Increasing evidence indicates that abnormal pain processing is present in the central nervous system of patients with Crohn’s disease (CD). The purposes of this study were to assess changes in gray matter (GM) volumes in CD patients in remission and to correlate structural changes in the brain with abdominal pain. We used a 3.0 T magnetic resonance scanner to examine the GM structures in 21 CD patients with abdominal pain, 26 CD patients without abdominal pain, and 30 healthy control subjects (HCs). Voxel-based morphometric analyses were used to assess the brain GM volumes. Patients with abdominal pain exhibited higher CD activity index and lower inflammatory bowel disease questionnaire scores than those of the patients without abdominal pain. Compare to HCs and to patients without abdominal pain, patients with abdominal pain exhibited lower GM volumes in the insula and anterior cingulate cortex (ACC); whereas compare to HCs and to patients with abdominal pain, the patients without abdominal pain exhibited higher GM volumes in the hippocampal and parahippocampal cortex. The GM volumes in the insula and ACC were significantly negatively correlated with daily pain scores. These results suggest that differences exist in the brain GM volume between CD patients in remission with and without abdominal pain. The negative correlation between the GM volumes in the insula and ACC and the presence and severity of abdominal pain in CD suggests these structures are closely related to visceral pain processing. Abdominal pain is an important clinical manifestation of Crohn’s disease (CD). Such pain occurs not only in approximately 50% to 70% of patients during acute inflammation  but alsoThe pathophysiology of abdominal pain in patients with CD in clinical remission is multifaceted. In these patients, pain is related to a dysfunction in brain-gut interactions , low-graIn this study, we hypothesized that the structural changes in GM vary between patients with and without abdominal pain and that sustained abdominal pain is associated with changes in brain GM in areas involved in visceral pain processing. Specifically, the aims of the study were (1) to determine the changes in GM volume in patients with and without abdominal pain and (2) to potentially correlate the GM structural changes in specific brain regions with pain severity.Among the 47 quiescent patients, 21 (44.7%) experienced abdominal pain. The average pain score ranged from 1 to 5.4, with a mean ± standard deviation of 2.68 ± 1.18.P < 0.01). The patients in the pain group had higher HADS-A and HADS-D scores than did the subjects in the HC group (P < 0.01). The patients in the pain-free group had higher HADS-A scores than those in the HC group (P < 0.05). No significant difference was observed between the pain group and the pain-free group. The patients with abdominal pain exhibited higher CD activity index (CDAI) scores and lower Inflammatory Bowel Disease Questionnaire (IBDQ) scores than those of the patients without abdominal pain (P < 0.01).There were no significant differences among the three groups in gender, age, height or weight. No differences existed between the pain and pain-free CD groups in disease duration, Montreal classification, or concomitant medication. The anxiety and depression scores of Hospital Anxiety and Depression Scale  in the pain, pain-free and HC groups were significantly different (P < 0.01). The Crohn’s disease endoscopic index of severity (CDEIS) scores of all the patients were below 3, with a mean (min∼max) value of 1.24 (0∼2.6) for the pain group and 0.89 (0∼2.0) for the pain-free group. No significant difference was observed between the two groups (Table The platelet (PLT) level and erythrocyte sedimentation rate (ESR) were not significantly different between the pain group and the pain-free group, while the C-reactive protein (CRP) level was significantly different between these two groups P < 0.0. The CroP < 0.01), CRP levels , PLT levels , and ESR levels .The CDAI scores of all the patients were correlated with the CDEIS scores  and putamen, and right anterior cingulate cortex (ACC) Table , were siThe post-hoc analysis showed that the GM volumes of the insula and ACC in the pain group were lower than those in the pain-free and the HC groups. The GM volumes of the HIPP/paraHIPP in the pain-free group were higher than those in the pain and HC groups. The GM volumes of the putamen in the pain and pain-free CD groups were higher than those in the HC group; however, the difference between the two patient groups was not significant Table .These results suggested that the patients with CD-related abdominal pain yielded the lowest GM volumes in the insula and ACC whereas the CD patients without abdominal pain exhibited the highest GM volumes in the HIPP/paraHIPP.P = 0.002; r = -0.69, P = 0.001, respectively; Figure P = 0.18).The GM volumes of the insula and ACC were significantly negatively correlated with the daily pain scores in the patients with abdominal pain  signals may be transmitted to the "visceral and cortical pain matrix" via the brain - gut axis in CD patients . SpecifiWe found that the GM volumes in the insula and ACC were negatively correlated with the daily pain scores in the patients with abdominal pain. The whole-brain analysis further confirmed the correlation and increased the reliability of the study. Structural GM abnormalities in the insula and ACC have been observed in nearly all pain-related diseases . SimilarIn general, the mechanism underlying GM changes may be attributed to frequent and chronic nociceptive input and the subsequent functional reorganization and plasticity of the brain. The lower GM volumes could be related to a decrease in the size of neuronal somata, cell atrophy, or a decrease in intra-cortical axonal architecture  . In addiThe patients without CD-related pain exhibited the highest GM volumes in the HIPP/paraHIPP, while the patients with CD-related pain exhibited lower GM volumes in this region. These findings suggest a role for specific brain structures in the control of abdominal pain in this disease: patients with the highest GM volumes exhibited better intrinsic pain relief (CD without pain) than patients with a lesser GM volumes increase (CD with pain). The HIPP/paraHIPP is associated with limbic and non-limbic system structures; the HIPP/paraHIPP regulates immune responses via the hypothalamic-pituitary-adrenal axis and neurohumoral pathways and plays an important role in neural immune regulation . StudiesThe present study has two limitations. First, this study was a cross-sectional study, which prevented the confirmation of a relationship between the abnormal GM changes in the CD patients in remission with the disease onset or the disease per se. In addition, neurotransmitter modulation and receptor binding in the associated brain areas and the correlation of these parameters with the GM structural changes must be elucidated. Future studies should observe longitudinal brain GM changes, together with the levels of related neurotransmitters in target brain regions, and to elucidate the neuroimaging biomarkers of CD.In summary, our study represents the first investigation to demonstrate differences in brain GM volumes between CD patients in remission with and without abdominal pain. The reduced GM volumes in the insula and ACC in patients with CD with abdominal pain suggest a potential role in visceral pain processing and correlate with the presence and severity of abdominal pain. The findings may expand our understanding of the pathogenesis of CD, particularly the pathophysiology underlying pain in patients with CD.All participants provided written informed consent. The study protocol was approved by the Institutional Review Board of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine at Shanghai University of Traditional Chinese Medicine.This study evaluated 21 patients with CD-related abdominal pain, 26 CD patients without abdominal pain, and 30 HCs. All the patients underwent a systemic and gastrointestinal examination, including a colonoscopy and pathological tissue biopsy. Laboratory tests and the colonoscopy were performed at 2 weeks and 1 month before the MRI scan, respectively. The CRP level, ESR, and PLT level were measured in all the patients. For the endoscopic examination, the CDEIS scores  were scoThe HCs were recruited via advertisements from Shanghai University of Traditional Chinese Medicine. These subjects were not treated with any medications, had no gastrointestinal symptoms or pain-related diseases, nor had negative findings in colonoscopic examinations.9/L); a history of CD-related abdominal surgery; treatment with corticosteroids, biological agents, psychotropic or opioid drugs in the previous 3 months; pregnant or lactating; a current or past history of psychiatric or neurological disorders, head trauma or loss of consciousness; claustrophobic; or had metal implants.The inclusion criteria were as follows: aged between 18 and 50 years, ≥ 6 years of education, right-handed, a CDAI of < 150, a CDEIS score of < 3 and in disease remission for > 12 months. Patients were excluded from the study if they met any of the following conditions: elevated biological disease activity indices  were included in the pain group. Patients without abdominal pain for at least 12 months were included in the pain-free group.The intensity of abdominal pain in the CD patients was evaluated using a 0-10 visual analog scale (VAS) . The aveThe HADS  was usedThe MRI data were acquired in an interleaved multi-slice mode using a Siemens TRIO 3T clinical scanner . A high-resolution T1-weighted sagittal 3-dimensional magnetization-prepared rapid gradient-echo sequence was acquired for each participant with the following parameters: TR = 2300 ms; TE = 2.98 ms; field of view = 256 × 256 mm; matrix size = 256 × 256; in-plane resolution = 1 mm × 1 mm; slice thickness = 1.0 mm; flip angle = 9°; and slices = 176.http://dbm.neuro.uni-jena.de/vbm8) in the Statistical Parametric Mapping software, version 12 , which was operated in a MATLAB  environment. All the structural images were transformed into a Montreal Neurological Institute (MNI) 152 standard space using linear transformations re-sampled to 1.5 × 1.5 × 1.5 mm3. The images were subsequently segmented into GM, white matter (WM), and cerebrospinal fluid (CSF). A modulation step was added to incorporate volume changes during spatial normalization [Structural image processing and analysis were performed using optimized VBM8 toolbox  and cluster P < 0.05 [false discovery rate (FDR) corrected]. The total GM volume, age, gender, weight, anxiety and depression were used as covariates.At the secondary level of analysis, we determined the differences in the GM volumes among the HCs and the patients with or without pain. A one-way analysis of variance (ANOVA) was performed at each voxel to assess the main effect, with a statistical threshold was set at P < 0.05 with Bonferroni’s correction. Second, whole-brain correlation analysis was applied to determine potential correlations between the brain regions and pain condition. The significance level was set at P < 0.005 (uncorrected), and the FDR was corrected with the cluster size at P < 0.05.For post hoc tests, regions of interest (ROIs) were selected from the sets of voxels within 6-mm spheres, with the centers at the peaks of the clusters with significant differences based on the ANOVA results of the VBM between the patients and the HCs. A 2-step correlation analysis was conducted in CD patients with abdominal pain: first, a Pearson’s correlation analysis was used to examine the relationship between the mean GM volume in each ROI and the pain score for the CD patients, with the total GM volume, age, gender, weight, anxiety and depression as covariates. The significance level was set at http://www.sph.s.c.edu/comd/rorden/mricro.html) for presentation. The behavioral data were presented as the means ± standard deviations. The Statistical Package for the Social Sciences (SPSS) software package , version 16.0, was used for the statistical analysis.The imaging results were overlaid on MRIcroN (


N-methyl-d-aspartate receptors are implicated, and antagonists are a pharmacological option. Ketamine is widely used in French pain clinics, but without consensus or recommendations. Furthermore, the association of ketamine with magnesium has been poorly studied. The aim of the present study is to evaluate the benefit of ketamine with or without magnesium in refractory neuropathic pain.Neuropathic pain is difficult to treat, and the efficacy of recommended drugs remains limited. A randomized, double-blind, crossover, placebo-controlled study will be performed in Clermont-Ferrand University Hospital, Clermont-Ferrand, France. The aim is to evaluate the effect of ketamine with or without magnesium in 22 patients with neuropathic pain. Intravenous ketamine/placebo, ketamine/magnesium sulfate, or placebo/placebo will be administered consecutively to each patient, in random order, once at 5-week intervals. The primary endpoint is the AUC of pain intensity assessed on a 0–10 Numeric Pain Rating Scale for a 5-week period. Data analysis will be performed on an intention-to-treat basis, and all statistical tests  will be performed with an α risk of 5% (two-sided).Considering the poor efficacy of the drugs available for neuropathic pain, ketamine with or without magnesium sulfate may be a valuable therapeutic option that needs to be standardized.2015-000142-29. Registered on April 9, 2015; version 1.4EudraCT number–The online version of this article (doi:10.1186/s13063-017-2254-3) contains supplementary material, which is available to authorized users. N-methyl-d-aspartate receptors (NMDARs) are involved in the development of NP and may provide an avenue to a pharmacological tool for treatment. Ketamine, an NMDAR antagonist, has been used for a number of years for the treatment of NP. In animals, it decreases NP symptoms [Neuropathic pain (NP), whatever the etiology or topography, presents with a number of clinical characteristics: sensory deficit, hypoesthesia, electric shock-like pain, allodynia, or hyperalgesia . N-methysymptoms –10. In hsymptoms , refractsymptoms , phantomsymptoms , posthersymptoms , and comsymptoms –17. Mostsymptoms –21, opensymptoms , 23, or symptoms , 25. Howsymptoms –17. Ketasymptoms , 22, 23.Another NMDAR modulator, magnesium sulfate, is a physiological blocker of NMDAR and has also been shown to be effective in the treatment of NP. In animal NP models, it decreased cold allodynia and thermal and mechanical hyperalgesia –29 and iConcerning the ketamine-magnesium sulfate interaction, a preclinical study showed a synergistic effect, blocking the hyperthermia caused by systemic administration of morphine . A recensee Additional file This is a randomized, placebo-controlled, double-blind, crossover, single-center clinical study with intravenous ketamine/placebo, ketamine/magnesium sulfate, and placebo/placebo injections given to each patient. This clinical trial is reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines  according to the usual procedures of the pain clinic.Ketamine will be given according to the protocol described above combined with an infusion of two ampoules of 0.15 g/ml of magnesium sulfate (1.5 g per 10 ml) diluted in 250 ml of physiological saline (0.9% NaCl),Physiological saline will be administered in injectable form (0.9% NaCl) in a 250-ml or 45-ml infusion via the electric syringe pump.Ketamine-placebo group: Ketamine will be administered for 2 h and placebo for 30 minutes.Ketamine-magnesium sulfate group: Ketamine will be administered for 2 h and magnesium sulfate for 30 minutes.Placebo-placebo group: Placebo will be administered for 2 h and placebo for 30 minutes.Each patient will receive successively in random order each of the three products with a period of washout between every administration. The duration of the washout will be 5 weeks (35 days). The duration of each infusion is 2½ h per patient as follows:The drugs used in the study  are prepared, conditioned, and released in the hospital pharmacy by one qualified person according to good manufacturing principles. Once the treatment is completed, the empty infusion bags are then returned to the packaging box, and the number of infusion bags in each dispensed container is verified and recounted at the end of the treatment by two persons totally independent of the protocol.To compare the additive analgesic efficacy of magnesium and ketamineTo study the time course of pain and analgesia after intravenous administration of ketamine, ketamine-magnesium, and placeboThe primary objective of this study is to compare, using a crossover design, the analgesic efficacy of intravenous ketamine with that of placebo in patients with intractable NP. Secondary objectives are as follows:Patients ≥ 18 years oldPatients with chronic pain (for > 3 months), having the characteristics of a peripheral or central neuropathy justifying implementation of a therapeutic program with courses of intravenous ketamine injectionPatients who have never received ketamine infusion for care of their NPHistory of illness compatible with an injury or disease of the somatosensory systemLocalized pain in a neuroanatomical territoryNeurological examination shows sensory abnormalitiesFor women of childbearing age, they will be enrolled in the study after a negative urine pregnancy test; in case of suspicion of pregnancy, a blood pregnancy test should be performed.Cooperation and willingness to follow the studyAcceptance to give written consentAffiliated with the French social security systemInscription or acceptance of inscription in the national register of volunteers involved in trialsPatients who have received an intravenous ketamine infusionPatients with one or many contraindications to ketamine administration: known hypersensitivity to ketamine in which one of the constituents of the product, uncontrolled high blood pressure, severe cardiac insufficiencyPatients with one or many contraindications to magnesium sulfate administration: patients with severe renal impairmentPatients with one or many contraindications to administration of sodium chloride: water inflation, fluid retentionPatients with a medical history and/or surgical history judged by the investigator not to be consistent with the clinical trialPatients with drug treatments judged by the investigator not to be consistent with the clinical trialPregnant or lactating womenPatient who participated in another clinical trial, located in the exclusion period, or received benefits > €4500 during 12 months before the beginning of the trialPatients with cooperation and understanding not strictly adherent to the conditions of the clinical trial Patients receiving a measure of legal protection Patients not affiliated with the French social security systemThe primary outcome is the AUC of pain intensity assessed on a 0–10 NPRS for a period of 5 weeks (35 days) from the day of intravenous treatment.Secondary endpoints are the evaluation of pain , anxiety and depression (HADS), quality of life (SF-36), and quality of sleep (PSQI) using a variety of scales and questionnaires. Furthermore, the intensity of the average and maximum pain scores as well as concomitant analgesic treatments will be reported in a daily pain diary. The various assessments and questionnaires are summarized in Fig. n = 22) is quite realistic according to the recruitment capacities of the pain clinic. The duration of recruitment is expected to be 2 years.This clinical trial will be carried out by the physicians of the pain clinic and of the clinical pharmacology center/CIC Inserm 1405 of CHU Clermont-Ferrand in charge of the project. The number of subjects needed  that may accompany ketamine infusion. If an adverse event occurs , treatment of the enrolled patients will immediately be suspended. The drug dose will not be changed, and treatment will be continued only upon agreement of the sponsor and the investigators if they conclude that the cause of the adverse event is not related or unlikely to be related to the study products. Unblinding will be allowed only in case of a serious adverse event. Only a doctor involved in the protocol but not in the administration or evaluation of the drug will be dealing with such events. All these steps will be conducted and documented according to the procedures of the University Hospital of Clermont-Ferrand and the current regulatory requirements. If an adverse event persists at the end of the study, the investigator will follow the patient until the event is resolved.Concerning missing data, if the participant misses one of the three treatment blocks, the patient will be excluded from the study. If missing data occur, a sensitivity analysis will be proposed in order to define the level of attrition and the statistical nature of the missing data, and the last data obtained will be reported.We have not established a data and safety monitoring board for this study. However, in order to improve adherence to the intervention, the case report forms will be monitored by a clinical research associate independent from the protocol and will address any safety or other concerns that may arise. During these visits, the following elements will be reviewed: informed consent; compliance with the study protocol and the procedures defined; and quality of data collected in the case report form, including accuracy, missing data, consistency of data with source documents , and management of the pharmaceutical drugs. Then the monitored case report forms will be retained at the data management center  in a secure, locked room. Then data will be entered by double data entry by two people independent from the protocol. The blocked database will be transferred to the statistician responsible for the statistical analysis. All original records  will be kept at the trial site for 15 years. All data will be anonymized and identified by a participant code.To highlight the analgesic efficacy of intravenous ketamine in patients with intractable NP, sample size estimation was based on a pilot study done at the pain clinic of the University Hospital of Clermont-Ferrand (administration of intravenous ketamine in a similar open-label population), showing an AUC (28 days) of the intensity of pain of 164 ± 38 (unpublished data). Furthermore, in a study comparing similar treatments (ketamine and placebo) in a different chronic pain setting (CRPS), the AUC graph estimate suggested a 35% reduction in AUC (at 28 days), that 18 patients are needed to detect a minimum difference of 57 in the primary outcome, with a two-sided type I error of 1.67% (to take account of multiple comparisons), statistical power of 90%, and an intraindividual correlation coefficient of 0.5 (owing to the crossover design and no carryover effect assumed) . ConsideStatistical analysis will be performed on an intention-to-treat basis using Stata software  for a two-sided type I error at α = 5%. Continuous data will be described as mean ± SD or median (IQR) according to the statistical distribution . Categorical parameters will be described as number and percent. The primary endpoint (AUC of pain intensity based on NPRS) will be compared between groups by repeated measures analysis of variance (ANOVA) for crossover designs, taking account of the following effects: treatment group (ketamine versus placebo), sequence, subject (as random effect), and carryover. Then, the “sequence × treatment” interaction will be tested; if it is significant, statistical analysis will cover only the first period of the crossover study. The normality of residuals will be studied. When quantitative endpoints do not meet the normality assumption, a nonparametric paired Wilcoxon test will be used. Sensitivity analysis will determine the statistical nature of missing data to apply the most appropriate imputation approach.p value < 0.05, a post hoc analysis for multiple comparisons (inflation of type I error) will be applied using the Tukey-Kramer test. For non-crossover comparisons, the usual statistical tests will be performed: (1) for quantitative parameters, ANOVA or Kruskal-Wallis test if the conditions for parametric tests are not met ; and (2) for categorical variables, the chi-square test or Fisher’s exact test. When appropriate (p < 0.05), an appropriate post hoc test will be applied: Tukey-Kramer post hoc ANOVA or Dunn post hoc Kruskal-Wallis. As discussed by Feise [Statistical analyses of secondary outcomes  will be performed similarly to those for the primary endpoint. For categorical parameters , the Stuart-Maxwell test for proportion paired data or a generalized linear mixed model will be used, taking the above effects into account. Random-effects models, useful to model between- and within-subject variability, will be performed for the effects described for the crossover ANOVA, to compare the additive analgesic efficacy of associating magnesium sulfate versus placebo to ketamine, and to study the evolution of pain and analgesia with the waning of the intravenous administration. In case of omnibus by Feise , type I Persistent pain is difficult to treat, and a range of evidence indicates that NMDARs play an important role in sensitization, windup, and neuroplastic changes in the central nervous system . KetaminFurthermore, it is also widely reported that NP is known to impact quality of life with psychological discomfort, anxiety, and/or depression . RecentlThe benefit expected for participating patients lies in better follow-up of pain and quality of life, with no additional risk. This double-blind randomized controlled clinical trial will provide objective data on the efficacy of ketamine in the treatment of NP and comorbidities associated with chronic pain, such as anxiety and depression. It will enrich good practice recommendations for ketamine, an anesthetic that is often used off-label for NP.Recruitment started in November 2015 and is currently ongoing.


In spite of the improvement of many aspects around Total knee arthroplasty (TKA), there is still a group of 10% to 34% of patients who is not satisfied with the outcome. The therapy of chronic pain after TKA remains a medical challenge that requires an interdisciplinary therapy concept. The aim of this prospective pilot study was to evaluate the efficacy of a multimodal pain therapy in chronic complaints after TKA.In a prospective cohort pilot study, we included patients with chronic pain after TKA who obtained in-patient care, especially multimodal pain therapy (MMPT), for at least 10 days. Essential elements of this therapy concept were physiotherapy, pain medication therapy, topical application of ketamine, local infiltration and Traditional Chinese Medicine. Patients with varying causes of complaints were excluded in advance. Before the start of the study all test persons were informed and gave their written consent. Moreover, each patient was examined and questioned at hospital admission, discharge and at its first as well as second follow-up. Additionally, knee joint mobility and stability were investigated at all examination times.From 03/07/2016 to 07/14/2016, 21 patients were included in the pilot study. 52% of the considered population were female (11 persons). The median age was 65 years (45–79 years) and the median stay in hospital amounted 9 days (8–14 days). The first follow-up was scheduled after six weeks  and the second one after six months . The number of patients of the first follow-up was 17 out of 21 (19% drop out). The drop out of the last follow-up accounted for 33%. All patients benefit from the presented applications and therapies with regard to pain, function and range of motion. Especially, during the period of in-patient treatment, nearly all patients have improved in all terms. However, during the first follow-up clear deteriorations occurred in all areas, which stagnated up to the second follow-up. The range of motion has even worsened slightly.With the presented pilot study on multimodal in-patient therapy of chronic complaints due to TKA, the improvement of pain, function and mobility could be verified, especially during the stationary stay. Even though the results deteriorate during the follow-up period, they did never relapse to their initial level. In order to ensure an effective treatment, a clear diagnostic algorithm is essential, by which treatable causes, such as low-grade infections or loosenings, are safely excluded. Further prospective studies are necessary to obtain precise statements on prospects of success of our therapy plan. Osteoarthritis of the knee is a common condition that affects approximately 10% of the general population above the age of 60 years . FrequenThe aim of this prospective pilot study was to evaluate the efficacy of a multimodal pain therapy of chronic complaints after TKA. Depending on the results of this pilot study, a prospective two-armed survey is planned for further evaluation.In a prospective cohort pilot study 21 patients with chronic pain after TKA were treated stationary by multimodal pain therapy (MMPT) for at least 10 days. All patients with differing causes of complaints were excluded in advance. In order to safely preclude implant loosening, inlay wear or other existing mechanical complications radiographs were used. A joint infection was excluded by blood tests and knee joint puncture. In individual cases further investigations  were carried out. In order to increase the accuracy of an exclusion of periprosthetic infections, a previous arthroscopy with 5 tissue samples is planned. This can also be used to confirm a suspicious diagnosis like an arthrofibrosis by means of tissue analysis.During the planning of the study, it was discussed with the local ethics committee. Since the investigation has been assessed as an individual test of salvation, there is no provision for the ethics committee. An ethics vote is planned for the randomized follow-up study. Before the beginning of the study all patients were informed and gave their written consent to the off-label use of the medication as an individual therapeutic attempt as well as to the publication of data.For medication, the subjects received 20 mg of prednisolone (Reduction of inflammation and pain modulatory effects), 10 mg of propranolol (influences of sympathetic tone and reflexive pain modulation) and 25 mg of amitriptyline  once a day over a period of 25 days. After initial exclusion of contraindications for this medication daily blood glucose control as well as measurements of pulse and blood pressure were performed. In addition, patients were treated with topical ketamine .) Ketamine hydrochloride was used as a pure substance according to the European Pharmacopoeia (Ph.Eur.). PLO gel 30 is a ready-to-use transdermal base, composed of an oily phase  and an aqueous phase (Pluronic gel 30%). The advantage of this organogel is that high amounts of active ingredients can be incorporated by the preparation which can easily pass through the skin into deeper tissues.In the course of in-patient therapy, all patients also received regular treatments in Traditional Chinese Medicine (TCM) with acupuncture, acupressure and cupping. Moreover, daily physiotherapeutic applications with passive physiotherapy, thermal applications (hot roller), reflexology, manual therapy and Kinesiotape were performed. The pain relief service was used to optimize pain therapy. Local infiltration of points of pain with local anesthetics  was applied, too. Figure Numerical Analog Scale (NAS) for pain ranging from 0 to 10 with 0: no pain and 10: worst imaginable pain.Knee Score of Ranawat and Shine  ranging from 0 to 100 with <60: inadequate, 60–69: moderate, 70–84: good and 85–100: excellent. The score includes pain 30%, function 22%, range of motion 18%, muscular strength 10%, flexion deficit 10% and stability 10% .Knee Society Score of Insall et al. consisting of a clinical (knee) score (50%) and a function score (50%), both ranging from 0 to 100. The score includes pain 25%, range of motion 12.5%, stability 12.5%, walking distance 25% and stairs 25% .All patients were examined and questioned at the time of hospital admission, discharge and at their first as well as second follow-up. Knee joint mobility and stability were investigated at all examination times. In this context, the following scores were applied.From 03/07/2016 to 07/14/2016, 21 patients were included in the pilot study. 11 of them were women (52%). The median age was 65 years (45–79 years). With regard to the median, primary TKA implantation took place 5 years ago (1–12 years). The median value of patient’s previous operations amounted 2 treatments (1–6 operations) including primary TKA. 16 patients (76%) had already received at least one change of TKA (1–3 changes). Concerning the median, the last operation has been performed 12 months (4–84 months) ago.Moreover, the median stay in hospital was 9 days (8–14 days). The first follow-up was planned after six weeks  and the second one after six months . The first follow-up included 17 out of 21 patients (19% drop out), whereas the following one showed a drop out of 33% (14/21).In this context, Table The treatment of patients with chronic complaints after TKA is a challenging task. Therefore, an adequate therapy is only possible due to an interdisciplinary team of experienced orthopaedic surgeons with great knowledge in the field of endoprosthetics, qualified physiotherapists and pain therapists.As a part of the MMPT the application of TCM had positive influence on the therapeutic process. Many patients described these treatments as particularly effective. Yang et al. proved a significant alleviation of pain and diminution of flexion contractures achieved by TCM . SpecifiIn most patients, a chronic abuse of pain medication was present. Therefore, we have optimized and adapted this medication application according to the WHO model with the assistance of the internal pain service. The above-described supplementary drug therapy was applied in accordance with the treatment success of Dr. Philipp Traut , 24. He Peripheral nociceptors express n-methyl-d-aspartate (NMDA) receptors  which are involved in the modulation of pain delivery. However, their systemic use is limited by adverse effects . NeverthThe broad field of physiological gymnastics represents an important part of the MMPT. Particularly in the therapy of arthrofibrosis it is known that forced exercises can aggravate adhesions . TherefoParticularly in immediate postoperative pain therapy after TKA, local infiltration analgesia  has significantly reduced the length of stay and the postoperative pain scores . But, itIdeally, the treatment should be supported by psychotherapists or psychologists with experiences in the area of psychosomatic medicine. Psychosomatic factors associated with individual pain relief and processing have already been extensively investigated . In thisAll patients benefit from the presented applications and therapies with regard to pain Fig. , functioWith the presented pilot study on multimodal in-patient therapy of chronic complaints according to TKA, the improvement of pain, function and mobility could be shown. While the results deteriorate after hospital discharge, they rebalanced during the follow-up period with no relapse to their initial level. Further prospective studies are necessary to obtain precise statements on the success prospects through the therapy plan of the University Hospital Leipzig.


Orofacial pain impairs a patient's speech, swallowing, eating and interpersonal relations. Thirty-seven patients with a premalignant oral lesion, 124 patients with oral squamous cell carcinoma (OSSC), and 21 patients with a recurrence of OSSC were evaluated for their orofacial pain. The University of California San Francisco Oral Cancer Pain Questionnaire was administered to these patients at their initial visit, before they were prescribed analgesics for pain and before any treatment. Significant differences with respect to orofacial pain between the groups could be evaluatedwere observed. Patients with recurrence had the highest facial pain and patients with precancer had the lowest. Patients with OSSC and recurrence of OSSC reported significant levels of orofacial pain and functional restriction because of pain. Moreover, patients with recurrence of OSSC experienced significantly higher function-related pain, rather than pain qualities. These findings suggest that an important predictor for recurrence of OSSC may be the onset of orofacial pain that is exacerbated during function. The present study examined orofacial pain depending on the disease severity of precancer and oral cancer patients. Earlier recognition of symptoms of OSSC may improve early detection of its recurrence. The 5-year overall survival rate of oral cancer is approximately 50%. Although modalities for the diagnosis and treatment of patients with OSCC are improving, treatment outcomes and patient prognoses have not improved greatly over the past 20 years.Oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the world. Worldwide, approximately 350,000 people are diagnosed with oral cancer annually2. After survival, the primary concern of the patient with oral cancer is pain. Pain is rated as the worst symptom by patients with OSCC3. Although treatment can prolong survival, an adverse effect is orofacial pain, which may limit patients’ oral function and physical activity. Orofacial pain late in the treatment course may be due to surgery and microsites4 and may affect the patient's prognosis, as well as their daily life. Orofacial pain is reported by approximately 30–40% of patients who are treated for OSCC6. Pain associated with the treatment of OSCC can interfere with eating, swallowing, speech, and other motor functions of the oral cavity. The aetiology of orofacial pain is multifactorial, with possible causes including RT (20–33% of cases), mucositis, epithelial atrophy, neuropathy, and temporomandibular disorder or myofascial pain. Radical excision destroys the oral structure, and resection of soft tissue and nerves may result in nociceptive nerve pain or neuropathic pain8.For patients with advanced stage disease, radical dissection and radiation therapy (RT) are the primary treatments9.Patient survival is of the highest importance for maxillofacial surgeons, because of the low survival rate and high recurrence rate of OSCC. To ensure patient survival, drastic surgeries are often performed with the tumour section being of central importance, while aesthetics, masticatory function, and ocular motility are only of secondary importance. The drastic surgeries that are often necessary are problems that are specific to OSCC. Orofacial pain and its assessment have become increasingly important in health care, especially in the field of oral cancer screening and follow-up. Although pain is often recognized as an important symptom, a clinical aphorism has been that early head and neck cancers often go unnoticed because they are asymptomatic, and pain usually arises only when the cancer has reached a remarkable considerable sizeA clinician has to manage patients with oral precancer, newly diagnosed oral cancer, and recurrence of oral cancer on a daily basis. Quite often, oral cancer is detected during regular check-ups. However, even if oral cancer is successfully treated, there is a risk that a patient will require further treatment because of recurrence. Therefore, it is very important that recurrence of OSCC be detected early. The purpose of the present study was to compare orofacial pain in groups of patients with oral precancer, newly diagnosed oral cancer, and recurrence of oral cancer. Here, we demonstrate that patients with oral cancer recurrence experience more intense pain than patients with oral precancer or newly diagnosed oral cancer.in situ, and 3 proliferative verrucous leukoplakia), and 21 had oral cancer recurrence (squamous cell carcinoma). All recurrence patients had undergone surgery and chemotherapy. The patients with precancer (N = 37) were aged between 31 and 75 years (mean 52.0 ± 10.7 years), the patients with oral cancer (N = 124) were aged between 27 and 78 years (mean 63.6 ± 14.3 years), and the patients with oral cancer recurrence (N = 21) were aged between 36 and 80 years (mean 66.2 ± 12.8 years). A comparison of the mean values of the 3 groups showed that there were a higher number of male patients in all 3 groups , 37 had oral precancer , unemployed , and married . Most patients were educated to elementary , junior high , or senior high  level. In addition, 23 patients held religious beliefs. Before treatment in hospital, more than half of the patients reported betel nut use, alcohol use, and smoking before the onset of disease. Few patients reported continued betel nut use (N = 5), alcohol use (N = 7), and smoking (N = 15) after the onset of disease.Oral cancer recurrence patients reported significantly greater functional restriction  and sensitivity to touch  in comparison with both precancer and oral cancer patients. Oral cancer recurrence patients also experienced significantly higher spontaneous sharpness (P2 = 0.000) and functional sharpness (P2 = 0.002) in comparison with oral cancer patients. In contrast, the pain levels of patients with oral precancer were not significantly different from those of patients with oral cancer in terms of either spontaneous or functional sharpness (P > 0.05). There was a significant difference in spontaneous aching , functional aching , and sensitivity to touch  between the precancer patients and oral cancer patients  and sensitivity to touch  in comparison with both precancer and oral cancer patients. Oral cancer recurrence patients also experienced significantly higher spontaneous sharpness (P2 = 0.000) and functional sharpness (P2 = 0.002) in comparison with oral cancer patients. Thus, we found that patients with oral cancer recurrence reported significant spontaneous and function-related pain at the time of cancer recurrence. These findings suggest that an important predictor of oral cancer recurrence may be the onset of orofacial pain that is exacerbated during function.13.In the present study, we found that sharpness and intensity of oral pain in all 3 groups were related to function rather than being spontaneous. Patients with oral cancer report pain during oral functions, including talking, eating, and drinking. In the OSCC groups, there was a significant difference between spontaneous aching (28.33 ± 14.56) and functional aching (33.33 ± 13.54). The functional sharpness (20.87 ± 13.03) pain level was significantly higher than that of spontaneous sharpness (15.60 ± 12.85). Similarly, patients with bone metastases develop acute breakthrough pain with movement of the involved skeleton14. The intense, spontaneous, sharp and aching pain reported by oral cancer patients suggests the sensitization and/or activation of both Ad and C fibres in oral cancer pain15. Cancer and associated cells in the cancer microenvironment may release a variety of pain mediators, including adenosine triphosphate, bradykinin, cytokines, chemokines, nerve growth factor, prostaglandins, and several vascular factors, including such as endothelin 1 and vascular endothelial growth factor to either excite or sensitize nociceptive primary afferents. Arachidonic acid metabolites, such as prostaglandins, are produced by various cancers, including oral cancer, and are well-known to sensitize nociceptive primary afferents16.Oral cancer pain is more likely to be a result of the sensitization and/or activation of primary nociceptive afferents by mediators liberated by the cancer and associated cells7.In our study, we found that there was no correlation between tumour size and reported pain levels, suggesting that oral cancer pain is not a result of the mass effect of the tumour. This finding is consistent with the clinical observation that small oral carcinomas can be profoundly painful. We did find increased levels of pain in the OSCC patients with lymph node metastasis. The process of tissue infiltration leading to metastasis could be responsible for the increased oral pain reported in these patients. The mechanism of pain in these patients likely involves either perineural infiltration and/or nociceptor hypersensitivity. The mediators responsible for infiltration and metastasis might also be involved with nociceptor hypersensitivityThere are a number of limitations in our study. The study period included only a few patients with a relapse (recurrence). Despite the low number of recurrence patients included in this study, we were able to establish statistically relevant correlations. Further studies will be performed using a longitudinal design to determine if and how the oral cancer pain of a patient develops during progression of the disease.In conclusion, earlier recognition of symptoms of OSSC may improve early detection of the recurrence of OSSC. Further investigations into the correlations between pain parameters and the specific biology of OSSC may improve quality of life and survival for OSSC patients.This study complied with the guidelines of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the First Affiliated Hospital, Zhengzhou University . Since this study involved retrospective review of existing data, a waiver of written informed consent was obtained from the Institutional Review Board. All primary data was collected according to procedures outlined in epidemiology guidelines that strengthen the reporting of observational studies. Patient information was anonymized and de-identified prior to analysis.This study was previously approved by the Ethics Committee on Research of the School of Dentistry at Zhengzhou University. From August 2012 to May 2015, a cross-sectional analysis was performed on 124 OSCC patients , 37 oral precancer patients , and 21 patients with squamous cell carcinoma recurrence  who were referred to the Department of Stomatology at the First Affiliated Hospital of Zhengzhou University. A comparison of the mean values of the 3 groups showed that they were well matched for age (P = 0.285) and sex (P = 0.059); however, there was a higher number of male patients in all 3 groups , oral cancer, or and aoral cancer recurrence were included in this study. Potential patients would have beenPatients were excluded from the study because of foreseeable missing opportunity ofif they were unable to attend a follow-up examination, were pregnant or nursing, had undergone recent surgery, or had heart, infectious, circulation, systemic, malignant, or immune system diseases, blood coagulation disorders, or allergic reactions to pharmaceuticals and antibiotics. In addition, patients diagnosed with a psychiatric condition, or had an addiction to pain medications or recreational drugs, or had taken pain medications in the previous 6 months were also excluded.Demographic information was also collected for each patient, which included age, sex, racial/ethnic identity, current smoking and high-risk drinking status, oral lesion location, and tumour size.The University of California San Francisco Oral Cancer Pain Questionnaire (UCSF-OCPQ) was used to assess patients’ pain and to identify the functions that lead to oral cancer pain. The questionnaire was designed to differentiate function-related and spontaneous pain, as well as to determine the nature and quality of pain. The questionnaire is specifically designed for patients with oral cancer and was used because it has been shown to be better for demonstrating changes in pain that occur because of illness.12. Briefly, the 8 questions differentiate spontaneous and function-related pain, and determine the quality of pain. Questions 1 through 6 examine the intensity, sharpness, and aching nature of orofacial pain. Question 7 focuses on the degree of sensitivity to touch. Question 8 determines the level of functional restriction as a result of orofacial pain. Patients were instructed to place a vertical line along the scale to approximate their orofacial pain level (if any).The UCSF-OCPQ was administered to patients meeting the inclusion criteria at their initial visit, and before they were prescribed analgesics for any orofacial pain or received any treatment. This questionnaire, consisting of 8 questions on a visual analogue scale of 0–100 mm, has been validated previouslyStatistical analysis was conducted using SPSS for Windows version 20.0 . The sociodemographic data and results of the UCSF-OCPQ were analysed using descriptive statistics. The data were tested for normal distribution with the Kolmogorov-Smirnov test, which revealed that the data do not significantly differ from normal distribution. Since the data were normally distributed, a t-test was used to compare the means of 2 interval-scaled independent samples. For categorical variables, the χ2 test was used for comparison. For all tests, P values of less than 0.05 were considered statistically significant.


There is little data regarding the effectiveness of palliative radiation with conventional fractionation for metastatic renal cell carcinoma (RCC), which has been described as radioresistant. We conducted a retrospective analysis of patients with metastatic bony disease from RCC treated with radiation therapy at our institution. Forty patients with histologically confirmed RCC with a total of 53 treatment courses were included. Pain response after radiotherapy was recorded and freedom from progression was generated using posttreatment radiographs. Patient data was analyzed to assess influence on local control.p = 0.02). In lesions with initial pain response, nonclear cell histology was associated with increased pain recurrence (p = 0.01) and a shorter duration to pain recurrence (p = 0.01). Radiographic control at 1 year was 62%. Patients had a median age of 63. Median follow-up was 9.3 months. The most common radiation dose was 30 Gy in 10 fractions. Pain control after radiotherapy was achieved in 73.6% of patients. Increasing age was associated with nonresponse at the initial pain assessment post-RT ( Pain response and control rates for osseous metastatic disease in RCC are comparable to other histologies when treated with conventional fractionation. These appear to be inferior to reported control rates from stereotactic treatments. The incidence of renal cell carcinoma (RCC) has been increasing in the developing world and accounts for 2-3% of all new cancer diagnoses worldwide , 2. WithSkeletal metastases play a major role in the quality of life of patients with metastatic RCC. A recent analysis of the Nation Wide Inpatient Sample showed that 144,899 US hospital admissions from 1998 to 2010, accounting for 20.8% of hospital visits for patients with RCC, were due to skeletal related events . As a reBone metastases from RCC have previously been described as radioresistant with limited duration of response after treatment . PreviouAfter obtaining Institutional Review Board approval, records were obtained for patients treated with radiation therapy for bone metastasis from RCC at our institution from 2009 to 2016. We identified 40 patients who underwent 53 treatment courses of radiation therapy. All patients completed a palliative course of radiation therapy (RT) as prescribed by the treating radiation oncologist. All patients had at least one month of follow-up. Of the cases identified, we collected patient age, sex, treatment site, surgical intervention, histology (clear cell or nonclear cell), initial pain response post-RT, and evidence of progression. Evidence of progression was captured by radiographic analysis for all patients and by self-report in patients who had a partial or complete initial pain response post-RT. Treatment sites for bone metastasis were recorded and analyzed as vertebrae, long bones, pelvis, and others .Previous systemic treatment for metastatic disease was recorded and included single or multiple drug therapies. The number of prior lines of systemic therapy at the time of radiotherapy were recorded. Systemic treatment recorded included tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin (mTOR) inhibitors, cytokine therapy (IL-2), monoclonal antibodies, and antimetabolites. Surgical intervention was recorded as the presence of surgery at the treatment site prior to radiation therapy.α/β ratio of 7, as has been commonly used in previous studies [Radiation was prescribed to bony sites for palliation of pain or postoperatively to prevent local recurrence. Radiation treatment courses were recorded as total dose in Gray (Gy) and number of treatment fractions delivered. Prescribed treatment dose and fractionation were at the discretion of the treating physician and were based on clinical factors and physician preference. Actual, rather than prescribed, treatment courses were recorded as there were occasional changes in dose prescription midtreatment due to patient refusal or toxicity. Radiation treatment courses ranged from 8 to 45 Gy in 1 to 15 fractionated treatments to metastatic sites. Multiple different fractionation treatment regimens were used, and biological effective dose (BED) was calculated for each treatment. BED was calculated using an  studies , 11, 17.Patients were assessed for both clinical and radiographic response following treatment. Initial pain response was recorded as either complete response , partial response (improved symptoms), or nonresponse (stable or worse pain after treatment) at the treated site based on patient report at the initial follow-up, which generally occurred one to three months from the end of treatment. Radiographic studies were reviewed for changes after treatment and were recorded as partial response, stable disease, or local progression. Pain progression was defined by an increase in pain from the initial post-RT-treatment response to follow-up responses; this was evaluated subjectively by patient self-report of either increased pain at the treated site or an increase in narcotic requirements to achieve similar pain control at the treated site. Radiographic progression was defined by local progression. Duration was calculated in months from the end of RT treatment to the date of patient follow-up or date of radiographic study.Logistic regression was used to analyze if patient age, sex, treatment site, BED, histology, presence of surgery, and prior systemic treatment were associated with pain progression or radiographic progression. Initial pain response was analyzed to determine if it was associated with radiographic progression. Kaplan-Meier curves were generated to analyze if patient age, sex, treatment site, BED, histology, presence of surgery, and prior systemic treatment were associated with time to progression. Initial pain response was analyzed to see if it was associated with time to radiographic progression.As each metastatic site had a separate treatment course and pain assessment, each was analyzed individually. However, if multiple metastasis occurred in a single patient, treatment decisions for one lesion may influence treatment for other lesion(s). To account for this, sensitivity analyses were run on a subset of data where only one lesion for each patient was included to ensure the overall trend of the results was the same. All tests were 2-tailed, and differences of 0.05 were considered statistically significant. Statistical analyses were conducted using the Statistical Analysis System .Patients treated at our institution for metastatic RCC to bone from 2009 to 2016 were analyzed retrospectively for response to treatment. All patients completed their prescribed radiation treatments and follow-up data from both radiation oncology and medical oncology was analyzed. 40 unique patients who underwent 53 treatment courses with radiotherapy were identified . A majorp = 0.1552). There were 29 patients who had a single lesion, 9 patients had 2 lesions, and 2 patients had 3 lesions. In patients with multiple lesions a majority most were diagnosed at the same time. There were 2 patients who had 2 lesions and 1 patient with 3 lesions diagnosed at different time points.There were 38 lesions treated in 31 men and 15 lesions treated in 9 women; however, this difference was not significant (All 53 metastatic lesions treated received the full prescribed course of radiation. As shown in Pain control after radiotherapy was achieved in 39 of 53 (73.6%) of lesions which completed radiotherapy . The medp = 0.0201; OR = 1.095, 95% CI: 1.014, 1.182). Sensitivity analysis showed a similar trend.Increasing age was associated with nonresponse at initial pain response assessment  were not associated with initial pain response .p = 0.0072). Nonclear cell histology was also associated with time to pain recurrence compared to clear cell histology . An estimated 71.4% of nonclear cell lesions had pain recurrence at 1 year compared to only 8.7% of clear cell, and only an estimated 30.0% of clear cell had reported a pain recurrence at 2 years.Although histology was not associated with initial pain response, nonclear cell histology had a higher rate of pain recurrence after treatment . In the Radiographic control was achieved in 32 of 53 lesions (60.4%) at last follow-up. 6 month, 1 year, and 2 year rates of radiographic control were 69.4%, 62.4%, and 41.3%.Patient age, sex, treatment site, number of systemic treatment courses prior to radiotherapy, histology (clear cell or not clear cell), and presence of surgery at treatment site were not associated with treatment response.p = 0.0332). The estimated median time to radiographic progression for nonresponders was 1.5 months compared to 22.8 months in partial or complete responders . Sensitivity analysis showed a similar trend.The only predictor of freedom from local progression was initial pain response . Of the RCC is described as a less radiosensitive tumor based on in vitro studies and studies of adjuvant radiation therapy in renal cell cancer. Because RCC is perceived to be a less radiosensitive histology, there is increasing use of very high dose radiation using stereotactic body radiation (SBRT) in this population. It is not clear whether SBRT is necessary to achieve adequate control and pain relief. We performed a retrospective analysis of patients treated palliatively for renal cell metastases to bone with conventionally fractionated radiation in the modern era to evaluate response to conventional fractioned radiation. We found 73.6% response in pain control and radiographic response in 60.4% of lesions. The most common treatment course studied was 30 Gy in 10 fractions.Our results are similar to an older study by Princess Margaret Hospital, which found 83% response in pain with 23 patients treated using 30 Gy in 10 fractions . An addiDespite the evidence that RCC is less radiosensitive than other tumors, these rates are similar to pain response rates expected with conventional radiation therapy for other tumor histologies considered to be more radiosensitive. In the RTOG 9714 trial of palliative radiation for bone metastasis from breast or prostate cancer, the overall pain response rate at 3 months was 66% . The mecThere was no significant association found between higher BED and improved pain control in our study. This is consistent with results reported by Wilson et al., who evaluated 143 treatments in 78 patients with metastatic RCC, including 72 bony lesions, treated with conventional fractionation and did not find response rates predicted by BED7 .Amini et al. compared 46 patients with 95 lesions, 45 of which were treated with conventional fractionation and 50 treated with SBRT. Patients who received SBRT had significantly improved symptom control rates. BED > 80 was noted to be correlated with clinical local control . JhaveriOther studies have examined the role of SBRT in the management of bone metastases from RCC. These have included treatment to bony metastases as well as spinal lesions, though interpretation of these studies is limited by their retrospective nature. In studies examining exclusively osseous metastases, crude local control rates range from 72 to 100%. A systematic review by Kothari et al. in 2015 looked at 10 studies in which patients with extracranial metastases from renal cell carcinoma were treated with stereotactic radiation, five of which studied patients with bony metastases only . WeightePain response in our study was correlated with histologic type of tumors, with patients with nonclear cell histology performing significantly worse than those with clear cell histology. Clear cell RCC is the most common subtype of RCC, comprising about 75–90% of total diagnosed RCC. Few studies have examined the effect of histology on local control in extracranial metastatic RCC . In our The use of TKIs has improved survival in patients with metastatic RCC. We did not find an association between use of TKI and improved pain response or local control in patients treated with conventional fractionated radiation. This contrasts with a recent study by Miller et al. who registered improved local control in patients receiving SRS for spinal metastasis in systemic-therapy naïve patients . These dThe only variable that predicted for radiographic control in our population was initial pain response. The pathophysiology of pain from bone metastases is multifactorial, and response to treatment may be a result of multiple processes . Since tα/β ratios of 3, 7, and 10; this may have affected our results. The small number of patients may have limited our ability to detect true differences between subgroups. Lastly, each lesion was analyzed independently; this may mask patient-specific factors that otherwise would account for patient response.The current study is limited by its retrospective nature, short-term follow-up, and variability in treatment, with numerous different dosage, fractionation, and lines of systemic therapy being used in treated patients. Additionally, treatment pain response was patient reported and was subject to multiple cofounders. Patients with multiple metastases may have had changing narcotic requirements as a result of their untreated metastases, which was not captured by our data. As a result, we relied on patient self-report of pain recurrence rather than more objective measures. We used BED7 to standardize differences amongst radiation fractionation schemes. However, the use of BED7 is controversial as well, as previous studies have used The role of systemic therapy in the management of metastatic renal cell carcinoma is a rapidly evolving one, particularly with the emergence of anti-PD-1 and anti-PD-L1 inhibitors as effective treatment options . The intIn summary, despite previous in vitro studies demonstrating radioresistance of RCC, there have been numerous clinical studies displaying the efficacy of radiation in the management of osseous metastases from this disease. Conventionally fractionated radiation therapy remains an appropriate option for management of these patients. Given the equivalent pain control rates but inferior local control rates of conventional fractionation when compared to SBRT, clinical judgment may play an important role in appropriate patient selection for these different treatment modalities. SBRT may be preferred in patients with longer life expectancy and good performance status, with lesions in weight-bearing bones, and with nonclear cell histologies. Further study is warranted to identify patients in whom the improved disease control provided by SBRT would be most appropriate.


The aim of the current study was to validate the self-report section of the American Shoulder and Elbow Surgeons questionnaire (ASES-p) into Spanish.Shoulder pathology patients were recruited and followed up to 6 months post treatment. The ASES-p, Constant, SF-36 and Barthel scales were filled-in pre and post treatment. Reliability was tested with Cronbach’s alpha, convergent validity with Spearman’s correlations coefficients. Confirmatory factor analysis (CFA) and the Rasch model were implemented for assessing structural validity and unidimensionality of the scale. Models with and without the pain item were considered. Responsiveness to change was explored via standardised effect sizes.Results were acceptable for both tested models. Cronbach’s alpha was 0.91, total scale correlations with Constant and physical SF-36 dimensions were >0.50. Factor loadings for CFA were >0.40. The Rasch model confirmed unidimensionality of the scale, even though item 10 “do usual sport” was suggested as non-informative. Finally, patients with improved post treatment shoulder function and those receiving surgery had higher standardised effect sizes.The adapted Spanish ASES-p version is a valid and reliable tool for shoulder evaluation and its unidimensionality is supported by the data.The online version of this article (doi:10.1186/s12955-016-0552-1) contains supplementary material, which is available to authorized users. Shoulder pathologies are among the commonest musculoskeletal problems, with subacromial pain, rotator cuff deficiencies, instability and fractures being some of the most frequent diagnoses –3. ShoulUp to date, no Spanish language validation of this scale exists. The aim of the current study was to cross culturally adapt and validate the ASES-p questionnaire for its use in Spanish populations. To this end, an extensive validation was performed by applying both confirmatory factor analysis (CFA) and the Rasch model.n = 10 randomly chosen shoulder pathology patients. They were asked to fill-in the scale and comment on its understanding and item relevance. None of the pilot study patients were included in the validation study.The cultural adaptation of the ASES-p questionnaire, from English to Spanish, was performed following the recommendations of the International Quality of Life Assessment (IQOLA) project. The IQOLA protocol is considered a reference standard for translating health status instruments , 21. TwoParticipants were recruited by the orthopaedic surgeons of five public hospitals, located in the Basque Country (Spain). Included patients were ≥18 years old, had a shoulder pathology, were going to receive a surgical or conservative treatment in the affected shoulder, and were able to speak and write in Spanish. Patients previously operated in the affected shoulder and those with cognitive impairment were excluded from the study.Upon recruitment, functional assessment of the affected shoulder was performed by the orthopaedic surgeons, with the CMS instrument. Information on age, sex, marital status, daily lifestyle habits, medication consumption, additional pathologies and other questions of interest were filled in by the participants in their homes. The socio-demographic and clinical variables were sent by postal mail and replies were received in the same way. A reminder letter was sent to those not responding within two weeks, followed by further phone calls if necessary. If despite all efforts no reply was obtained, the patients were considered drop-outs. All assessments were performed twice: at recruitment and after the treatment. Conservatively treated and operated patients were assessed at 3 and 6 months respectively. Only one shoulder per patient was considered in the validation analyses.The ASES-p scale is composed of 11 items, divided in 2 subscales: pain (1 item) and function 10 items). The pain item evaluates current pain level on a 10 cm VAS with minimum and maximum values “0 = no pain at all” and “10 = pain as bad as it can be” respectively. The 10 function items evaluate the ability to perform certain daily life activities, and are answered on a 4 point Likert scale from “0 = unable to do” to “3 = not difficult”. Each subscale is assigned from 0 to 50 points, with higher values indicating better health status. Points are calculated as: (10-VAS × 5) and ((5/3) × sum of 10 function items) for the pain and function subscale respectively. The total ASES-p score is the sum of the two subscales, with possible values ranging between 0 and 100 points. The originally published form of the scale was implemented in this study [ items. TFor analyses where individual item replies were considered, the pain item was reversed. In order to ease interpretation, this item’s replies were transformed to be on the same direction with the function items . Maximum and no pain at all were thus given 0 and 10 points respectively. For certain analyses, the pain score was further categorized in four groups, approximating the 4 point Likert responses. In those cases, values 0–1 were considered as “3 = no pain”; values 2–5 were “2 = some pain”; 6–8 as “1 = a lot of pain” and values 9–10 as “0 = maximum pain”. This categorization was decided by examining this item’s responses in relation to pain and general health items of SF-36. All analyses are based on available data. No imputations have been performed in this study.O) score assigns 15, 20, 40 and 25 points to each of its four components and its total score ranges between 0 and 100 points with higher scores indicating better shoulder function [R) as suggested by the original CMS author [NS) [The Constant-Murley score (CMS) was published in 1987 and was approved by the executive committee of the European Society for Surgery of the Shoulder and the Elbow (ESSSE) . It asseS author  and an aThe 36-Item Short Form health Survey (SF-36)  is a genFor surgically treated patients, data related to hospital admission and intervention of the affected side was gathered from the clinical history files. Patients not receiving any treatment during the study course were also assessed at the end of follow-up.t-test or Wilcoxon rank-sum test respectively. Pre-post comparisons of the ASES-p scores performed with the paired t-test.Categorical data are presented with frequencies and percentages. Continuous data are presented with means and standard deviations (SD) when normally distributed, or medians and interquartile range (IQR) when skewed. Between-group comparisons of categorical and continuous data were performed with the chi-square, Student’s S). Values ≥0.70 and ≥30 respectively were considered acceptable [Reliability was estimated with Cronbach’s alpha . Item-itceptable . Item-toConstruct validity was studied with two separate methods: confirmatory factor analysis (CFA)  and the S) with the CMS, the physical dimensions and physical component of SF-36, and Barthel. Lower correlations were expected with the mental dimensions and component of SF-36. Known-group validity was studied by examining the ASES-p score values against CMS, PCS and Barthel after transforming them to categorical variables. Comparisons were performed with the Jonckheere–Terpstra [t-test when two categories where compared.Convergent and divergent validity was explored via correlations with other scales. The ASES-p total score was correlated with the CMS, the SF-36 scale, and the Barthel index. It was hypothesized that ASES-p would present higher correlations . The SES is the mean difference between baseline and follow-up scores divided by the SD of the baseline score [Adj was calculated considering the pooled effect size and the correlation of the respective pre-post observations [At follow up, patients were asked to evaluate whether their ROM and capacity in doing their ADL had improved, compared to baseline. Those with a positive reply to both questions were considered as improved. We hypothesized that these patients would present higher ASES-p pre-post score differences, compared to the rest. Three effect sizes were calculated: the standardized effect size (SES), the standardized response mean (SRM) and the SRM adjusted for paired observations , Mplus  and Winsteps .Statistically significant results were considered those with During the translation-back-translation process of the ASES-p questionnaire, the only item that presented a certain difficulty was the fourth function item “manage toileting”. In the English-Spanish translation, one of the translators considered this item to refer to washing, dressing and attending one’s appearance, whereas the other perceived it as the difficulty one may have in cleaning oneself after urinating and defecating. By contacting the main author of one of the first ASES-p validations , it was n = 180 eligible subjects were recruited in the study and n = 164 returned the mailed baseline questionnaires. Three subjects who left all ASES-p items and many other questions unanswered, were excluded, leaving a total of n = 161 valid replies at baseline. Among these replies, missing data ranged from 1 to 6 % for most items, with the exception of item 10 “do usual sports”, which was not filled in by 23 % of the participants In total, n = 151 subjects replied to the pain item and n = 112 answered all function items. The ASES-p scale was fully answered by n = 106 subjects at baseline . The majority had subacromial pathology with rotator cuff rupture (64 %), presented mostly on the right shoulder (68 %). Thirty-five per cent of the responders were manual workers (heavy or light tasks); around one-third had taken at least one sick-leave due to their shoulder problem in the last 5 years and many suffered additionally by back (52 %), neck (47 %) or lower extremity (39 %) problems (Table  %. The mp < 0.0001). Sixty-six (n = 66) of the participants received a surgical intervention, while for n = 2 the intervention was still pending at the end of the study; n = 28 underwent infiltration; n = 8 rejected surgery and the rest underwent a rehabilitation program, followed by a health professional at hospital or at their home. The mean age of those not responding to item 10 was 64.9 (SD: 10.3) years. No differences in terms of age (p = 0.348), sex (p = 0.339) and the three CMS versions (p > 0.900) were found between responders and non-responders at baseline.The option “unable to do”, across all ASES-p items, was chosen by 5–56 % of the responders, while “not difficult” by 5–31 %. The mean scale value of the affected shoulder at baseline was 46.5 (SD: 22.9) points. Neither floor nor ceiling effects were observed for the total questionnaire score, as only 1 % of the participants obtained 5 and 100 points respectively. Eighty-two (51 %) of the responders provided valid ASES-p answers for the non-affected shoulders too. Based on these replies, the contralateral shoulder had a mean ASES-p of 66.3 (SD: 21.1) points, with the difference between the two sides being statistically significant  and item 3 “wash back” (rS = 0.291). The item-scale total correlations, oscillated between 0.73 and 0.40, with the lowest value corresponding to item 10  with relatively more pain (≤25 points), or worse function (≤25 p) and less pain (>25 p).The function and pain subscales presented a substantial correlation rIn the CFA analysis, factor loadings were >0.50 for all items, with the TLI and CFI coefficients being >0.90 Table . The modst contrasts  of the 11 and 10-item models being 2.12 and 2.10 respectively.The results of the respective Rasch models are presented in Table S >0.50 with all CMS versions and with the CMSO components of pain and ADL. As far as the SF-36 scale was concerned, correlations were higher with psychical functioning and role, bodily pain, vitality, and with the PCS component. Lower values were derived for the rest SF-36 dimensions, MCS, and Barthel. A similar tendency was seen in the correlations of the function subscale score, even though the derived coefficients were slightly lower. It is worth highlighting that when this subscale was correlated with the CMSO components, the highest correlation was seen with ADL. Finally, the pain subscale correlated higher with the pain CMSO component, with bodily pain and PCS. Lower correlations were observed with all other measures. As far as the known-group validity was concerned, better health status patients according CMSO, PCS, and Barthel also had higher ASES-p scores. The pain subscale did not differentiating well among the three ordered Barthel groups.Convergent, divergent and known group validity data are presented in Table n = 120 patients provided follow-up data. Of those n = 10 did not reply the ASES-p pain item and n = 50 left unanswered at least one function item. Based on the respective valid replies, scale score differences and standardized effect sizes were higher for improved subjects, compared to non-improved ones. Total and function ASES-p scores, had SES and SRM values around 1, while the pain subscale presented moderate to low effects .A total of When responsiveness was explored according intervention type, surgery patients has higher standardized effects compared to infiltration and other treatment patients Fig. .Fig. 2StThe current study provides data on the validation of the self-administered ASES-p questionnaire into Spanish. The selection of this scale was based on the results of a systematic review and standardized evaluation of HRQoL shoulder instruments, previously performed by our group .Reliability, validity and responsiveness to change were tested considering jointly all 11 scale items and the 10 function items alone, in separate models. Cronbach’s alpha estimations were high and agree with those presented in previous cultural validation studies –16, 18, th function item “do usual sports”. This particular item had the highest frequency of baseline missing data; presented lower correlations with two other scale items; had the lowest, even though acceptable, item-total correlation; whereas its distribution did not fit the Rasch model well [However, the current analyses draw attention on the 10del well . Given tdel well . The meadel well . This madel well .Another interesting finding was the ranking of the pain item, which turned out to be the fourth easier item for the participants. Pain may have been expected to be of higher difficulty, especially considering that it constitutes 50 % the ASES-p total score. However, the baseline pain levels experienced by the study subjects were indeed moderate. It is worth highlighting that this item evaluates current pain intensity (i.e. How bad is your pain today?), meaning that a good or bad day, as far as pain is concerned, could have distorted certain replies. This could explain why some subjects with generally better shoulder status reported higher pain levels than subjects with worse shoulder status, and vice versa. This particular characteristic may have been responsible for the elevated outfit MNSQ of the pain item, which implies detection of outlying responses .In addition, item 7 “lift 10 lbs. above shoulder” and item 8 “throw a ball overhand”, were the most difficult to perform, while item 4 “manage toileting” was the easiest. These findings make clinical sense and offer additional insight on the scale’s construct validity. The first two actions impose an important stress to the shoulder, especially to the mechanisms responsible for its stability. Frequent repetition of these actions increases prevalence of shoulder pathologies . On the O components and the mental SF-36 dimensions. The function subscore behaved in a similar way. The pain subscore correlated higher, as expected, with the pain CMSO component, the PCS and the bodily pain dimension. On the other hand all ASES-p scores presented lower correlations with the Barthel Index. Given that 50 % of the ASES-p total score corresponds to daily life activities, we initially hypothesized that the two instruments would present substantial positive correlations. However, despite having ADL difficulties, most participants were actually BADL independent. This resulted in a small range of Barthel values and consequently low correlations with the scale of interest. On the other hand known-groups validity results were satisfactory and in line with previous hypotheses, including for the Barthel defined groups. Only the ASES-p pain subscore, did not differentiate between the first two Barthel categories. This was not surprising though, given that Barthel does not evaluate pain levels per se [As far as convergent, divergent and known-group validity was concerned, the ASES-p total score presented higher correlations with the different versions of the functional CMS shoulder tool, the pain and ADL components of the latter, as well as with the physical SF-36 dimensions, and PCS. Lower correlations were derived with the ROM and strength CMSs per se .In previous ASES-p cultural validations, convergent and divergent validity were studied with the aid of the Penn , DASH orResponsiveness was also supported by the data. Standardised effect sizes of the total ASES-p score were moderate, but patients with improved self-evaluated ROM and ADL capacity presented higher effect size values compared to the rest. Similar estimations were obtained for the function score. When responsiveness was additionally explored according intervention type, surgery patients had the highest values, while infiltration and other intervention types had low effect sizes. The pain subscore suggested low to moderate responsiveness in all cases.Certain limitations of this study should be addressed. Our results are based on a sample of public hospitals orthopaedic clinics patients and may not be applicable to shoulder pathology patients in other setting. Also, the current results may not extrapolate to shoulder fracture patients either. Given that most required information was based on self-administered questionnaires, full data was not available for all responders. We refrained from imputing any missing information and only available data were implemented in this study. As far as the CMS instrument was concerned, certain variability across centers existed in the assessment of its strength component. In particular, the weight system used was not always the same. Adjustable dumbbells and weights were used depending on the available resources of the participating centers. For this reason, the four CMS components were also explored separately and a CMS version excluding strength was considered. Finally, no test-retest data is available. This is the subject of another study, currently undertaken by the investigators.To the best of our knowledge, this is the first extensive validation of the ASES-p scale, implementing both classical and modern test theory. It is also the first in examining the item of pain as part of the scale’s construct. Future studies could focus on the construct validity of ASES-p in different contexts and shoulder pathologies; while the scale’s scoring system is an interesting field for further exploration.The presented results, based on classical CFA and Rasch analyses, suggest that the Spanish ASES-p version is a valid and reliable HRQoL tool for shoulder evaluation. Difficulty in doing usual sports was not informative, but neither degrading for the measurement system. Unidimensionality of the scale is supported by the current data.


This study aimed to test the efficacy of cupping therapy to improve symptoms and quality of life in patients diagnosed with the fibromyalgia syndrome. Participants were randomly assigned to cupping therapy, sham or usual care. Cupping was administered five times at twice weekly intervals on the upper and lower back. The primary outcome measure was pain intensity at day 18. Secondary outcomes included functional disability, quality of life, fatigue and sleep quality as well as pressure pain sensitivity, satisfaction and safety at day 18 and 6 months. Altogether 141 patients were included in this study . After 18 days patients reported significant less pain after cupping compared to usual care  but not compared to sham . Further effects were found for quality of life compared to usual care. Patients were mildly satisfied with cupping and sham cupping; and only minor side effects were observed. Despite cupping therapy being more effective than usual care to improve pain intensity and quality of life, effects of cupping therapy were small and comparable to those of a sham treatment, and as such cupping cannot be recommended for fibromyalgia at the current time. The fibromyalgia syndrome is a condition characterised by chronic widespread pain in combination with fatigue, cognitive disturbances, sleep disorders and pronounced somatic and/or psychological distress115Cupping therapy is an ancient medical therapy, and the common denominator in all cupping variations is the application of suction to the skin79121314161718This study aimed to investigate the efficacy of cupping therapy compared to usual care and a sham procedure to improve symptoms and quality of life in patients diagnosed with the fibromyalgia syndrome.The trial was conducted between October 2012 and February 2015 in the Department of Complementary and Integrative Medicine in Essen, Germany. The study was approved by the ethics committee of the University Hospital Essen  and registered at ClinicalTrials.gov , prior to patient recruitment. The study was conducted according to common standard guidelines for clinical trials  revised version, Somerset West, Republic of South Africa, 1996).This was a randomised sham-controlled three-armed parallel group trial. The intervention group received five sessions of dry cupping, whereas the control groups received either five sessions of sham cupping, or usual care. Each group received the allocated intervention within 18 days; measurements were conducted at day 0, day 18 and after 6 months. After the measurements at day 18 usual care group patients received the cupping treatment.Patients were recruited via newspaper advertisements, with medical students screening interested people by phone to assess their eligibility. Patients who met the inclusion criteria were invited for assessment where they were provided with detailed written information about the study; and their written informed consent was obtained. The study physician checked patients’ medical histories, examined their physical health, and checked patients’ medical records. If patients met the inclusion criteria, and did not meet any exclusion criteria, they were included.Trial participants were required to be between 18 and 75 years of age, and to suffer from the fibromyalgia syndrome diagnosed by a specialist. The 2010 American College of Rheumatology diagnostic criteriaThe trial exclusion criteria included pain due to inflammatory rheumatic disorder, any major psychiatric disorder, severe depression or substance abuse, any severe comorbidity such as cancer or neurological disorders, recently initiated or modified drug treatment, prior injections or acupuncture , treatment with opioids or steroidal pain medication. Medications with non-steroidal anti-inflammatory drugs or antidepressants were admitted if the dosage was kept constant during the trial. Finally pregnant or lactating women or patients taking part in other clinical trials were excluded.Patients were allocated to one of three groups in sequential order adopting a computer-generated  stratified block randomization with randomly varying block sizes. The following stratum was applied: Patients taking antidepressants vs. those without. The trial coordinator who was not involved in patients’ outcome assessments prepared sealed opaque envelopes. Envelopes were labelled according to the study participant’s identification number and after inclusion, the envelopes were opened in ascending order by the study physician and the patients were allocated to the respective intervention.Patients were blinded twice: 1) to the fact that a sham procedure was used, instead they were told that two different cupping techniques would be compared against each other, i.e. traditional cupping vs. modern gentle cupping; 2) to whether they have been allocated to the real or sham cupping. Success of blinding was checked at day 18. Outcome assessors were blinded to the patients’ group allocation  at outcome assessment.After the baseline measurement and randomization patients received the allocated treatment.® 200S, Pneumed GmbH, Idar-Oberstein, Germany). The negative pressure was adjusted to a comfortable level, and cups were fixed by means of elastic tapes. After 10 to 15 minutes cups were removed. The cups were placed on predefined locations such as the trapezius, the levator, the latissimus dorsi, or the gluteus maximus muscles; as well as individually according to the patient’s physical examination. One treatment session lasted about 30 minutes in total.Patients in that group received five cupping treatments, two treatments per week. Cupping was performed on the patients’ upper and lower back in a semi-standardised manner. Four to eight 50–100 mm diameter acrylic glass cups were placed on the skin, and air was partially evacuated from the cups by means of a mechanical device 27Health-related quality of life was assessed using the Short Form 36 Health Survey Questionnaire (SF-36)The Multidimensional Fatigue Inventory (MFI-20) - a 20-item, multi-dimensional, self-report instrument – was used to measure severity of fatigue30Sleep disturbance was assessed on the Pittsburgh Sleep Quality Inventory (PSQI)All patients used a log to record the intensity on a 100 mm visual analogue scale, whether they took analgesics or received other treatments. For analgesics the defined daily doses were calculated2 probe. Pressure was applied in increments of 40 kPa/s until patients indicated a perception of pain in addition to pressure. They were measured unilaterally over the patient’s right thenar eminence for demonstration35Patients’ pressure pain thresholds (PPT) were measured using a digital algometer  with a 1 cmTo determine whether blinding was successful patients were asked to indicate which form of cupping therapy they had received in their opinion.After 18 days patients were asked to judge how beneficial the respective treatment was on a 100 mm visual analogue scale with 100 mm indicating highest possible benefit, whether they would utilise this intervention in the future and whether they would recommend it to family or friends on a yes/no basis.All adverse events were recorded. Patients experiencing such events were asked to see the study physician to assess their import and initiate any necessary response.The primary outcome measure was pain intensity at day 18 as measured by the visual analogue scale (VAS). Secondary outcome measures included pain (VAS), physical function (FIQ), quality of life (SF-36), fatigue (MFI), sleep quality (PSQI) at day 18 and 6 months; pressure pain sensitivity (PPT) at day 18; and pain intensity (VAS), pain medication and concomitant treatments from the daily log, compliance, satisfaction, success of blinding and safety.et al.No data were available for a priori sample size calculation for cupping therapy in patients with fibromyalgia. Instead data from a reanalysis on cupping therapy were usedAll analyses were based on the intention to treat population, i.e. each patient providing baseline data was included in the final analysis. Missing data were substituted using the arithmetical average of 50 complete data sets created by the Markov-Chain-Monte-Carlo multiple imputation procedure in SPSS. Pain and medication diary were analysed using the per-protocol population only.The primary outcome was analysed using the univariate analysis of covariance (ANCOVA) which modelled the post-treatment outcome as a function of treatment group (classified factor), and the respective baseline value (linear covariate). A stepwise analysis was conducted; starting with the comparison cupping therapy vs. usual care; followed by cupping therapy vs. sham cupping, each with a p-value of 0.05 indicating significant differences. Within this model the treatment effect was estimated, accompanied with a 95% confidence interval. The p-value was based on a two-sided t-test within this statistical model. All other outcomes were defined as secondary outcomes and were analysed exploratively only using comparable models, without reporting p-values. This way, no alpha level adjustment was necessary to maintain the overall type I error rate of 5%382 tests. Results from the daily log were analysed using a repeated measurement analysis of variance (ANOVA) with group as the between-subject-factor and pain outcomes at the different time points as the dependent variables. Medication and treatment logs were analysed with the same model. In case of significant main or interaction effects, post hoc tests  were conducted. All analyses were performed using the Statistical Package for Social Sciences software .For secondary outcomes the same statistical models were used. The frequencies of responders, i.e. patients experiencing at least 30% or 50% pain reduction, were compared between groups using χFrom 362 patients initially screened by telephone, 150 patients were seen by the study physician, of whom 141 were enrolled. The most common reasons for excluding patients were violations of the inclusion criteria, or lost interest in the study. Of the 141 patients finally enrolled, all were randomised and allocated to their intervention. During the intervention seven patients each were lost to follow-up in cupping therapy and sham cupping, due to adverse events, private or unknown reasons. In the usual care group five patients were lost for similar reasons. A high proportion of patients withdrew from the study during the long-term follow up .Altogether 38 out of 47 patients received five cupping treatments (80.9%), and 38 out of 48 received five sham treatments (79.2%).Analysis of pain intensity revealed a significant group difference between cupping therapy and usual care  at day 18 in favour of cupping, see After 18 days 12 patients in cupping therapy (25.5%) and nine patients in sham cupping (18.8%) reported a 30% pain reduction while only one patient in usual care did (2.2%) (p = 0.006). At least 50% pain reduction was reported by four (8.5%), five (10.4%) and zero (0.0%) patients in cupping therapy, sham cupping and usual care respectively (p = 0.091).No difference between cupping therapy and usual care was found for physical function (FIQ) or sleep quality (PSQI). For quality of life, group differences in favour of cupping therapy were found for the scales bodily pain , vitality , social role functioning  and mental health , as well as for the mental component summary , see Compared to sham cupping no differences were found for any outcomes except for one on the scale bodily pain of the SF-36 at day 18 , see 2 test. Altogether 32 out of 39 (82.1%) of the patients in cupping therapy, and 30 out of 41 (73.2%) of the patients in sham cupping correctly identified their respective group allocation indicating lack of success of blinding (p < 0.0001).Success of blinding was tested using χA small but consistent decline in pain intensity was found in cupping and sham cupping, but not in usual care . RepeatePatients were mildly satisfied with both interventions at day 18 . Furthermore 25 out of 39 (64.1%) would consider using cupping therapy again, so did 22 in sham cupping (57.9%). And 32 out of 39 (82.1%) and 34 out of 40 (85.0%) would recommend cupping therapy and sham cupping to family and friends respectively.The following non-serious adverse events were recorded in the cupping group: two patients reported severely increased pain after cupping, one patient had an accident with bruised rips and one patient had the flu. All events resolved without intervention. A fifth patient suffered from acute torticollis which radiated into the arm but was resolved without treatment within days. In sham cupping two serious adverse events were reported: one patient with a torn meniscus and one patient with persistent pain after spinal operation. Both patients had consulted a specialist on their own. A third patient in that group had the flu. No patient in the usual care group reported adverse events.This trial included 141 mainly female patients with the fibromyalgia syndrome, and found that five cupping treatments were more effective than usual care to improve pain and mental quality of life. Cupping however was not superior to sham cupping. Patients were able to distinguish the two types of cupping, and were mildly satisfied with either intervention. Adverse events related to cupping therapy mainly included increased pain, no serious adverse events related to the intervention were observed.Only one trial could be located during literature searchCupping was also less effective than for chronic non-specific neck pain124142434446et al.Interestingly the present trial found no difference between cupping and sham cupping. This is even more surprising since the majority of patients were able to determine their respective group allocation correctly. This is in contrast to findings from Lee One would think that once the patients uncover their group assignment the sham intervention would be inefficacious. But it was never revealed to the participants that a sham intervention was used, it was introduced as ‘gentle’ cupping instead. This is in line with findings from a systematic review that found the magnitude of the placebo effect larger in trials with physical placebos and trials where the use of a placebo interventions were not disclosed50The strengths of the study include the randomised study design; the use of two different comparators; and the blinding of patients in the active treatment groups as well as outcome assessors. Outcomes were further chosen according to the guiding symptoms of fibromyalgia according to current definitions4Limitations include the non-successful blinding of patients, however due to the positive connotation of the seemingly gentle cupping the placebo effect was preserved. Patients in the study were mainly female in their mid-40 and 50’s, limiting the significance of the trial’s findings for male, younger and older patients with fibromyalgia. It is known that the vast majority of fibromyalgia patients are female with only 1 in 10 patients being maleMore studies are warranted to evaluate the effects of different cupping techniques of different durations on chronic pain syndromes. For fibromyalgia in particular the effects in patients with certain subtypes should be determined. It may also be interesting to test cupping as part of a multimodal treatment approach, or in combination with therapies like acupuncture. Further studies should also re-evaluate the sham cupping device and – if necessary – develop reliable alternatives.Five cupping treatments were more effective than usual care to improve pain intensity and quality of life in patients diagnosed with the fibromyalgia syndrome. Given that effects were small, and cupping was not superior to sham cupping treatments currently no recommendation for cupping in the treatment of fibromyalgia can be made. Further research is warranted for conclusive judgement of the efficacy of cupping therapy for chronic pain.How to cite this article: Lauche, R. et al. Efficacy of cupping therapy in patients with the fibromyalgia syndrome-a randomised placebo controlled trial. Sci. Rep.6, 37316; doi: 10.1038/srep37316 (2016).Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.