Identifier: ChiCTR1800016603), was conducted in compliance with the Declaration of Helsinki, and was approved by the ethical committee of Eye & ENT Hospital of Fudan University. Written informed consent was obtained from all participants.The clinical trial consisted of the intracanalicular occlusion treatment as well as a 12-week visit after the treatment . After iA total of 50 DED patients between 18 and 75 years of age were enrolled in the clinical trial after screening. The inclusion criteria were as follows: diagnosed with dry eye according to the criteria of the International Dry Eye Workshop , visual The hydroxybutyl chitosan solution is preserved in sterile tubes at 4–8°C. Before injection, drop topical anesthetics to the conjunctival sac to release the unpleasant feeling during the operation. Syringe the upper and lower lacrimal passages in both eyes with saline before injection to ensure the passages are unobstructed. Attach a rinse needle to the tubes containing HBC solution and insert the needle 2–3 mm into the punctum. Inject the HBC solution into the puncta of the upper and lower canaliculi in both eyes until overflow. At the same time, press the dacryocyst sac to avoid downflow of the HBC solution. After injection, press the dacryocyst sac for another 1 min and give antibiotic eye drops to prevent infection. The treatments for all participants were conducted by the same operator.Outcome measures include safety and changes related to efficacy. All the patients underwent an Ocular Surface Disease Index (OSDI) questionnaire, tear break-up time (TBUT), corneal fluorescence staining (CFS), OCT imaging for tear meniscus height (TMH), and phenol red thread test at Day 0 (baseline) and Weeks 1, 4, and 12. Ocular adverse events (AEs) related to the treatment are recorded.Ocular Surface Disease Index was used to assess the subjective symptoms at each visit. The questionnaire consisted of the bothersome symptoms, visual function, and environmental triggers subscales. The subjective symptoms were scored on a 5-point scale, with a score of 0 indicating least severe, and a score of 4 indicating most severe. A derived index score of ≤ 100 was calculated for each evaluation based on the total number of questions answered .TBUT was used to assess the tear film stability. A fluorescein-impregnated strip  was wetted with saline solution before use. Placed the wetted strip in the lower conjunctival sac and the patient was asked to blink several times. TBUT was defined as the time between the last complete blink and the first black spot appearing in the stained tear film on the cornea. It was measured three times to get the mean TBUT.According to the NEI criteria, CFS characteristics in five corneal zones were scored on a 4-point scale as follows: 0 = no staining, 1 ≤ 5 staining points, 2 ≥ 5 staining points but <10 staining points, and 3 ≥ 10 staining points or the appearance of corneal filaments .Tear secretion was measured by the phenol red thread test without topical anesthesia. The phenol red thread  was placed approximately 1/3 of the distance from the lateral canthus of the lower eyelid. The length of the wetted thread was measured as the lacrimal secretion 15 s after placement.The lower TMH was measured using an anterior segment OCT system  . The sinP < 0.05, using t-tests or Chi-square tests for inter-group comparisons and repeated measures analysis of variance or non-parametric tests for intra-group comparisons.Statistical data were analyzed using SPSS 19.0 . Results were expressed as means ± SD. Differences were considered to be significant at a level of Fifty patients were enrolled in the trial and were randomized into two groups: the HBC group  and the VisiPlug group; 25 patients in each group, respectively. Eight patients dropped out after treatment since they refused follow-up. Twenty patients of the HBC group and 22 patients of the VisiPlug group  completed the clinical trial .The distribution of age, gender, and baseline DED indexes  between the two treatment groups were all well balanced . No signThe assessment of efficacy puts emphasis on both the efficacy of intracanalicular HBC injection and the difference between the HBC group and the VisiPlug group in treating DED.P < 0.001), indicating an onset effect of as early as 1 week. At Weeks 4 and 12, the OSDI score basically maintained in the VisiPlug group . While in the HBC group, the OSDI score slightly increased at week 12 . No statistical difference of the OSDI score was found between the HBC group and the VisiPlug group at any time (P > 0.05). So, it is believed that the HBC injection and the VisiPlug could improve the symptom of DED equally.The subjective symptoms of DED were relieved in both groups . One weeP = 0.009). The results showed that both groups were effective in improving tear secretion. However, 12 weeks after treatment, the HBC group was not as effective as the VisiPlug group. We suppose that it is caused by the difference in the degradation speed of different absorbable materials.Improvements were also observed in the phenol red thread test after treatment . GeneralP < 0.05). Likewise, TMH in the HBC group increased after HBC injection  compared to the baseline . Similarly, TMH also reflects the tear secretion, so that the VisiPlug treatment was better than the HBC injection in improving TMH at Week 12 (P = 0.041).Both treatment groups showed an improvement in TMH . After tP = 0.127; VisiPlug: P = 0.060). TBUTs at Weeks 4 and 12 also had no difference with baseline in both groups.Both groups seemed to have little effect on TBUT . AlthougNo significant change in CSF was observed in both the inter-group comparisons or the intra-group comparisons, either. It is probably caused by the fact that all the patients enrolled showed little or no CFS score even before the treatment .During the clinical trial, no serious AE was reported in the HBC group or the VisiPlug group. The AEs include epiphora, increased secretion, conjunctival congestion, foreign body sensation, eye itching, and blurred vision. All of them were of mild intensity, which relieved automatically without any treatment. They are specifically listed in in vivo. An innovative thermosensitive phase-changing biomaterial, hydroxybutyl chitosan (HBC), makes the idea possible. Research studies showed that HBC can change from a liquid phase to a hydrogel solid phase in a short time. At body temperature (37°C), the phase-changing process will finish in 50 s , the National Natural Science Foundation of China (Grant No. 82000855 to LT), and the Shanghai Rising Stars of Medical Talents Youth Development Program .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.


This randomized clinical trial assesses the efficacy and cost-effectiveness of liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone for postoperative recovery and pain management among patients undergoing knee replacement. Among patients undergoing knee replacement surgery, does liposomal bupivacaine and bupivacaine hydrochloride administered at the surgical site improve postoperative recovery at 72 hours and postoperative pain from 6 to 72 hours compared with bupivacaine hydrochloride alone?In this randomized clinical trial of 533 patients undergoing knee replacement surgery, no difference in the coprimary outcomes of Quality of Recovery 40 score at 72 hours or pain visual analog scale score area under the curve from 6 to 72 hours was detected between patients receiving liposomal bupivacaine and bupivacaine hydrochloride and those receiving bupivacaine hydrochloride alone. In addition, liposomal bupivacaine was not found to be cost-effective.This study found that liposomal bupivacaine did not improve postoperative recovery or pain compared with bupivacaine hydrochloride alone among patients undergoing knee replacement surgery. More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain.To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement.This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis.Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery.The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed.P = .64) or the pain VAS score AUC at 6 to 72 hours . Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery . No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups.Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 ; This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery.ISRCTN54191675isrctn.com Identifier:  Liposomal bupivacaine  is a novel liposome-encapsulated local anesthetic developed to improve postoperative analgesia and reduce the need for supplementary opiate analgesia.6 In the knee, liposomal bupivacaine is licensed for single-dose periarticular local infiltration at the time of surgery.Knee replacement is a highly successful operation for patients with symptomatic advanced arthritis refractory to nonoperative treatment; however, recovery from surgery can be painful despite multimodal opiate-sparing techniques.7 The present study was a large randomized clinical trial assessing the clinical efficacy and cost-effectiveness of liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone (control condition) for postoperative recovery and pain after knee replacement to guide best clinical practice. We sought to assess the null hypothesis that no true difference in postoperative recovery and pain exists after knee replacement between liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone when administered by periarticular infiltration at the time of surgery.Current evidence on the effectiveness of liposomal bupivacaine is inconclusive owing to small study size and nonstandardized comparators.9 The study followed the Consolidated Standards of Reporting Trials (CONSORT) and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guidelines. The trial was approved by the National Research Ethics Service, Oxfordshire Research Ethics Committee C in 2017, with written informed consent obtained from all participants before their involvement in the study.This trial was a multicenter, randomized, patient-blinded, active comparator-controlled, superiority clinical trial conducted across 11 National Health Service institutions in the UK. A summary of the study protocol has been published previously and is available in Eligible participants were adults 18 years or older with American Society of Anaesthesiologists grades 1 to 3 physical classification status inclusive who underwent unilateral primary total knee preplacement (TKR) or unicompartmental knee replacement (UKR) for end-stage osteoarthritis. Patients were excluded if they had rheumatoid arthritis, an allergy or intolerance to amide-type local anesthetics, objective evidence of nerve damage in the affected lower limb, or contralateral knee replacement within the 12 months before randomization or had participated in another research trial involving an investigational medicinal product in the 6 months before randomization. A list of the participating centers is available in eAppendix 1 in Patients were randomized 1:1 to the intervention  or control (bupivacaine hydrochloride) arms using a secure online system. Randomization was stratified according to recruitment site and type of surgery (TKR or UKR). Treatment group numbers were balanced using random permuted blocks of sizes 2, 4, and 6.All patients underwent knee replacement with the surgical technique, implants used, and alignment philosophy in line with surgeons’ usual practice. Patients randomized to the intervention arm received 266 mg of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride without epinephrine. Those randomized to the control arm received 100 mg of bupivacaine hydrochloride without epinephrine. In both groups the volume was expanded to 120 mL with normal saline. Liposomal bupivacaine and control drugs were administered via a standardized periarticular injection technique with a reference guide provided in each operating theater. Preoperative, intraoperative, and postoperative analgesia regimens and management were in line with local protocols and did not differ based on patient randomization.10 at 72 hours and pain visual analog scale (VAS) score from 6 to 72 hours after surgery.11 Predefined secondary outcomes included QoR-40 and VAS scores at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption; functional outcomes measured using the Oxford Knee Score and American Knee Society Score; quality of life measured using the 5-level EQ-5D (EQ-5D-5L); use of health care resources; and complications measured using the Clavien-Dindo classification.15The coprimary outcome measures were the Quality of Recovery 40 (QoR-40) score9 The sample size for the trial was 500 patients. A total of 240 patients per arm were required to detect a 5-point difference in global QoR-40 scores at P = .025 significance level with 90% power, assuming an SD of 15.5. Allowing a 4% loss to follow-up increased this sample size to 500 patients overall. This sample size was also sufficient to detect a standardized difference of 33% between treatment groups in cumulative pain score calculated as the area under the curve (AUC) from 6 to 72 hours after surgery, with P = .025 indicating statistical significance and allowing for 10% loss to follow-up.The full statistical analysis plan has previously been published and can be accessed in 11 Continuous secondary outcomes were analyzed using multilevel mixed-effects linear regression models; categorical secondary outcomes were analyzed using multilevel mixed-effects logistic regression models.The QoR-40 scores at 72 hours after surgery in the treatment groups were compared using a mixed-effects linear regression model adjusting for type of surgery, baseline QoR-40 scores, age, and sex as fixed effects and recruitment site as a random effect. Cumulative pain scores were compared between the treatment groups using parameters from a repeated-measures mixed-effects linear regression model to calculate the summary measures AUC from 6 to 72 hours after surgery.P = .025 indicating statistical significance to adjust for multiplicity associated with the coprimary outcomes, with all other analyses performed with a 2-sided P < .05 indicating statistical significance.Sensitivity analyses to assess the impact of missing data were conducted on both coprimary outcomes. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat (ITT) analysis. The primary outcome analyses were performed with a 2-sided 16 opioids, and liposomal bupivacaine injection), self-reported use of health care and social services resources, and hospital readmissions obtained from trial sites. Missing baseline and follow-up data were handled by mean and multiple imputation, respectively.Patients were followed up for 1 year, until March 1, 2021. We conducted a within-trial cost-utility analysis during the follow-up, adopting the perspective of the National Health Service in the UK and personal social services. Details of the analysis are available in the eMethods and eTables 1 to 5 in Differences in total health care costs and QALYs were estimated using linear regression models adjusted for randomized treatment allocation, type of surgery performed (TKR vs UKR), and baseline utility (QALYs only); robust standard errors were used to account for clustering by site. We estimated the incremental cost-effectiveness ratio by dividing the mean cost difference by the mean QALY difference. We assessed the joint uncertainty around incremental total costs, QALYs, and cost-effectiveness via bootstrapping, used to calculate the probability that liposomal bupivacaine is cost-effective compared with bupivacaine hydrochloride alone at a willingness-to-pay threshold of £20 000 (US $26 400)/QALY gained. An intervention was judged to be cost-effective if the incremental cost-effectiveness ratio was less than £20 000 (US $26 400)/QALY gained. A cost-effectiveness acceptability curve was used to show the probability that liposomal bupivacaine is cost-effective at different willingness-to-pay threshold values to £60 000 (US $79 200)/QALY.In sensitivity analyses, we considered a wider perspective and included patient costs  and productivity losses. To facilitate comprehension of the cost data, we converted UK health care costs to US dollars using 2019 power purchasing parities for gross domestic product (1.45), 2019 exchange rates (1.28), and 2017 power purchasing parities for health (1.33) as sensitivity analysis. Because the economic results in the UK setting cannot be applied directly to the US setting, we did not estimate incremental cost-effectiveness ratios or cost-effectiveness acceptability curves in US dollars. All analyses were undertaken using Stata, version 15 (StataCorp LLC).From March 29, 2018, to February 29, 2020, 1360 participants were assessed for eligibility for the trial. A total of 827 participants were excluded before randomization, with the remaining 533 participants randomized into 2 groups. A CONSORT flow diagram is provided in Among the 514 patients with available data, 461 (89.7%) received a TKR and 53 (10.3%) received a UKR. The type of surgery, anesthetic technique used, and time in the operating theater were similar between groups  withdrawing before receiving their knee surgery  and the adjusted mean difference for pain VAS score AUC at 6 to 72 hours was −21.5 . Based on the significance level of .025, there was no statistical evidence of a difference between the intervention and control groups with regard to either QoR-40 score at 72 hours after surgery or pain VAS score AUC from 6 to 72 hours after surgery . All other time points showed no evidence of statistically significant difference for the pain VAS scores  or worst-case cumulative opiate use  was detected between treatment arms (eTable 15 in Cumulative mean (SD) best-case oral morphine equivalent opioid consumption from days 0 to 3 in the liposomal bupivacaine arm was 126.5 (88.9) mg and 127.4 (132.6) mg in the control arm. No statistically significant difference in best-case cumulative opiate use , there was no significant difference in outcomes at other time points. This difference on day 0 was not viewed to be of a clinically relevant magnitude, nor at a clinically relevant time point with respect to the mechanism of action of the investigational medicinal product. Cost-utility analysis found periarticular liposomal bupivacaine with bupivacaine hydrochloride not to be cost-effective compared with bupivacaine hydrochloride alone after knee replacement surgery.Our findings show no clear benefit to the use of periarticular liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone in the treatment of postoperative pain after knee replacement surgery. No significant difference in QoR-40 score at 72 hours or pain VAS score AUC from 6 to 72 hours was detected between treatment groups. In addition, analysis of secondary outcomes, including QoR-40 scores, cumulative opioid consumption on days 0, 1, 2, and 3, and patient-reported functional outcomes at 6 weeks, 6 months, or 1 year found no significant differences in these outcomes. Aside from pain VAS score on the evening of surgery (day 0), where the liposomal bupivacaine intervention group was found to have lower scores , and 3 additional studies31 reported lower pain scores at isolated time points within the analysis, with only 1 study22 demonstrating concurrently lower opioid intake at this time point. All other studies33 found no difference in mean pain score or opioid consumption at the time points assessed.We are aware of 17 previous randomized clinical trials28 opioid medication was restricted postoperatively, and staff and patients were educated about the risks associated with opioids, with opioids only given on request for breakthrough pain. Under these circumstances, the investigators found the opioid consumption in the liposomal bupivacaine arm (20.9 [8.7] mg) to be markedly lower than others reported in the literature, including the present study. Theoretically, high baseline levels of opioids may mask any effect of the treatment intervention; however, we identified 4 further trials with a restrictive opioid policy,29 but without patient and staff education, with none demonstrating any difference in pain scores or opioid consumption between the liposomal bupivacaine and control groups. In our trial, 456 of 459 participants (99.3%) received opioids, which is similar to the PILLAR trial,28 in which 90% of patients received opioids in the intervention group and 100% in the control group; however, in only 1 center, the mean cumulative opioid consumption was similar to that reported in the PILLAR trial , with the remaining centers having a value of a minimum of 3-fold higher.In the PILLAR trial,A balance must be found between preemptive and reactive prescribing. Current surgical practice in the UK is to prescribe preemptive opioid-based analgesia; therefore, the UK practice must be regarded as opioid-sparing, not opioid-free. In this setting, we found no benefit to the use of periarticular liposomal bupivacaine. Whether liposomal bupivacaine has a role in the setting of opioid-free knee replacement remains unknown, but at present opioid-free surgery is rare and not a reality for most patients.35 have investigated the roles of continuous intra-articular infiltration after knee replacement. Although these studies appear to provide improved pain control, compared with single-shot local anesthetic infiltration, it must be noted that the pain scores remain above 0 and typically range from 2 to 4 of 10 from 12 to 72 hours after surgery, indicating that not all pain can be targeted by intra-articular local anesthetic injection. Another reason may relate to the pharmacokinetic profile of liposomal bupivacaine. Liposomal bupivacaine exhibits a bimodal, dose-related release profile with an initial peak release within 1 hour of administration related to extra liposomal bupivacaine, followed by a further peak 12 to 36 hours later, related to release from the liposomes.36 The rate at which liposomes release bupivacaine has been proposed to be related to the vascularity of the surrounding tissue, with knee replacement being the least vascular of the 4 surgical models assessed and having the slowest rate of release.37 In knee replacement, 30% of the bupivacaine is released in the first 24 hours, compared with the more vascular hemorrhoidectomy, in which 90% is released.37 This will have an effect on the periarticular local anesthetic concentration, and it may be that a higher dose of liposomal bupivacaine is required in knee replacement, with the original phase 2 dose-finding trial in knee replacement finding a significant reduction in pain score AUC at rest from days 2 to 5 with 532 mg, but not with lower doses, which have subsequently been licensed.17Other potential reasons why a treatment effect was not seen with liposomal bupivacaine may relate to the source of pain as well as the pharmacokinetics of liposomal bupivacaine in knee replacement. Several studiesTo our knowledge, this is the largest study of liposomal bupivacaine for the management of postoperative recovery and pain. It addresses many of the limitations of previous studies in that it has a patient-centered outcome measure and is appropriately powered with a standardized intervention with good adherence to the injection technique. Conducted across 11 centers within the National Health Service, this pragmatic randomized clinical trial reflects current clinical practice in the UK, with the results being directly applicable to decision-making by patients, clinicians, and policy makers.This study is not without limitations. As a pragmatic randomized clinical trial, it reflects real-world experience and is not subject to the same standardization as other trial designs. A consequence is that variation in anesthetic and surgical practice as well as patient selection for knee replacement, which may influence outcomes, is expected between trial sites. Although stratification of randomization and adjustment for potential confounders during statistical analysis is designed to minimize the influence of this variation, the results of this trial represent the outcomes of the population studied as a whole. Within this population, there may be subgroups of patients in whom liposomal bupivacaine is associated with a positive (or negative) treatment effect but that the study is not powered to assess. Another limitation of this study is that outside of those recorded using the Clavien-Dindo classification, opioid-related adverse events were not specifically recorded; however, because no difference in opioid consumption was detected between groups, and, given that opioid-related adverse events are known to be dose dependent, a difference would not be expected. Last, because pain score and opioid consumption have been reported to be positively correlated, opioid consumption may represent a confounding factor for our primary outcome.In this randomized clinical trial, periarticular liposomal bupivacaine together with bupivacaine hydrochloride did not improve postoperative recovery or pain compared with bupivacaine hydrochloride alone in patients who had undergone knee replacement surgery. In addition, the intervention was not found to be cost-effective.


Chest tube causes severe pain during removal because it attaches to the endothelium in the chest cavity.This study aimed to determine the effectiveness of cold application with ice pack and gel pad in the control of pain experienced during chest tube removal.The sample of prospective, parallel three-arm (1:1:1), randomized controlled clinical trial consisted of 180 patients in two experimental groups (ice pack/gel pad) and one control group. The primary outcome was effect of cold application materials on severity of pain during chest removal. Secondary outcomes were duration of cold application and analgesic requirements of the patients.The study found that the cold application using either of the materials reduced the severity of pain and the need for analgesics after the removal of chest tube compared to the control group (p<0.05). But cold application with ice pack allowed the skin to drop to the temperature effective in pain control in a shorter time than gel pad application (p<0.05).Despite entirely covering the area around the chest tube, the gel pad was more disadvantageous than ice pack in pain control due to the longer duration of cold application. Chest tube used in the treatment of acute or chronic problems caused by thoracic surgery or trauma allows the air and fluid to be drained from the pleural space.The material used must be in completely contact with the skin so that cold application can be effective in pain control. In cold application with ice pack commonly used in clinics, it is possible that the material does not come into completely contact with some areas of the skin around the chest tube and this may lead to less effective cold application in pain control. On the other hand, in cold application with gel pad, which completely surrounds the chest tube and conforms to the body curves, whether the skin temperature required for the cold application to be effective is reached or not has not been tested so far.H1 hypothesis: There is difference between two cold application materials affects the severity of pain during chest tube removal.H2 hypothesis: There is difference between two cold application materials duration of cold application during chest tube removal.H3 hypothesis: There is difference between two cold application materials analgesic requirements of the patients during chest tube removal.This study was a prospective, parallel three-arm [1:1:1], randomized controlled clinical trial at the Thoracic Surgery Unit of a university hospital in Turkey between September 2016 and November 2017.This trial was registered with ClinicalTrials.gov (NCT04200859) and approved by the Mersin University Clinical Researches Ethics Committee (Number/date: 219/2016). Written and verbal consent was obtained from all the patients, too.The study sample consisted of 180 patients aged ≥18 years who underwent chest tube at the Thoracic Surgery Unit. Patients included in the study were conscious, orientated and cooperated, who could speak and understand Turkish, had no psychiatric disease, had chest tube and had stable general status, aged 18 and over, who had written and oral permission to participate in the study (n=180). A total of 10 patients were excluded from the sample because six of them had language problems, two of them did not agree to participate in the study and it was impossible to communicate with two of the patients due to their psychiatric problems .In order to calculate the sample size, a pain reduction of at least 0.5 standard deviation in the Numerical Rating Scale (NRS) by cold application with gel pack or ice pack was taken as statistically significant, and Demir and Khorshid's study was taken as the reference for this study with 5% Type I Error and 80% test power.The patients were invited to participate in the study between September 2016 and November 2017. Consenting eligible patients were randomly assigned to experimental groups and control group, according arrival sequence in blocks of 3 in a 1:1:1 ratio using the block randomization method. The randomization sequence was developed using a computer generated table of random numbersThe study protocol was reviewed and approved by on Clinical Trials.gov (NCT04200859).Conventional care: Routine analgesic drugs are not administered to patients before removal of the chest tube in thoracic surgery clinic. However, analgesic is performed according to the severity of pain after the procedure.Cold application with ice pack/gel pad group: Before the chest tube was removed, two ice packs with a size of 15.5x9cm were inserted around the chest tube so as to make as much contact as possible. Before the chest tube was removed, a gel pad with a radius of 15 cm was completely inserted around the chest tube .The temperature of the cold application materials (-10 °C) was measured with the barbecue thermometer  before starting the intervention.The primary outcome of this study was the effect of cold application materials on severity of pain.Numerical Rating Scale: The scale was used to determine the severity of pain during chest tube removal process. Black and Matassarin-Jacobs developed the NRS17The secondary outcomes of this study were duration of cold application and analgesic requirements of the patients.The Patients Information Form was used to determine patients characteristics, duration of cold application and analgesic requirements of the patients. The form consisted of items designed to collect data about the patients such as age, gender, education status, cause of chest tube insertion, duration of cold application, presence of analgesic administration before and after chest tube removal, type of analgesic administered, time passed between the last analgesic time and chest tube removal time and time passed between chest tube removal time and the first analgesic administration time.Before removal of chest tube, nurse researcher (D.S.) who is working in the thoracic surgery clinic as a nurse, explained aim of study and take informed consent all patients. Data were collected with Patient Information Form and NRS.Patient Information Form was filled out for each using the information obtained from patients/patients' relatives, patient files and health professionals of the clinic and the patients' pain severity was measured with NRS.The patients were randomly assigned by a computer program to either intervention groups (ice pack or gel pad) or control group. Before the chest tube was removed, nurse researcher (D.S.) made cold application with ice pack the first experimental group and cold application with gel pad the second experimental group. The control group did not receive any intervention. Since the cold application temperature should be reduced to 13.6°C in order to have local analgesic effect in both of the experimental groupsPain severity of all the patients was measured with NRS immediately after and 15 minutes after chest tube removal.Data were analyzed on a computer.In this study, there were significant differences between the groups in terms of the NRS mean scores measured before, immediately after and 15 minutes after chest tube removal (p<0.05) .The severity of pain prior to chest tube removal was significantly higher in patients treated with cold application with gel pad than the patients with treated with cold application with ice pack and than the patients in the control group (p<0.05). The severity of pain at the time of chest tube removal was significantly lower in the patients treated with cold application with ice pack than the patients with treated with cold application with gel pad and than the patients in the control group(p<0.05). Also, the severity of pain 15 minutes after chest tube removal was significantly lower in the patients treated with cold application with ice pack than the patients treated with cold application with gel pack (p<0.05). Finally, the severity of pain 15 minutes after chest tube removal was significantly lower in the patients treated with cold application with gel pad than the patients in the control group (p<0.05) .The severity of pain before chest tube removal in the patients treated with cold application with ice pack or gel pad was significantly higher than their pain severity scores measured immediately after and 15 minutes after chest tube removal (p<0.05). Similarly, the severity of pain in these patients at the time of removal was significantly higher than the pain severity scores measured 15 minutes after chest tube removal (p<0.05). In addition, the severity of pain at the time of chest tube removal in the control group patients was significantly higher than their pain severity measured before and 15 minutes after chest tube removal (p<0.05). Similarly, the severity of pain in these patients 15 minutes after chest tube removal was significantly higher than the pain severity measured before chest tube removal (p<0.05) .In this study, an average of 30 minutes of cold application was given to the patients with gel pad while an average of 18.9±2.6 minutes of cold application was given to the patients with ice pack. The application duration for the patients who received cold application with gel pad was significantly longer than the duration for the patients who received cold application with ice pack (p<0.05) .In addition, there was no statistically significant difference between the groups in terms of the status of analgesic administration before chest tube removal and the time elapsed between the last analgesic administration and chest tube removal (p>0.05). Prior to chest tube removal, the control group patients were given significantly higher doses of paracetamol but lower doses of diclofenac sodium and tramadol HCl than the patients treated with gel pad (p<0.05). Analgesic administration in the patients treated with cold application with ice pack after chest tube removal was significantly less than the patients treated with cold application with gel pad and the control group (p<0.05). Also, analgesic administration in the patients treated with cold application with gel pad after chest tube removal was significantly less than the control group (p<0.05). Analgesic administration within 1 to 3 hours after chest tube removal in patients treated with cold application with ice pack was significantly less than the patients treated with cold application with gel pad (p<0.05). Similarly, analgesic administration within 4 to 6 hours after chest tube removal in patients treated with cold application with ice pack was significantly less than the control group (p<0.05) .In this study was determined that cold application with two different materials decreased the severity of pain after chest tube removal in comparison with the control group. In similar studies, the severity of pain after the procedure of patients who received cold application before chest tube removal was measured with Visual Analog Scale/NRS at different times, such as 5 and 15 minutes after the procedure, and it was shown that cold application was effective in pain control and reduced pain over time.An important result of this study is that ice pack was found to be more effective in reducing severity of pain compared to gel pad. This result may have been caused by the fact that the patients who received cold application with gel pad had higher pain before the procedure and the application was terminated in some patients without reaching the skin temperature (13.6 °C) required for cold application to be effective.In the present study, it was determined that cold application with ice pack reduced the temperature of the skin, which is effective in pain control, in a shorter time than the application with gel pad.In order for cold application to show local analgesic effect, the skin temperature should drop below 13.6°C.In this study, the group who received the most analgesics after chest tube removal was the control group, followed by the experimental group treated with gel pad and the experimental group treated with ice pack, respectively. This result of the study showed that, no matter either ice pack or gel pad was used in pain control, cold application was more effective than no intervention in decreasing the need for analgesia and relieving pain.The limitations of this study; in some patients who had cold application with gel pad, cold application was terminated due to rebound effect in 30 minutes without skin temperature falling to 13.6°C.The results of this study showed that cold application with both materials decreased the pain severity and the need for analgesia after chest tube removal compared to the control group, but cold application with ice pack allowed the skin to drop to the temperature effective in pain control in a shorter time than gel pad application.In interventions that cause acute pain, such as chest tube removal, non-pharmacological methods such as cold application as a part of independent functions of the nurse in addition to pharmacological methods should also be used in pain control. In pain management due to chest tube removal, nurses should develop a cold application protocol taking into account more effective cooling materials. Thus, analgesic requirements that may lead to serious respiratory complications such as respiratory depression in the patient may be reduced.A further result of this study is that although gel pad was completely wrapped around the chest tube, it was more disadvantageous in pain control than ice pack probably due to the longer duration of cold application.


The comprehensive complication index (CCI) is a new tool for reporting the cumulative burden of postoperative complications on a continuous scale. This study validates the CCI for urological surgery and its benefits over the Clavien-Dindo-Classification (Clavien).Data from a prospectively maintained data base of all consecutive patients at a university care-center was analyzed. Complications after radical cystectomy (RC), radical prostatectomy (RP), and partial nephrectomy (PN) were classified using the CCI and Clavien system. Differences in complications between the CCI and the Clavien were assessed and correlation analyses performed. Sample size calculations for hypothetical clinical trials were compared between CCI and Clavien to evaluate whether the CCI would reduce the number of required patients in a clinical trial.p < 0.001; PN: CCI 8.4 ± 14.7 vs. Clavien 7.0 ± 11.8, p < 0.001 and RP: CCI 5.8 ± 11.7 vs. Clavien 5.3 ± 10.6, p = 0.102. The CCI was more accurate in predicting LOS after RC than Clavien (p < 0.001). Sample size calculations based in the CCI  resulted in a reduction of required patients for all procedures .682 patients  were analyzed. Overall, 9.4–46.6% of patients had > 1 complication cumulatively assessed with the CCI resulting in an upgrading in the Clavien classification for 2.4–32.4% of patients. Therefore, scores between the systems differed for RC: CCI (mean ± standard deviation) 26.3 ± 20.8 vs. Clavien 20.4 ± 16.7, The CCI is more accurate to assess surgical complications and reduces required sample sizes that will facilitate the conduction of clinical trials.The online version of this article (10.1007/s00345-020-03356-z) contains supplementary material, which is available to authorized users. Through the ongoing development of new surgical innovations , highly complex procedures can generally be carried out in a safe and standardized manner. However, postoperative complications are inevitable, especially when elderly and multimorbid patients are deemed candidates for surgery . The obj surgery . The CCIDespite its acceptance in general surgery, the CCI is not yet validated for urological procedures. Despite Vetterlein et al. and Furrer et al. applied the CCI to report on their respective patient cohorts undergoing radical cystectomy (RC) , the CCIPatient information was retrieved from prospectively-maintained databases for RC, RP and PN . Therefore, it should be acknowledged, that we did not start a prospective data collection at the beginning of the study, but reviewed our database. For the RC and PN cohorts, all patients between January 1st, 2017 and December 31st, 2018 were considered. For PN, patients who had bilateral tumors or additional procedures at the same time were excluded from analysis. For RP, patients between January 1st, 2018 and December 31st, 2018 were considered. The time frames differ because prospective data acquisition was established at different points of time at our department. Only events that occurred during the hospital stay or within 30 days of the initial procedure were considered.www.assesssurgery.com. As mentioned before, the CCI provides a continuous scale between 0 and 100 (100 indicating death of a patient). To this end, each of the Clavien grades is assigned a specific CCI value and weight of complication (wC) as follows:Data was extracted and entered into a dedicated spreadsheet which listed all complications for each patient (noting the highest-grade complication based on the Clavien classification). For each of the three data bases  an urologist from our department is responsible for the quality and integrity of the data. Before the data bases were established, the complications were defined based on the EAU proposal. This also guaranteed consistency during the assessment. With this data a CCI score was generated for each patient using the freely available online tool The overall CCI score is then calculated with the formula:Finally, in order to adhere with the EAU guidelines for reporting and grading complications, detailed information on mortality was additionally reported .Characteristics of the reported procedures  are summarized in Table R [Patient characteristics such as age, gender, body mass index (BMI), surgical approach, and length of hospital stay (LOS) were extracted and reported with descriptive statistics (mean ± standard deviation (SD), relative and absolute frequencies). Scatter and bar plots were created to easily visualize the data. The Shapiro-Wilks test was performed and Quantile–Quantile-Plots (Q-Q-plots) were created to test for normality and thereby analyze whether parametric or non-parametric testing should be applied in future studies . ParametR  using anOverall there were 682 included patients, of which 172 underwent open RC (2017–2018), 213 underwent PN (2017–2018), and 297 underwent open or robotic-assisted RP (2018). Baseline characteristics can be found in Table The total number of complications stratified by the Clavien system can be found in Fig. Figure p < 0.001 for each). In addition, Q-Q-plots (Supplementary) and visualization of the data distribution confirmed these findings  while correlation indices for RP  and PN  were not significantly different from each other  and PN cohorts . However, there were no differences for the RP cohort .Comparing the overall complication burden of the CCI with the Clavien syste, resulted in a significant difference for the RC  or severity (minor/major). This results in the loss of pertinent information that can otherwise be accounted for with the CCI through its weighted complication estimates. Slankamenac et al. supported the aforementioned benefit by using the CCI to demonstrate a sample size reduction in a pancreatic and esophageal surgery clinical trial . Since tt test remains viable with large sample sizes even if the assumption of normality is violated [U test for group comparison appears adequate [In terms of data distribution, normality of the CCI cannot be assumed for all three procedures based on samples from the current cohort . This is important to consider since plans for statistical analysis in clinical trials should be defined a priori. Furthermore, preliminary testing may result in uncontrolled error rates which is discussed in detail elswhere . On the violated . When inadequate .One limitation of the present study is that the CCI is based on the Clavien system which has several limitations. For example, complications of different morbidities may be classified similarly e.g., stenting of hydronephrosis and radical nephrectomy may both be performed under general anesthesia thereby classifying each as IIIB. Furthermore, grading of the same complications may differ based on patient preference of hospital-workflow e.g., the same intervention done under general vs. local anesthesia. These issues were already discussed in detail by Rassweiler et al. . HoweverFurthermore, as compared to other countries, the use of robotic-assisted PN is underrepresented in Germany, mainly due to reimbursement issues. This becomes obvious looking the study by Flegar et al. who compared trends in renal tumor surgery between the United States and Germany and might also influence the LOS .Lastly, additional procedures such as retroperitoneal lymphadenectomy or radical nephrectomy were not included and may be subject of future studies.The CCI serves as a valuable metric for more accurately assessing postoperative complications in the three most common uro-oncological procedures. Particularly for RC, the CCI provided a significant comprehensive overview of the true complication burden. It can reduce required sample sizes and thereby facilitate future clinical research. Due to a skewed data distribution, statistical analysis via non-parametric testing is recommended.Supplementary Figure Q-Q-plots to test for normality (JPG 95 kb)Below is the link to the electronic supplementary material.


Sixteen million people suffer with chronic low back pain and related healthcare expenditures can be as high as $USD 635 billion. Current pain treatments help a significant number of acute pain patients, allowing them to obtain various treatments and then “exit the market for pain services” quickly. However, chronic patients remain in pain and need multiple, varying treatments over time. Often, a single pain provider does not oversee their care. Here, we analyze the current pain market and suggest ways to establish a new treatment paradigm. We posit that more cost effective treatment and better pain relief can be achieved with multi-disciplinary care with a provider team overseeing care. The cost of chronic pain to our society is staggering and has been quoted as up to $USD 635 billion in health care expenditures, disability and loss of productivity . Pain diChronic pain is defined as pain that lasts more than 3 months despite treatment. Patients with chronic pain are desperate to find a solution for managing their pain, but only half of these patients report having control over their pain . The issPatients with acute low back pain are often desperate to obtain pain relief and will often seek any number of medications or devices to achieve that relief . They may then go for a massage, to a chiropractor, or to an acupuncturist. In the vast majority of patients, the acute pain dissipates within 2 weeks  and theyUp to 80% of acute pain exacerbations improve within 6 weeks , at whicBy 12 weeks, 95% of patients have resolution of pain . Over thChronic back pain patients become very familiar with multi-modality treatment that consists of medications, physical therapy, alternative therapies, injections, surgery, and/or neuromodulation. Though some medications for the treatment of chronic pain are reasonably priced, they often have notable side effects and are not well tolerated by patients. The relative low cost of opioids, in part, contributes to their overuse  despite Often, physical therapy and core-strengthening/stretching may actually be more effective than medications , 19. HowOther forms of physical manipulation have even greater financial barriers as acupuncture and chiropractic are often not covered by insurance. Biofeedback and cognitive behavioral therapy, though proven beneficial for chronic pain, are often met with resistance by patients who feel like clinicians are telling them their pain is not real. In addition, there are significant barriers for pain patients obtaining psychological evaluation and follow-up due to a relative paucity of psychologists who see patients with chronic pain and psychologists/psychiatrists in general .Ultimately, for the reasons above and human nature, patients often look for a quick fix which may or may not be beneficial depending on the pathology and the procedure chosen. Patients will often see pain management providers who more commonly offer invasive options instead of medications or body therapies, based on their area of expertise . The co-If there is a primary issue with the spine, an appropriate surgery may be performed. There is variability in what type of surgery, if any, will be offered from surgeon to surgeon and region to region. Patients often have a co-pay anywhere between $50–1,000. The cost submitted to insurance for the procedure however can range from $USD 10,000 to over 100,000 depending on the type of surgery performed . DespiteAfter a year or two of repeating the cycle above, patients may then move onto more neuromodulation therapies- that is, treatments that alter their perception of the sensation. These therapies may include spinal cord stimulation or intrathecal pumps. These procedures are successful in 50-80% of people, where success is defined as 50% pain relief . HoweverOften, regardless of what therapies the chronic back pain patient has undergone, there is continued healthcare utilization, with the majority of spine and spinal cord stimulation patients requiring multiple medications and/or cycles of injections, physical therapy, and/or surgery over time , 38. BasThe consumer is the patient in pain. The market generally works well for the acute pain patient, as 95% of these patients exit the market by 12 weeks . HoweverUnfortunately, the output is often not achieved within the current market. More commonly, patients have some degree of pain relief with one therapy and move onto treatment by the next firm, leaving patients to continue in the pain relief market with no single physician specializing in pain management overseeing their care plan. Further, the market is limited by resources. As treatment of chronic pain is difficult and may lead to physician burnout , there aIn the last decade, another barrier has arisen. In some cases, the primary care physician and the patient have found a medication regimen that works “well enough.” A subset of these patients have been treated successfully with low dose opioids for a decade. This option, though not recommended for the vast majority of patients, is highly successful in a small minority , 44. RecWhat has resulted is patients having more costly procedures that may be less effective. Patients become frustrated, feel deserted, and look for practices which prescribe medications. There are many practices that focus on prescribing opioids in a reasonable fashion and have either found ways to make this financially viable or are part of a tertiary care facility or state facility which focuses on serving public health needs. However, there are also practices that have been described as “pill mills.” In these businesses, the profit associated with writing prescriptions/drug screens may complicate motivation to wean patients to the lowest dose or off medications entirely, even if they have pain relief . FortunaTaken together, while the current market may work for the acute pain patient with a straightforward problem, it does not fulfill the needs of the chronic pain patient. We posit that concentrating care into comprehensive, multidisciplinary firms would be highly beneficial and would likely lead to improved patient outcomes and reduced healthcare expenditures.We have already seen the overall costs of chronic pain. For the 16 million Americans who have chronic back pain, expenses are estimated at $USD100 billion , 10. ThiOutside of the ER, multidisciplinary pain clinics have resulted in cost savings of $6.68 per day in prescription costs . The impMost importantly, patients in multidisciplinary clinics have better outcomes. These patients generally report less pain, have fewer effects of pain on activity and have more appropriate use of non-opioid medications , 61. TheWhen thinking about developing a multidisciplinary pain clinic, it is necessary for all those involved in treatment of chronic pain to reach a consensus on the organizational structure of the clinic. This requires an assessment of internal strengths and weaknesses and external threats and opportunities. Much depends on what already exists in the community and where the needs are. A bit depends on the demographics of the community and appropriately determining who would be a candidate. In a community with limited resources and a large demographic of manual laborers who have performed decades of heavy lifting, there is a mismatch between resources and need. A patient who has undergone three courses of physical therapy, three courses of injections, four spine surgeries and 10 MRIs, would be appropriately served in this clinic. The patient who has only had one of the four interventions, no matter how many times, may or may not be a candidate. In a community with more resources, a patient after one surgery with continued pain may be appropriate. Each community should work together to perform a needs assessment.This point would warrant discussion and depend on the other firms in the market, the capacity of the multidisciplinary clinic and the number of chronic pain patients the market serves. However, in the majority of markets, it is likely that the input to the firm  would still be too high, based on the firm's resources for achieving the desired output. To avoid overwhelming the system, a more reasonable entry point into the pain market may be after 6 months of pain and the failure of two therapies. Additional data is needed to test this hypothesis and again may vary from community to community. The multidisciplinary firm we discuss in this article focuses on back pain, but it is important to note that the entry point should be altered depending on the disease process and the external market. For example, all patients with pelvic pain that come into care with any of our providers can be entered into the system because there are so few resources available to these patients that they often have been suffering for more than a decade before they seek care . PatientThird-party payers are essential stakeholders in the discussion. The most established multidisciplinary program for chronic pain has been at the , 67. MorPartnerships with insurance companies in these initiatives has increased . Such pradequate pain relief, rather than total pain relief is the goal  strategies can be adapted for pain practices, based on metrics selected by pain providers, rather than metrics which are less relevant. This has been an issue for specialties in the early attempts of P4P. Quality in these metrics should initially be incentivized and, over time, penalized in order to make sure that the outputs are adequate.Another option is patient cost sharing. which has been shown to reduce health care expenditures. However, it is important to note that the reduction does not differentiate between high- and low-value care . FurtherOne potential strategy is to offer different co-payments depending on how likely a patient is to benefit from a therapy. If the patient is likely to benefit based on the medical literature, the co-pay would be lower. If the patient is unlikely to benefit or likely to have only a modest benefit, the co-pay would be higher. Unfortunately, in chronic pain the data is lacking as to which patients are likely to benefit and pain phenotypes are difficult to determine from the medical care as ICD10 codes do not accurately reflect patient status . InsuranAlternatively, patients could be given all the information and review it with their treatment providers and then make decisions in conjunction with their care team. They could be given a certain number of annual resources and determine how they will use those resources based on their pain. This strategy may be effective, as the patient and the multidisciplinary team are most likely to have the best insight into the patient phenotype. It would be essential for patients to be clear on the treatments and the cost sharing; thus, the plan must be straightforward and relatively simple . AdditioSixteen million suffer with chronic low back pain at an annual cost of $100 billion. The current market for pain relief does not meet the needs for patients for chronic low back pain. We posit that a multidisciplinary care clinic can be beneficial for the patients, providers, hospitals and insurance companies. Implementation will require appropriate partnerships and organizational structures. Opportunity costs, cost-sharing and relationship with external firms will vary regionally. Future work should examine best practices and expand this model from lower back pain to chronic pain, generally.JP conceived of and coordinated the review and assisted in writing the manuscript. OK and NW also assisted in writing the manuscript. All authors contributed to manuscript editing, and approved the final submission.JP is a consultant for Boston Scientific, Nevro, Medtronic, Saluda and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, NIH 2R01CA166379-06 and NIH U44NS115111. She is the medical advisor for Aim Medical Robotics and Karuna and has stock equity. The remaining 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.


Despite the emergence of new therapies during the last decade, metastatic castration-resistant prostate cancer (mCRPC) remains fatal. Recent work showed that the timing of treatment initiation seems critical for patient outcomes. Thus, it is key to identify factors that can help in deciding when to start treatment. In the PROSELICA prospective international phase III trial (NCT01308580), mCRPC patients received cabazitaxel at two dose levels. We performed a retrospective analysis to determine what type of disease progression patients displayed at the cabazitaxel initiation and how this progression affected the patient’s clinical outcomes. Pain progression was associated with aggressive disease and shorter survival, compared to other progression types . Systematic classification of patients enrolled in future phase III trials according to disease progression at treatment initiation may help further practitioners to determine the best timeline for treatment initiation.2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only , no pain), RADIO-p , or pain progression . Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients . Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups . In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS . PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m Several therapies have demonstrated an overall survival (OS) benefit in metastatic castration-resistant prostate cancer (mCRPC), including novel androgen receptor targeted therapies  ,2, taxan2 every 3 weeks (CABA25) and the lower dose of 20 mg/m2 every 3 weeks (CABA20) in mCRPC patients previously treated with DOC [The large phase III randomized study PROSELICA (NCT01308580) evaluated the non-inferiority of two doses of CABA, at the standard dose of 25 mg/mwith DOC . The prePROSELICA was a phase III randomized study evaluating the non-inferiority of CABA25 and CABA20 every 3 weeks with daily prednisone in 1200 mCRPC patients previously treated with DOC. The primary endpoint was OS. Inclusion criteria, evaluation criteria, and results have been published . PatientProstate-specific antigen (PSA) was measured at baseline and every 3 weeks during therapy. Chest, abdomen, and pelvic CT-scan or MRI were performed at baseline and every 6 weeks during therapy and repeated after 4 weeks to confirm progression. Bone scan was performed at baseline and every 12 weeks during therapy. In this post hoc analysis, all randomized patients were classified into three groups according to the type of disease progression at randomization : PSA proOur primary objective was to explore the prognostic impact of the type of disease progression at initiation of CABA, all arms combined, on OS. To control for a lead time bias, OS was also calculated from the date of diagnosis of mCRPC (estimated by the date of start of subsequent anticancer therapy after the first androgen deprivation therapy (ADT)).Univariate and multivariate Cox regression analyses with backward elimination (5% level) were performed, all arms combined, stratified for the region of treatment , Eastern Cooperative Oncology Group performance status (ECOG-PS) (0–1 vs. 2) and disease status (measurable or not). The following variables were tested: Gleason score at diagnosis; duration of initial ADT; prior therapy with curative intention ; age, pain status , and metastatic sites as per Halabi classification  , and type of first progression event during therapy . rPFS was defined as the time from randomization to the first radiological progression event diagnosed according to RECIST 1.1 (for measurable lesions) or PWCG2 criteria (for bone lesions), or death from any cause.A total of 1200 patients with mCRPC were enrolled between April 2011 and December 2013, of whom 598 and 602 were randomly assigned to receive CABA20 and CABA25, respectively . The typBaseline characteristics at randomization according to the type of progression are presented in p < 0.001). This effect was consistent in both treatment arms: median OS from CABA20 initiation was 11.6 (10.1–12.5) months in the PAIN-p group versus 14.7 (11.1–17.7) months in the RADIO-p group and 18.5 (15.1–22.3) months in the PSA-p group (p < 0.001); median OS from CABA25 initiation was 12.5 (11.1–14.4) months in PAIN-p versus 17.9 (14.7–21.9) months in the RADIO-p group and 18.7 (15.1–21.1) months in the PSA-p group (p < 0.001).Median OS from CABA initiation, all arms combined, was shorter in the PAIN-p group : 12.0 (9p < 0.001). Similar findings were also observed in both treatment arms . Low hemoglobin (HR = 1.62), high ALP (HR = 1.47), high LDH (HR = 1.22), high neutrophil count (HR = 1.21), short PSA doubling time (HR = 1.3), high PSA levels (HR = 1.27), ECOG PS 2 (HR = 1.35), and presence of measurable disease (HR = 1.36) at baseline were also significantly associated with a worse OS   . Analyzep = 0.4) (data not shown).The number of patients  who experienced a pain response ) was slightly higher in the CABA25 arm (37.3%) than in the CABA20 arm (34.7%), but this difference was not found significant (p = 0.752) and 18.7 (15.1–21.1) vs. 14.7 (11.1–17.7) months (p = 0.109), respectively). In the PSA-p group, median OS was similar with CABA25 versus CABA20 (17.9 (14.7–21.9) versus 18.5 (15.1–22.3) months (p = 0.855), respectively). In the PSA-p group, OS was similar between CABA 25 (17.9 (14.7–21.9)) and CABA 20 (18.5 (15.1–22.3)).Median OS from CABA initiation was numerically higher but not statistically significant with CABA25 versus CABA20 in PAIN-p and RADIO-p groups: 12.5 (11.1–14.4) vs. 11.6 (10.1–12.5) months (p < 0.001) (p = 0.653) and RADIO-p , but did not differ between arms for patients with PSA-p .Median rPFS, all arms combined, was also shorter in the PAIN-p group than in the RADIO-p and PSA-p groups (7.8 (6.9–8.4) vs. 8.1 (7.0–8.8) and 10.0 (9.3–11.3) months, respectively, < 0.001) . Analyzen = 424) of patients, followed by PSA-p only in 36.7% (n = 395) of patients, and RADIO-p in 12.5% (n = 134) of patients. PAIN-p without rising PSA was observed in 283 patients (26.3%), and RADIO-p without rising PSA was observed in 105 patients (9.8%)  .p < 0.001) and from mCRPC diagnosis . Third, PAIN-p was an independent predictor of poor OS in multivariate analysis. Fourth, in patients with PAIN-p, CABA25 showed a numerically greater activity than CABA20 in terms of PSA response, rPFS, and OS. Lastly, PAIN-p was the most common first progression event during therapy (39.4%), followed by PSA-p only (36.7%) and RADIO-p (12.5%).This post hoc analysis of the large, randomized phase III study PROSELICA confirms that PAIN-p at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. First, patients with PAIN-p had clinical and biological features of aggressive disease, including higher rates of ECOG PS 2 and visceral metastases, lower hemoglobin values, and higher values of ALP, LDH, absolute neutrophil count, and NLR at treatment initiation as compared to PSA-p. Second, patients with PAIN-p at randomization had a worse OS versus those with PSA-p only, calculated from both CABA initiation  evaluating the efficacy of chemotherapy in first-line mCRPC : pain atProstate cancer progression in phase III mCRPC trials is consistently defined by progression of measurable lesions (as per RECIST), or appearance of new bone lesions, or confirmed rising PSA (as per PCWG 2 or 3 criteria) ,31. We bThe high frequency of bone metastases in all types of progression, and in particular in the PAIN-p group, highlights the unmet need for more frequent imaging evaluation. PSA is not the ideal biomarker since 25% of patients show clinical or radiological progression without any PSA rise. Therefore, bone imaging should be highly recommended as a regular evaluation in mCRPC patients .2 in the US but not in Europe. The recent phase III CARD study applied the 25 mg/m2 dose. The incidence of neutropenic fever was no more than 3.2%, possibly due to the use of systematic primary G-CSF prophylaxis [p = 0.0143) [Our data suggest that the type of disease progression may provide some guidance to tailor the CABA dosage of each patient. PROSELICA concluded that CABA20 is non-inferior to CABA25 in terms of OS, the primary end point, and had a favorable adverse event profile . Based ophylaxis . Our anaphylaxis . In pati 0.0143) . The sliOur study has several limitations. Although we used a phase 3 clinical trial database, our analysis was not pre-planned and the classes of disease progression used were not pre-specified. However, pain at randomization was well documented and closely monitored by the mean of standardized and referenced scales over seven days before randomization, providing a robust evaluation of its intensity . PSA valThis post hoc analysis of a large phase III study in mCRPC patients post-DOC further confirms that pain progression at CABA initiation is associated with clinical and biological features of aggressive disease and worse outcomes. Since pain progression and/or radiological progression may happen without rising PSA, it is crucial to carefully monitor mCRPC patients by performing regular imaging and symptom evaluation. Considering the strong impact of pain on outcomes, we suggest that patients enrolled in future phase III trials are to be systematically classified according to PSA, radiological, and pain progression at treatment initiation.