Hip osteoarthritis (OA) is a major contributor to reduced quality of life and concomitant disability associated with lost working life months. Intra-articular injection of various biological materials has shown promise in alleviating symptoms and potentially slowing down the degenerative process. Here, we compared the effects of treatment of a cohort of 147 patients suffering from grade 1–4 hip OA; with either micro-fragmented adipose tissue (MFAT), or a combination of MFAT with platelet-rich plasma (PRP). We found significant improvements in both the visual analogue score for pain (VAS) and Oxford hip score (OHS) that were similar for both treatments with over 60% having an improvement in the VAS score of 20 points or more. These results suggest a positive role for intra-articular injection of MFAT + PRP as a treatment for hip osteoarthritis which may be important particularly in low body mass index (BMI) patients where the difficulty in obtaining sufficient MFAT for treatment could be offset by using this combination of biologicals. Osteoarthritis (OA) is the most common joint disease, affecting more than 250 million people worldwide and being the fourth leading cause of disability in men. Hip OA is a major contributor to the number of years lived with disability worldwide, with the lifetime risk of symptomatic hip OA thought to be around 25 percent .Currently (not taking into account the slow down due to COVID-19), over 95,000 hip replacements are carried out in the United Kingdom each year , while wHip chondral defects, injuries, and labral tears are the most common sources of hip pain, with femoro-acetabular impingement (FAI) also implicated in the development of hip OA. Recent advances in precision medicine have made it possible to identify earlier stages or pre-symptomatic hip pathology at risk of development of hip OA  have provided an infrastructure supporting better management and potentially more treatment options for this pathology . Despite the improvement in anatomical design and material composition of prosthesis components, total hip arthroplasty (THA), although highly successful as a surgical intervention, is a highly invasive approach that should be delayed for as long as possible. Hip conservation surgeries, particularly arthroscopic hip surgery, have increased in importance and demonstrated consistent and sustained benefits, however, there is a significant subset of patients  treated in this manner for whom OA symptoms persist, and in addition, treatments such as hip arthroscopy have a similar recovery time to THA surgery .Attempts to alleviate pain and symptoms, thereby delaying THA, beyond the standard protocols involving debridement, labral reconstruction  microfraCombined with appropriate physiotherapy, and as an adjunct to traditional surgical procedures, intra-articular injections of hyaluronic acid and platelet-rich plasma (PRP) have been indicated in several studies to be partially effective, at least in relieving pain. Recent meta-analyses have, however, indicated variable outcomes with many clinical trials demonstrating equivalence only when compared with saline placebo ,11. MostThere are many more studies of injectables conducted on KOA than with hip OA and our study here equates, to our knowledge, as the largest study of its type to be recorded . A previMicro-fragmented adipose tissue (MFAT) possesses unique biological properties. The adipose tissue has an innate anti-inflammatory quality and contains the highest concentration of MSCs of any tissue in the body (up to 2% of cells sited in the MFAT tissue are MSC compared to a 0.02% in the bone marrow), being derived from the microvessel pericytes, these multipotent cells maintain the capacity to differentiate into chondrocytes with adequate stimuli. Recently, there have been several clinical studies where ultrasound-guided intraarticular injection of MFAT have demonstrated significant improvement in pain and mobility in patients with KOA. A recent observational study of 110 OA knees treated with MFAT  reportinA combination of MFAT with PRP may provide an even more effective therapeutic benefit. In this case, it is believed that the additional anti-inflammatory/pro-angiogenic secretions from the platelets can enhance the overall beneficial effects synergizing with the MFAT delivery payload. Therefore, in this study, we report on the reduction in pain and improvement in function following either a single injection of MFAT or MFAT + PRP for the treatment of hip OA. Our null hypothesis is that there will be no difference in effectiveness between these two treatments.The study was carried out within a private clinical practice setting. The study was conducted in accordance with the principles of Good Clinical Practice (NIHR) and the General Medical Council (GMC) guidelines on research, patient consent to research, and future publication, in adherence to and in accordance with the Declaration of Helsinki. This observational, intention-to-treat study was conducted over a 2-year period and the patients were recruited from 2018 to 2020. The cohort included 57 patients injected with MFAT and 90 patients injected with MFAT + PRP who consented to be scored for pain ) and function (Oxford hip score (OHS)) at baseline irrespective of later changes to adherence or status at follow-up.Patients had a clinical review and physical examination by an orthopedic surgeon. The Kellgren–Lawrence (KL) system was used to grade hip OA  and preoThe initial cohort of 57 patients was treated with MFAT alone as this was the normal practice of our private clinic. Following assessment of relevant publications ,17 demonThe inclusion criteria were as follows: the presence of hip OA as diagnosed on X-ray and/or MRI.Exclusion criteria were as follows: recent injury (<3 months) of the symptomatic hip, malignancy, infectious joint disease, anticoagulation, pregnancy or thrombocytopenia, coagulation disorder, as well as intra-articular steroid injections given within the last three months.The patients were made aware of all other available options for hip OA treatment including conservative interventions, intra-articular injections of steroids, hyaluronic acid, platelet-rich plasma, and MFAT. All patients were made aware of alternative surgical options including hip resurfacing, hip arthroscopy, and THA.A Bayesian analysis was performed for the individual groups of MFAT versus MFAT + PRP indicating variability status of the patient information and appropriate reasoning associated with the group means and variation ,19.To our knowledge, there is no existing study comparing MFAT versus MFAT + PRP-specific responses in pain and function to the biologic treatment of hip OA, and on this basis we assumed no prior knowledge on the comparative responses, utilizing minimally informative priors: i.e., normal priors with a large standard deviation for the mean and a broad uniform priors for standard deviation, as described by Kruschke ,20.In order to make statistical analysis reproducible and results replicable, we utilized open-access software R version 4.0.3 (2020-10-10) and later. In addition, all figures have been generated automatically by software R and are therefore reproducible and replicable.Our dataset consisted of 57 sets of observations and 8 variables per set of observation for MFAT for a total of 456 data points; and for the MFAT + PRP, 90 patients for a total of 720 data points . with a The mean patient age at the time of the treatment for the MFAT group was 60 and for MFAT+ PRP was 60 . Both gr® system. The device is prefilled with saline where stainless steel ball bearings work to mechanically fragment the fat as it is agitated by the clinician. This progressively reduces the size of the clusters of adipose tissue . The chamber was then flushed with saline to wash out impurities . The resulting product was then filtered through a 500-micron filter making it ready for use [In a sedated patient, in an operating theatre, Klein sterile solution  was injected into the subcutaneous fat. Adipose tissue was then manually harvested, in a standard fashion, via a 13 G blunt cannula connected to a Vaclock 20 mL syringe. The lipoaspirate was injected into and processed using the Lipogems for use .Endoret®(prgf®) Technology  [w/v) sodium citrate. The presence of 2 tubes allowed for balanced centrifugation. The tubes were centrifuged for 8 min at 580 G (1902 rpm) at room temperature. The 2 mL of plasma located above the buffy coat was collected, with a total PRP volume of 4 mL per patient. The PRP was activated by adding calcium chloride (10% w/v). This technique has been shown to yield PRP enriched in platelets and reduced in leucocytes.PRP was prepared for each patient using the , Spain) ,22. EighEither 6 mL of MFAT or 4 mL of MFAT + 2 mL of PRP was injected under ultrasonographic guidance into the hip joint. Once the needle was inside the hip joint capsule, it was kept there until the injection of MFAT and PRP was completed. Following full recovery, the patients were discharged with a physiotherapy protocol.The visual analogue scale (VAS) was used to measure the outcomes for pain and the Oxford hip score (OHS) for function. All patients completed these questionnaires prior to treatment and at three months, six months and one year after the treatment.The VAS is the most commonly used method allowing individuals to measure and monitor pain intensity using a continuous scale of values. Patients are shown a horizontal line that is anchored by two extremes, between 0 and 100 . They are then asked to identify the place along the VAS line representing their current level of pain .The OHS has 12 questions, scored 0–4 with 0 classified as severe and 4 as no symptoms, covering pain and function of the hip . Out of The improvement of patients was defined by the following terms: showing an improvement (responder) or no improvement (non-responder) after the inter-articular injection of MFAT ± PRP into the hip. There were three groups in each outcome parameter, those being super-responder, responder, and non-responder. For the VAS, individuals without improvement were defined as non-responders, and those improving between 1–19 points higher than pre-treatment on the scale were defined as responders, and those who achieved a score higher than 20 or more were categorized as super-responders .For the OHS, patients who did not improve were designated as non-responders, and those who improved by 1 to 7 points higher than before treatment on the scale were classified as responders. An increase of 8 points or more was classified as super-responder .Super-responder groups consisted of individuals where the degree of improvement in these outcome measures has considered a minimum clinically important difference (MCID).The data shown here are reported following treatment and analysis from the dataset. The median pre-operative OA grade was 3 for both the MFAT and MFAT + PRP groups, respectively. The mean pre-operative VAS scores were 44 and the mean VAS at 6-months post injection was 28. The full distribution density of these is displayed graphically in In the MFAT group, of those who completed follow-up, a total of 22 of 35 (63%) responded to the treatment, 14 (64%) being super-responders showing a 20 or more drop in their VAS score for pain .In the MFAT + PRP group, of those who completed follow up, a total of 32 of 44 (73%) responded by showing an improvement to the treatment, with 20 (63 %) being super-responders realizing a 20 or more drop in their VAS score for pain .In the MFAT group, a total of 22 of 27 (81%) responded to the treatment, with 11 (50%) super-responders showing an improvement of 8 or more in the OHS functional score .In the MFAT + PRP group, 15 of 23 (65%) improved with the treatment, with 11 (73%) super-responders showing an improvement of 8 or more in the OHS functional score .The density distribution of the VAS and OHS was plotted as shown in There was a significant reduction in pain in both the MFAT and MFAT + PRP groups. Slightly higher improvements in VAS were recorded in the MFAT group while OHS improved to a similar extent in both groups.The difference in the means is shown in Conversion to total hip replacement (THR).In each of the MFAT and MFAT + PRP groups, 10 patients went on to have a THR as they did not respond to the treatment. Of these 20, most had higher grades of OA (KL 3 and 4). Full details are tabulated below .The values shown here demonstrate the entire probability distribution of the difference in the improvement in VAS between the two treatments. The mean of the differences between the treatments is −9.19. The probability of this difference being a meaningful one with the minimal clinically important difference of VAS = > 20 is 12.1%. This difference is not a significant one and suggests that the treatments are equivalent.The values shown here demonstrate the entire probability distribution of the difference in the improvement in OHS between the two treatments. The mean of the differences between the treatments is −0.145. The probability of this difference being a meaningful one with the minimal clinically important difference of OHS = > 8 is 0.9%. This difference is not a significant one and suggests that the treatments are equivalent.Similarly, for the MFAT + PRP-treated group, We did not observe any infections or thromboembolic events. The most common issues included joint pain and pain at the fat harvest site. Joint pain occasionally required more analgesia than was prescribed as a part of the standard postoperative pack.Here, we have identified similar pain and functional improvements and outcomes between the bioactive substances MFAT vs MFAT + PRP intraarticularly injected into patients with hip OA. Our data demonstrated that there were 91 individuals responding with reduced pain in MFAT and MFAT + PRP groups , the number of super-responders was similar between the two groups (VAS 64% in MFAT versus 63% in MFAT + PRP). Pre-treatment, mean VAS scores were 41 for MFAT and 46 MFAT + PRP, indicating a similar level of joint pain, and by the end of this study, the VAS means in both groups improved by a similar amount . It is also important to note that a total of 20 patients in our cohort went on to have a THA due to the failure of the treatment to improve their condition. These patients had grade 3 and 4 OA. From this small group, we noted that once the hip reaches an advanced state of OA and there is any loss in the sphericity of the joint, the likelihood of improvement with biological therapies diminishes. The hip may indeed be better treated at an earlier stage of arthritis to gain the most benefit.Hip replacement surgery has been demonstrated to be one of the interventions alongside cataract surgery that brings the most dramatic improvement to the quality of life . Hence, In terms of joint function, both MFAT vs MFAT + PRP groups showed notable improvement in OHS at 12 months follow up. Pre-treatment, mean OHS scores were 30 for MFAT and 29 MFAT + PRP, indicating a similar level of joint function, and by the end of this study, the VAS means in both groups improved by a similar amount .It may be important to note that where PRP was added in the combinationally treated group, concomitantly , this meFrom a biological perspective, it is possible that combining PRP with MFAT could synergistically improve the paracrine capacity of the graft. Secretion of complementary cytokines and in some cases identical anti-inflammatory and pro-regenerative molecules such as PDGF and FGF-2 could further promote pain relief whilst enhancing the protective self-response of the joint . In addiThe use of MFAT has already been proven successful in the knee with mild and moderate OA showing improved clinical and functional scores at mid-term follow-up with no treatment-related adverse effects reported. Its ready availability and minimal tissue manipulation allow for maintenance of intact viable MSCs and functional peri-vascular niche in an unaltered micro-architecture, creating delivery of a stable transplantable mini tissue graft ,32. Regarding the combination of MFAT with PRP, some evidence for the potential therapeutic advantage was provided by Smith et al. , who conA recent systematic review of PRP injection alone in patients with hip OA indicated overall improvements in the majority of albeit, limited trials, Ref.  whilst mPreliminary data from a study by Dall’Oca et al.  examininMSC can act ‘intelligently’ and detect microenvironmental changes acting in a paracrine fashion to release a plethora of growth factors and cytokines with immunomodulatory, antimicrobial, angiogenic, and trophic/regenerative effects on tissue ,40, encoRecently, Guo et al.  demonstrIn this multi-factorial disease, higher body mass index clearly can contribute to additional pressure on joints, and through ethnic, genetic, or medical issues, e.g., diabetes condition increases susceptibility to the development of hip OA at an earlier age ,44. Compared with knee OA, the investigation of the overall effects of these injectable therapies on hip pain improvement and protection has been neglected. This is one of the first studies highlighting the potential beneficial therapeutic effects of MFA-based treatment in this condition.Hip OA in women is more often connected to a more complex group of underlying abnormalities and they tend to seek treatment at a later stage; therefore, THA is performed more often in women than in men .Although we have not quantified or included statistical analysis here, overall, women fared better than men and there were more female super responders than male, although the small numbers of individuals within each group and the relatively large missing data points does not allow us to statistically confirm a real-term better response in women. Interestingly, a recent paper by Fossett and Khan  showed tThe main limitation of this study is the absence of a control or a PRP alone group in our sample. This self-selected group did not want to have major surgery when they came to our clinic and were treated with an ultrasound-guided single injection of MFAT or MFAT + PRP. We included all grades of arthritis. It can be argued that this represents a heterogeneous group of disease. Combining the age range of our cohort (42 to 94) as well as the severity of their conditions (KL grade I–IV) makes for many variables and thus makes subgroup analysis difficult. However, this is a pragmatic representation of our clinical practice, and the highly statistically significant improvement of pain, function, and quality of life cannot be ignored.The missingness map and study flow diagrams show an attrition rate of 12% in our data collection. Responder fatigue is a well-documented phenomenon and may introduce bias.In this study, we were unable to perform a gender-bias-mitigated analysis due to missing data points because of poor rate of patient engagement in follow-up.We did not collect and report compositional data on MFAT and PRP. In future studies, it would be important to include these parameters although many current studies still do not contain this information. In this first of its kind clinical study, we have shown the efficacy of MFAT and combinational preparation in successful amelioration of hip pain together with improved joint function in patients treated with OA. Both MFAT and MFAT + PRP intra-articular injections were equally effective in improving VAS and OHS scores over 6–12 months. A larger clinical trial is warranted in order to characterize in detail the effectiveness in patients with different grades of OA, to determine long-term benefits over 2–5 years, and any gender-related differences in response.


Preoperative impaired endogenous analgesia correlates with chronic pain after knee replacement. Preoperative psychological distress is also related with this bad surgical outcome. Persistent pain after total knee replacement is an underestimated outcome leading to significant health burden. Sensory testing has been explored to help surgeons in decision making and better patient selection. Patients with different chronic pain syndromes exhibit a poor descending pain inhibition that can be quantified through experimental paradigms (conditioned pain modulation). A poor preoperative descending pain inhibition response predicted persistence of pain after surgery in previous studies.This study investigated the correlation between a preoperative inefficient endogenous analgesia and a bad postoperative pain outcome (painful prosthesis). One hundred forty-six patients were studied preoperatively by quantitative sensory testing. Conditioned pain modulation was calculated as the relative decrease in pain intensity  during heterotopic painful stimulation.P < 0.004). Correlation between conditioned pain modulation values and postoperative intensity of pain was also established. Besides, a preoperative lower quality of life  predicted a worse pain outcome, too.Approximately 21.2% of patients had a bad pain outcome (painful prosthesis), 6 months after surgery. Preoperatively, 47.9% of patients exhibited an insufficient endogenous analgesia. The probability to develop persistent pain after surgery in that group was higher than that in patients with a sufficient endogenous analgesia . A 4-fold increase in its prevalence is anticipated by 2030 because of the progressive raising of its major risk factors (age and obesity).12 The few published reports about this subject show various incidences of persistent pain after KR surgery (20%–40%), and their definition is rather vague for time of diagnosis, pain assessment (rest vs movement), and impact on function and quality of life.21Chronic pain after KR has not been adequately quantified. Painful prosthesis is defined by the community of orthopaedic surgeons as the persistence of pain in the operated knee after replacement surgery, without any evidence of infection, loosening of components, or knee misalignment.4 Its physiopathology has not yet been elucidated, but preoperative (pain and anxiety), intraoperative (nerve damage), and postoperative (intense pain) risk factors have been proposed. The identification of consistent perioperative clinical risk factors allows us to develop risk scores to inform our patients of their probability of developing persistent postoperative pain23 before some types of surgery.Persistent pain after surgery has been increasingly studied since first reported in the literature in 1998.29 Thus, psychophysical evaluation (sensory testing) has been advocated as a valuable tool in persistent postsurgical pain research and the integration of clinical and experimental data recommended for future quality studies.13In parallel, some research groups have focused their efforts on the study of the relationship between the efficacy of descending inhibitory systems  and the development of persistent pain after surgery. In this way, a poor result in the conditioned pain modulation (CPM) experimental protocol (pain inhibition by heterotopic painful stimulation) or the presence of temporal summation (windup phenomenon) showed significant predictive power.Preoperative identification of patients at risk of developing persistent pain after surgery could allow us to focus research on this patients group and implement (future) preventive strategies only in the susceptible population. The objective of this study is to investigate whether preoperative CPM can predict persistent pain after KR surgery.http://www.clinicaltrials.gov (NCT01811888).From August 2014 to February 2017, 180 patients scheduled for primary total knee arthroplasty were recruited consecutively by the orthopaedic surgery department. Patients were aged older than 18 years. Important exclusion criteria were treatment with antidepressants in the past 3 months, previous surgery on the target knee, and documented peripheral neuropathy. These conditions (previous surgery and neuropathy) could interfere with CPM, and antidepressant drugs are known modulators of descending pain inhibitory systems. A complete list of inclusion and exclusion criteria can be found at All patients gave their written informed consent before enrolment. The protocol fulfilled the requirements of the Spanish Organic Law 15/1999 of December 13, 1999, which regulates the protection of personal data, and was approved by our institution's ethics committee (2013/4728/I). The study was undertaken in accordance with the Declaration of Helsinki and performed according to the principles of the International Conference on Harmonisation Guidelines for Good Clinical Practice (1996 revision) in the European Community.26 The list of patients scheduled for KR was facilitated by the orthopaedic surgery department on a monthly basis. Patients on the list were consecutively contacted by phone to be invited to participate in the study. A first visit (baseline) was arranged to thoroughly inform them about the clinical and experimental aspects of the study. After agreement and informed consent signature, patient-reported outcomes as well as clinical characteristics of patients were provided by patients on case report forms in a quiet office. Afterwards, the experimental CPM protocol was performed in a silent and temperature-controlled (23 ± 1°C) room. All experimental procedures were performed during the week before surgery by a single examiner (Y.S.).This research project was a cohort study, and the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines were used to ensure appropriate reporting.Patients were seen at scheduled study visits at baseline and after 6 months. Between the visits, patients were contacted by phone at 3 months to register their pain scores .The primary outcome was the proportion of patients with persistent pain (NRS >3 at rest) 6 months after surgery. The secondary outcomes included pain scores at rest and in movement  and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 3.1), Neuropathic Pain Symptom Inventory (NPSI), Hospital Anxiety and Depression Scale (HADS), and SF-36 quality of life questionnaire .Conditioned pain modulation was calculated as the negative difference in pain rating between 2 identical noxious “test stimuli” applied first at baseline and then concomitantly with another “conditioning” remote noxious stimulus, with the following formula:9). The pain magnitude of the 30-second “test stimulus” was the mean of 3 stimuli, administered every 10 seconds during stimulation.A decrease in the “test stimulus” pain score from the baseline indicates efficient pain inhibition, expressed as a positive CPM value. The “test” stimulus was a 30-second contact heat stimulus  applied to the volar aspect of the dominant forearm. The intensity of this stimulus was previously estimated for each individual using a short series of ascending and descending thermal stimuli, culminating in the identification of the temperature that induced a pain score of 6 on a 0 to 10 NRS  with a stirring system  for 1 minute. A second assessment of the “test stimulus” was performed during the last 30 seconds of the immersion time, and patients were asked to report pain magnitude 3 times  during this repeated test stimulus.Total knee arthroplasties were performed by 4 different expert orthopaedic surgeons using the same technique, components , and cement . All patients received prophylactic intravenous antibiotic  and were operated on under tourniquet at a pressure of 350 mm Hg with previous exsanguination. A midline skin incision and a medial parapatellar capsulotomy were made.−1) every 6 hours, when needed.All surgeries were performed under spinal anaesthesia with hyperbaric 0.5% bupivacaine (10–15 mg), and patients received a routine intravenous postoperative pain management protocol, consisting of 1 g of paracetamol/6 hours, 50 mg of dexketoprofen/8 hours, 100 mg of tramadol/6 hours, and a femoral and sciatic nerve block . Patients received subcutaneous rescue morphine ; gait training and transfer; and training on stairs, ramps, and obstacles. At 3 weeks, patients who did not achieve 90° of flexion or had a total length deficit continued outpatient therapy; patients who achieved a satisfactory range of motion were discharged with instructions to perform their exercises at home.27) and an estimated 15% dropout ratio. We accepted an alpha risk of 0.05 and a beta risk of 0.2 in a unilateral contrast, assuming a persistent pain after a surgery rate of 44% (highest persistent pain rate described in previous studies) for patients with insufficient endogenous analgesia and a reduction of up to 20% for patients with efficient endogenous analgesia.A study size of 180 patients was chosen based on the assumption of the presence of insufficient endogenous analgesia in 30% of the general population  test, depending on the inherent characteristics of the studied variables. Comparisons of categorical variables were made using the Pearson χ2 test. Comparisons between preoperative and postoperative SF-36 and WOMAC 3.1 questionnaire scores were made with the paired t test or Wilcoxon signed-rank sum test in case of nonnormal data distribution.Data are presented as means and standard deviation, unless otherwise stated. Comparative analysis was made with an independent sample r) as a measure of the strength of the association between the variables studied. If a normal distribution of data was demonstrated, the t test was used to establish whether the correlation coefficient was significantly different from zero, suggesting an association between the 2 variables. Data management and statistical analysis were performed using SPSS v.18.0 .Correlations were calculated using the Pearson correlation coefficient . Of the 176 evaluable patients, the total missing (30 patients) were attributable to different reasons: surgery finally not performed (6), lost to follow-up 6 months after surgery (6), early termination of experimental protocol (2), and experimental protocol not commenced because of out-of-range pain thresholds (16). Figure 2.The mean age (and SD) of the 146 patients who completed the study was 73.1 (7.1) years and 73.3% of them were women, with a mean body mass index of 31.2 (5.4) kg/mMean preoperative pain (and SD) intensity (target knee) measured with an NRS was 3.6 (3.2) at rest and 7.9 (2.0) in movement . 50.7%  of patients and 97.9%  of patients had a pain score more than 3 (NRS > 3) at rest and in movement, respectively, as summarized in Table A broader pain topographic investigation showed that 63.7%  of patients had pain in other locations, with low back pain (with and without leg radiation) and contralateral knee and shoulder pain being the most common. Mean pain intensity in these other body parts was similar to that obtained in the studied knees  compared with men (Table P < 0.001), doubling the proportion found in men. Higher preoperative pain levels in other locations (in movement) were also found in women compared with those in men (P < 0.019), as well as higher preoperative anxiety level .Statistically significant differences in preoperative pain scores (target knee) were observed between women and men, detecting higher pain levels at rest and in movement in women  of patients were treated with paracetamol + nonsteroidal anti- inflammatory drugs (NSAIDs), 13.7%  with a combination of paracetamol + NSAIDs + tramadol, and only 6.2%  with strong opioids added to their treatment (paracetamol + NSAIDs + strong opioids). Surprisingly, 14.4%  of patients received no analgesic treatment at all.The proportion of patients with persistent pain at rest (NRS > 3) at 3 months after surgery was 31.7% , whereas the incidence of persistence of pain at rest at 6 months after surgery (our primary outcome) was 21.2% . This decrease in pain at rest observed 3 months later could not be demonstrated for pain in movement  at 3 and 6 months after surgery, respectively).P < 0.001) compared with preoperative scores , demonstrating a global favourable outcome for KR surgery for quality of life , as summarized in Table Postoperative SF-36 physical and mental component summary scores  were significantly higher . Higher incidences of preoperative depression were also observed in women compared with those in men , but the difference was not statistically significant (P < 0.052), as summarized in Table Women exhibited a higher preoperative incidence of anxiety compared with men  of CPM value was 0.39 1.82), with a range of −6 to +6. A Kolmogorov–Smirnov test showed a , with a Patients with insufficient endogenous analgesia (poor pain inhibition) had CPM values equal or less than 0, whereas patients with positive CPM values were considered to have an efficient endogenous analgesia (strong pain inhibitors). Approximately 47.9%  of patients showed insufficient endogenous analgesia before surgery.No association was found between CPM values and any other variables measured in our study .P < 0.004 (Table P < 0.006).No differences in pain persistence were observed between patients with insufficient endogenous analgesia and those with efficient endogenous analgesia 3 months after surgery. In addition, no early correlation was found between preoperative CPM values and postoperative intensities of pain (at rest or in movement) on the operated knee. However, a correlation was found between preoperative insufficiency of endogenous analgesia and the presence of persistent pain 6 months after surgery, P < 0.038) was also found between preoperative CPM values and pain intensity at rest (not in movement) 6 months after surgery. Thus, patients with lower preoperative CPM values (poor pain inhibitors) exhibited a higher pain level compared with patients with higher preoperative CPM values (strong pain inhibitors).A statistically significant correlation (This study showed that preoperative CPM is able to predict persistent pain after KR surgery in patients with advanced osteoarthritis. Patients with a preoperative low score in CPM protocol (poor pain inhibitors) exhibited a 2-fold increase in the incidence of persistent pain 6 months after surgery. In addition, the only nonexperimental preoperative variable associated with persistence of pain was a low score in the mental component of SF-36 quality of life questionnaire.16Conditioned pain modulation protocol demonstrated that nearly half of the patients (47.9%) had a poor preoperative pain modulation profile . These results are consistent with previous studies in osteoarthritis, which propose CPM as a robust tool for a large age range and reliable for long-term follow-up studies.24 Regarding the ability of preoperative CPM to predict persistent pain after KR surgery, a Danish group revealed no association for CPM values but a good correlation for temporal summation.17 Later on, they demonstrated that a patient group with a high preoperative pain facilitation to inhibition ratio exhibited less pain relief after surgery.18 A more recent study showed lower pain scores after total KR in patients exhibiting hypoalgesia after a cold pressor test and aerobic exercise.25Previous works demonstrated alterations in the pain modulatory profile after KR surgery, with low CPM values in patients with persisting pain and restoration of CPM function in patients without persisting pain.14 but comparison of values obtained in the same population with different CPM protocols (different conditioning and test stimuli used) has been inadequately studied. A recent study showed that intersession reliability was robust for a diverse test and conditioning stimuli . No significant CPM effect was found in the electrical and heat pain thresholds with the cuff conditioning stimulus in contrast to the other pain detection thresholds, suggesting the possibility that the CPM phenomenon could be divided into deep-somatic conditioning stimulus-driven and cutaneous conditioning stimulus-driven circuits, which calls for deeper insights into future studies. Thus, different results when different tools and outcome measures are used cannot be dismissed because they would account for the differences obtained in similar populations studied with different tools.Discrepancies between our findings and those of previous studies could be attributed to differences in the type of conditioning and test stimuli used, as well as the outcome measurement methods used. Results obtained using the cold pressor test as a CPM paradigm may be different from using heat pain as a test stimulus and a hot immersion bath as a conditioning stimulus. Unfortunately, these discrepancies are difficult to explain, and the best CPM protocol is not yet established. Test and retest reliability of the CPM protocol has been proved in a review,28 However, another study did not find any association between the preoperative pain catastrophizing scale and pain intensity 1 year after surgery.11 Anxiety and depression are common preoperative features in surgical population. In our study, female patients (73.3%) exhibited anxiety and depression ; surprisingly, a specific questionnaire for anxiety and depression (HADS) was not able to predict persistent postsurgical pain.Another interesting finding of our work is the presence of a lower preoperative mental component of the SF-36 quality of life questionnaire in patient group exhibiting persistent pain after surgery. Not only clinical but also preclinical studies have consistently identified psychological preoperative risk factors of chronic postsurgical pain, including negative affective constructs, anxiety symptoms, depressive symptoms, pain catastrophizing, and general psychological distress.5 Assuming that nearly 20% of patients will develop persistent postsurgical pain (painful knee arthroplasty), the search for tools addressed to identify the group at risk of developing persistent pain after surgery becomes more important. The osteoarthritis population has been widely studied , but most of the published works are still lacking fusion between experimental and clinical variables. This study aimed to contribute to this research field not only with the CPM paradigm but also associating clinical preoperative and postoperative relevant parameters . Considering CPM alone to help orthopaedic surgeons with decision making will most likely be a reductionist approach; combining CPM with predictive clinical-based algorithms could be the best strategy. After the identification of the best tool to classify KR candidates in different risk groups, a perioperative preventive intervention could be designed to be used only in the high-risk group, avoiding to treat the whole surgical population. Future advances in physiopathology of pain modulation knowledge and its relationship with specific chronic pain syndromes should be based on studies that combine clinical predictive tools with experimental CPM protocols.Knee replacement surgery will be one of the most frequently performed surgical interventions in the near future. Estimations of rates of total KR in European (and other) countries are alarmingly high, and the economic implications will require specific health policies .The authors have no conflicts of interest to declare.


The aim of this study was to report outcomes following mini-open lower limb fasciotomy (MLLF) in active adults with chronic exertional compartment syndrome (CECS).n = 27/38] male) underwent MLLF. There were 21 unilateral procedures, 10 simultaneous bilateral and 7 staged bilateral. There were 22 anterior fasciotomies, five posterior and 11 four-compartment. Early complications were determined from medical records of 37/38 patients (97%) at a mean of four months (1–19). Patient-reported outcomes  were obtained via postal survey from 27/38 respondents (71%) at a mean of 3.7 years (0.3–6.4). From 2013–2018, 38 consecutive patients : superficial infection , deep infection  and wound dehiscence . Eight per cent (n = 3/37) required revision fasciotomy for recurrent leg pain. At longer-term follow-up, 30% (n = 8/27) were asymptomatic and another 56% (n = 15/27) reported improved symptoms. The mean pain score improved from 6.1 to 2.5 during normal activity and 9.1 to 4.7 during sport (both p < 0.001). The mean EQ-5D was 0.781 (0.130–1) and EQ-VAS 77 (33–95). Of 25 patients playing sport preoperatively, 64% (n = 16/25) returned, 75% (n = 12/16) reporting improved exercise tolerance. Seventy-four per cent (n = 20/27) were satisfied and 81% (n = 22/27) would recommend the procedure.Complications occurred in 16% (MLLF is safe and effective for active adults with CECS. The revision rate is low, and although recurrent symptoms are common most achieve symptomatic improvement, with reduced activity-related leg pain and good health-related quality of life. The majority return to sport and are satisfied with their outcome. Chronic exertional compartment syndrome (CECS) is a condition which accounts for up to 34% of exercise-induced leg pain , with anAlthough non-operative management may be effective in some instances , CECS syThe aim of this study was to report outcomes for a consecutive cohort of unselected adults undergoing mini-open lower limb fasciotomy (MLLF) for CECS using a standardised technique. The primary short-term outcome measure was the rate of complications. The primary longer-term outcome measure was patient-reported symptomatic improvement. Secondary longer-term outcome measures included the EuroQol Five-Dimension Three-Level Health Outcome score (EQ-5D) and Visual Analogue Scale (EQ-VAS) , return Patients were retrospectively identified from outpatient records and operating theatre lists Table . Thirty-n = 27/38) were male. Ten patients (26%) had documented medical comorbidities. Of patients for whom data regarding smoking and body mass index (BMI) were available (n = 27/38), 7% (n = 2/27) were smokers and the mean BMI was 29.1 kg/m2 (range 21.0–36.0). All patients reported exercise-induced leg pain preoperatively. Nine patients (24%) had unilateral symptoms and 29 (76%) bilateral symptoms. Sensory disturbance was reported by 11 patients (29%), exercise-induced leg swelling by six patients (16%) and subjective weakness by one patient (3%). The mean duration of preoperative symptoms was 4.9 years  and 71% n = 7/38 weren = 27/38), 93% (n = 25/27) were involved in sport prior to symptom onset, 44% (n = 12/27) playing socially/recreationally and 48% (n = 13/27) playing competitively. However, by the time of surgery, 56% (n = 15/27) were no longer participating in sport as a result of their symptoms, leaving only 37% (n = 10/27) involved in sport .Of patients for whom complete data regarding preoperative sporting participation were available (n = 4), MRI (n = 3) and arterial Doppler ultrasound (n = 1).Thirty-one patients (82%) underwent preoperative compartment pressure measurement (CPM). The remaining seven patients gave a clear and typical history of CECS , and CPM was not considered necessary to confirm the diagnosis. To exclude alternative diagnoses, five of these seven patients underwent other imaging studies as part of their preoperative work-up, including plain radiographs , which was identified using the ‘squeeze test’ . Details regarding post-operative symptom recurrence and severity were recorded. Current symptoms, including pain during normal activity/sport (as above), abnormal sensation at the site of their surgery  and scar satisfaction , were documented. Quality of life was assessed using the EuroQol Five-Dimension Three-Level Health Outcome score (EQ-5D) and Visual Analogue Scale (EQ-VAS) . Particip < 0.05.Statistical analysis was performed using SPSS version 23.0 . The difference between pre- and post-operative pain scores was assessed using the Wilcoxon signed-rank test. Significance was set at n = 4/37), deep infection  and partial wound dehiscence . No instances of post-operative peroneal nerve palsy were documented and no patient required further operative intervention for surgical complications.One patient (3%) did not attend follow-up post-operatively and was excluded. At a mean of four months (range 1–19), complications occurred in six patients (16%), including superficial infection , sensory disturbance  and subjective muscle weakness . Three patients (8%) required a revision fasciotomy for recurrent exercise-induced leg pain (Table Recurrent symptoms were documented in 14 patients 38%), including leg pain  declined to complete the postal survey and five (13%) had moved out-of-region and were uncontactable; the remaining 27 (71%) completed the survey. At a mean of 3.7 years (range 0.3–6.4), eight patients (30%) were asymptomatic. Nineteen patients (70%) had recurrent symptoms, but with 15 (56%) reporting symptomatic improvement, three (11%) reporting no change and only one whose symptoms were worse post-operatively. Twenty patients (74%) were satisfied or very satisfied following their procedure, five (19%) were neutral and two (7%) were dissatisfied. Twenty-two patients (81%) were likely or very likely to recommend the procedure, four (15%) were neutral and one (4%) was unlikely to do so.p < 0.001), and during sport from 9.1 to 4.7  reported recurrent pain post-operatively. However, mean pain VAS during normal activity improved from 6.1 to 2.5 , 16 (64%) returned to their main sport. Five (31%) reached their pre-symptom level of participation, seven (44%) were better than preoperatively (but did not reach their pre-symptom sporting level), and four (25%) were unchanged. Seventy-five per cent (n = 12/16) returned to sport within six months  reported a sustained symptomatic improvement in the longer term. Overall, leg pain improved during both normal activity and sport, and around two-thirds of patients returned to sport post-operatively, three-quarters at an improved level of participation and within six months of surgery.This study documents patient-reported outcomes following MLLF in an unselected consecutive cohort of active adult patients. Despite the modest rate of complications, no patient required early secondary surgical intervention. Three patients underwent revision surgery for recurrent leg pain following their primary procedure. Although recurrent symptoms increased over time, 85% (The rate of complications in our study 16%) is similar to other series reporting on both open % is simi, 10, 18 Despite the prevalence of recurrent symptoms, 85% reported a sustained symptomatic improvement compared with their preoperative level. Although the MLLF technique appears to be effective in reducing pain, most patients reported some degree of leg pain at longer-term follow-up, in keeping with existing studies , 13, 14.Health-related quality of life following MLLF was comparable to age-matched populations . Maffulln = 12), although this may be an avenue for further qualitative research. Future prospective randomised studies should aim to compare outcomes following minimally invasive techniques with traditional open procedures.We acknowledge this study is limited by its retrospective design. Despite good short and longer-term retention rates, loss to follow-up may have restricted our ability to determine factors associated with outcome. Preoperative symptoms were obtained from contemporaneous outpatient records, but preoperative pain scores were recorded at longer-term follow-up and were susceptible to recall bias. Obtaining some desirable baseline data, particularly preoperative patient-reported outcomes, was not possible in the context of this retrospective study. Not all patients underwent preoperative CPM, however, we feel this reflects everyday clinical practice, in which a typical history  can be sufficient to make the diagnosis. It was not possible to explore the reasons why patients with bilateral symptoms elected not to undergo staged contralateral-sided surgery following their index procedure (MLLF is safe and effective for active adults with CECS. The rate of complications and revision procedures is comparable to the existing literature. Recurrent symptoms are common, but most patients report symptomatic improvement and a reduction in activity-related leg pain in the longer term. The majority successfully return to sport post-operatively, report good health-related quality of life and are satisfied with their outcome.


Optimal treatment of nonradiographic axial spondyloarthritis depends on accurate and timely diagnosis of the underlying disease; however, patients present with common symptoms that, in the absence of radiographic changes, may confound diagnosis.In this narrative review, a PubMed literature search was conducted through January 2021, with no date limits, to identify English-language publications discussing classification of nonradiographic axial spondyloarthritis, with an emphasis on clinical features and presentation, differential diagnoses, and mimics of disease. This review describes the epidemiology, clinical features, and burden of disease of nonradiographic axial spondyloarthritis as it relates to the overall axial spondyloarthritis spectrum and discusses mimics and differential diagnoses of nonradiographic axial spondyloarthritis that should be considered when evaluating patients with suspected nonradiographic axial spondyloarthritis in clinical practice.Recognition of clinical features of nonradiographic axial spondyloarthritis, along with an understanding of comorbid conditions such as fibromyalgia, allows for differentiation from its mimics. Appropriate diagnosis of nonradiographic axial spondyloarthritis is important for aggressive management of disease to reduce pain, avoid loss of function, and improve quality of life. Axial spondyloarthritis (axSpA) is an inflammatory disease continuum that ranges from nonradiographic axSpA (nr-axSpA) to radiographic axSpA (r-axSpA), also known as ankylosing spondylitis (AS) . The conHere, we provide an overview of the current understanding of nr-axSpA, with a focus on its proper diagnosis and distinguishing clinical features in light of the variety of potential presenting symptoms and mimics. This narrative review was developed for rheumatologists and the wider population of healthcare providers  who should be aware of nr-axSpA, its mimics, and the potential need to refer to a rheumatologist. We begin with a brief overview of axSpA and the classification of nr-axSpA within this disease spectrum. Subsequently, we discuss the clinical diagnosis of nr-axSpA with a focus on its mimics and differential diagnoses. Finally, we briefly outline the management and treatment of nr-axSpA.A series of PubMed searches between August 2020 and January 2021 were conducted to identify English-language publications of interest. Search terms included  AND , with no date limits. Publications mentioning classification of nr-axSpA, clinical features and presentation (including differences between men and women and between nr-axSpA and r-axSpA), differential diagnoses, and nr-axSpA mimics were considered for inclusion. Additional searches were conducted to further probe specific differential diagnoses. Articles deemed irrelevant based on study type or content diverging from topics of interest were excluded from consideration through review of the title and abstract. Publications cited within relevant articles, as well as any additional studies identified by the authors, were included based on these criteria.Nr-axSpA is a part of the spectrum of axSpA , which iSince 1984, AS has been classified using the modified New York criteria , which rThe classic presentation of nr-axSpA is onset of chronic lower back pain before 45 years of age . HoweverDiagnosis of nr-axSpA is a clinical judgement based on the pattern recognition, clinical reasoning, and summation of evidence by an expert rheumatologist , 23, 24.Assessing human leukocyte antigen B27 (HLA-B27) status is important as positivity is strongly associated with axSpA . GloballLaboratory tests for inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) may be helpful, although their sensitivity (50%) for axSpA is modest .The sacroiliac joint should be imaged by radiography; if nr-axSpA is suspected in the absence of radiographic sacroiliitis, MRI should be performed. MRIs need to be assessed carefully as a substantial proportion of healthy individuals (23%), without current or past back pain, have an MRI positive for sacroiliitis  using thMotivated by long delays in the diagnosis of AS, rheumatologists developed strategies for diagnosing early AS , which may be of utility in the diagnosis of nr-axSpA. The original Berlin diagnostic algorithm gave rise to a system combining the positive/negative likelihoods of individual signs and symptoms to calculate a posttest probability of axSpA Fig.  20, 21], 2120, 2For simplified screening decisions in nonrheumatology practices, we recommend that patients < 45 years old with chronic back pain (≥3 months) are referred to a rheumatologist for suspected nr-axSpA if they have ≥1 of: HLA-B27 positivity, current inflammatory back pain, or sacroiliitis on MRI (sacroiliitis on plain radiography would indicate suspicion of AS) . This siThe diagnosis of nr-axSpA is complicated by the lack of definitive diagnostic criteria, the absence of specific blood biomarkers, and the wide variety of conditions that can lead to chronic backache. Differential diagnosis of nr-axSpA and appropriate referrals to rheumatologists are essential if the long delays in diagnosis are to be reduced.Some conditions mimic nr-axSpA and several, notably fibromyalgia , can co-occur. In our experience, the most common mimics of nr-axSpA and confounders of diagnosis are fibromyalgia and mechanical back pain. The most important mimics of nr-axSpA and their differentiating features are listed in Table Fibromyalgia is an idiopathic syndrome characterized by widespread musculoskeletal pain that is thought to be a clinical manifestation of central sensitization , 40. FibThe criteria for classification and diagnosis of fibromyalgia have evolved over time, resulting in substantial differences in the estimates of prevalence (0.4 to > 11%) and the proportion of female patients (≤60 to > 90%) , 55. TheA higher prevalence of fibromyalgia (10 to 30%) has been reported in patients with rheumatologic diseases , and a rIsolated fibromyalgia can be differentiated from nr-axSpA by the lack of any objective evidence of inflammation in the musculoskeletal system  or elsewhere  and an absence of inflammatory sacroiliitis on MRI , 42. ConThe term “mechanical back pain” is used to describe a symptom and is also used as a diagnosis. Unlike the symptoms of inflammatory back pain, the symptoms of mechanical back pain generally worsen with exercise and improve with rest . It is iDegenerative disc disease, a common cause of mechanical back pain, may mimic nr-axSpA in the absence of associated radicular pain. Because degenerative changes on MRI have been found in a majority of patients with nr-axSpA across all ages , it is aMechanical back pain due to spinal osteoarthritis is more likely in older patients; the prevalence of moderate or severe lumbar facet joint osteoarthritis is reported to be 36% in adults < 45 years old . Co-occuStress fractures (or defects) of the pars interarticularis, causing spondylolysis and subsequent spondylolisthesis, are a potential source of chronic lower back pain . SpondylSacral stress fractures, which can occur post partum or as a sports injury in younger patients, can manifest as chronic lower back pain, which may present similarly to inflammatory back pain associated with sacroilitis , 61. SacSeptic/infectious sacroiliitis is rare but can occur through multiple mechanisms  and with a variety of microorganisms (most commonly staphylococci) –50. SeptScheuermann kyphosis is a potential cause of chronic back pain with onset in early adolescence . LateralA spinal tumor or malignancy, the most common of which is spinal astrocytoma , may cauPatients with familial Mediterranean fever can exhibit several characteristics of nr-axSpA: back pain, sacroiliitis (more likely in HLA-B27–positive patients), peripheral arthritis, and enthesitis , 54. TheClinicians should also be aware that other conditions affecting bone metabolism can mimic the radiographic signs of AS, although these conditions are not always considered in the differential diagnoses of early axSpA or nr-axSpA. Osteitis condensans ilii (OCI) is characterized by a triangular sclerosis on the iliac side of the lower end of the sacroiliac joints and can sometimes be confused for radiographic sacroiliitis . MRI chaDiffuse idiopathic skeletal hyperostosis (or Forestier disease) leads to the ossification of entheses and ligaments and mimics the syndesmophytes associated with AS, particularly in the spine . AlthougNote that patients may assume that backache is part of the universal human condition and not mention it unless askedAsk about the patient’s age at the onset of backache and about its persistencyAsk questions related to the clinical items defining inflammatory back pain: improvement with exercise, pain/waking up at night, alternating buttock pain, insidious onset, age of onset, improvement with NSAIDs, and no improvement with rest , 17Note Obtain blood tests for inflammatory markers (C-reactive protein and erythrocyte sedimentation rate)Test for HLA-B27 Increase suspicion of axSpA if conditions associated with SpA  are present along with backacheOrder imaging studies that include the sacroiliac joints—these are often missed as practitioners tend to focus on the lumbar spineBeware the potential pitfalls of a positive MRI—additional SpA features are required to confirm a diagnosis of nr-axSpA, although a newer data-driven approach to defining positive MRI has been proposedThe following are important considerations for clinical workup of patients with suspected nr-axSpA:The burden of disease experienced by patients with nr-axSpA is similar to that experienced by patients with AS, as is the response to treatment . The mosAlthough certolizumab pegol and 3 other TNFis  have been approved by the European Commission (EC) for the treatment of nr-axSpA, certolizumab was the first biologic approved for this use and is the only TNFi to be US Food and Drug Administration (FDA) approved for nr-axSpA after showing significant, sustained improvement over placebo in the signs and symptoms of nr-axSpA . ClinicaFor patients with suspected fibromyalgia, the patient’s response to treatment may further inform the diagnosis .Current treatments for nr-axSpA can reduce disease activity and improve patients’ physical function and quality of life –30. StudNr-axSpA is not as uncommon as one might suppose from its relatively recent definition. Its prevalence appears to be approximately 0.5% in the general population, which means that it should be kept in mind by healthcare providers beyond the rheumatology specialty when assessing patients with chronic back pain and onset at < 45 years of age. Although the prevalence of nr-axSpA is similar between men and women, women present with more peripheral symptoms, are more likely to have widespread pain and/or fibromyalgia, and have fewer radiological abnormalities than men , 78; as Nr-axSpA is associated with a substantial burden of disease, and diagnostic delays can negatively affect patient outcomes, as untreated chronic inflammation may lead to irreversible damage. A variety of approved treatments are now available, and patients with nr-axSpA should be referred to rheumatologists for appropriate care.


Multimodal pain management protocol effectively relieves pain following simultaneous bilateral total knee arthroplasty (SBTKA) but is associated with administration of large amounts of opioids in the perioperative period. In this prospective, randomized, assessor-blinded, single-surgeon clinical trial, the goal was to validate the efficacy of an opioid-sparing protocol for SBTKA with a reduced opioid dose, while achieving similar pain relief with few adverse events. Fifty-six patients who had undergone SBTKA were randomly allocated to receive either an opioid-sparing or opioid-based protocol. The primary outcome parameters were visual analogue scale (VAS) scores at rest, with movement, and cumulative morphine dose, through time. Secondary outcome parameters included drug-related adverse events and range of motion with continuous passive motion device, through time. In the opioid-sparing group, a lower VAS score with movement at postoperative 24 and 72 h was observed compared with the opioid-based group, but the difference did not reach the minimal clinically importance difference. A reduced cumulative morphine dose was noted in the opioid-sparing group at postoperative 24, 48 and 72 h. In conclusion, the opioid-sparing protocol may be used as an alternative modality for pain management following SBTKA. Similar pain relief effects may be achieved utilizing a reduced cumulative opioid dose, with few opioid related adverse events. However, opioid overdose, addiction and drug-related adverse effects continue to be a challenge for physicians 8. Therefore, efforts have been made to reduce the need for opioids within multimodal analgesia protocols9.Multimodal pain management in total joint arthroplasty has been widely adopted for better pain relief, higher patient satisfaction and faster recovery after surgery11. However, postoperative pain management continues to be a challenge for physicians15. Although it has been validated that pain intensity following SBTKA and unilateral TKA procedures are similar, the narcotics required to relieve the pain during the perioperative period can be 20% higher in patients that underwent SBTKA15. Current studies regarding opioid-sparing protocols consisting of intravenous parecoxib assessed patients that had undergone a unilateral TKA procedure19. As anticipated, intravenous parecoxib was associated with lower pain scores in the postoperative period, compared with the placebo group18. However, the postoperative cumulative opioid doses in the parecoxib group were relatively higher (28.93–48.86 mg) at postoperative 72 h 20, which did not meet the expectation of an “opioid-sparing” effect.Simultaneous bilateral total knee arthroplasty (SBTKA) is a safe, cost-effective and, when successful, highly satisfying procedureTherefore, this trial was designed to validate the efficacy of a multimodal opioid-sparing protocol that consisted of intravenous parecoxib for patients that had undergone SBTKA. These patients were considered more likely to benefit from the opioid-sparing protocol that reduced opioid use and thereby possibly minimize adverse events associated with opioids. The purpose of this study was to compare the efficacy of two standardized multimodal pain management protocols in patients who had undergone SBTKA procedures: (1) an opioid-based protocol, or; (2) an opioid-sparing protocol that consisted of multiple doses of intravenous parecoxib.The hypothesis was that the opioid-sparing protocol will be non-inferior to the opioid-based protocol, in terms of pain scores at various postoperative time points, while the total dosage of opioid rescue for breakthrough pain in the opioid-sparing protocol will be minimal.This randomized, assessor-blinded, single-surgeon clinical trial was performed in a single tertiary referral center. From March 20, 2020 through June 20, 2020, patients who were to undergo SBTKA, were randomly allocated to either an opioid-sparing or an opioid-based multimodal pain management protocol immediately prior to the procedure. The study protocol was approved by the ethics committee of Taipei Veterans General Hospital (IRB-2020-02-008C) and was registered on ClinicalTrials.gov (NCT04314505) on March 19, 2020. The study was conducted according to the Declaration of Helsinki and reported based on the statement of Consolidated Standards of Reporting Trials (CONSORT). No funding was provided for this study. Written informed consent was obtained from all patients recruited into this study.Inclusion criteria for this study: (1) patients 18 years of age, or older, who had undergone a SBTKA procedure for non-inflammatory conditions such as osteoarthritis or spontaneous osteonecrosis of the knee; (2) a signed, informed consent agreement to participate in the study and to be randomly allocated to either the opioid-sparing or opioid-based protocol.2 on at least 2 occasions 90 days apart); (4) severe hepatic impairment (Child–Pugh score ≥ 10 points); (5) chronic opioid-dependent patients  at time of recruitment); (6) coronary artery disease (CAD); (7) peptic ulcer disease; (8) substance abuse , or; 9) refusal to participate in the study.Exclusion criteria of this study were, patients with history of: (1) total knee arthroplasty procedure for inflammatory arthritis, e.g. rheumatoid arthritis, septic arthritis or gouty arthritis; (2) allergy to any medication used in either protocol; (3) chronic renal impairment  in order to generate the random allocation sequence that ensured concealed randomization. The randomization decision was made prior to the surgery. Patients were randomized into two multimodal pain management protocols: opioid-sparing group or opioid-based group. An independent research assistant who collected all postoperative outcome parameters was not aware of the study design or patient allocation.Patients were randomized using the block method to ensure equal sample size across the groups over time. Randomization was performed using an automated, internet-based randomization system: Random Allocation Software  and propofol (1.5–2.5 mg/kg). After loss of eyelash reflex, patients were administered rocuronium (0.6–1 mg/kg) as a neuromuscular blocking agent to facilitate intubation. General anesthesia was maintained with sevoflurane or desflurane throughout to achieve an adequate anesthetic plane. Ventilation was controlled to maintain an end-tidal CO21. Tourniquet pressure was set between 260 and 280 mmHg, dependent upon systolic blood pressure prior to inflation. The maximum pressure was 280 mmHg. The maximum time of tourniquet used on either side was 120 min. Posterior-stabilized, cemented total knee arthroplasty (TKA)  was used in all patients. Standard intramedullary alignment tools were used to perform the femoral cuts. An extramedullary guide was used for the proximal tibial cut. After implantation of the prosthesis, the tourniquet was deflated, a periarticular injection and irrigation were completed, a Hemovac drain was inserted  and wound closure performed. Vicryl #1 suture for the joint capsule and Vicryl #2 for the subcutaneous layer , and 4–0 Polysorb  for the subcuticular suture, were utilized.All SBTKA procedures were performed by a single, high-volume, fellowship-trained surgeon. The surgery was performed under the application of a tourniquet via the mid-vastus approachAfter a general anesthesia procedure was performed, an experienced anesthesiologist performed an ultrasound-guided, single-injection adductor canal block. The patient was placed supine with the operated leg externally rotated and the knee slightly flexed. The proximal end  and distal end  of the adductor canal were identified. The needle was advanced from anterior side through the sartorius muscle, toward the midpoint of the canal, where 10 ml of 0.25% bupivacaine was injected. The sealed group allocation envelope was then opened and the patient was assigned to opioid-sparing or opioid-based group. The package contained instructions on the drugs to give before the operation  device or intravenous parecoxib), data collection sheets and pre-printed prescription labels to be attached to the drug chart.In the opioid-sparing group, a dose of parecoxib sodium  40 mg was administered intravenously immediately after the nerve block procedure. After surgery, parecoxib sodium 40 mg was given intravenously every 12 h, for 4 more doses. The patient was informed that an intravenous bolus of rescue morphine (0.1 mg/kg) was available every 4 h if the pain was intolerable.In the opioid-based group, an intravenous PCA device (Hospira Gemstar PCA Infusion Pump) was applied and initiated right after the nerve block procedure. During the first 72 h postoperatively, analgesia was provided by using IV PCA with morphine (1 mg/mL). The pump was set at a loading dose of 0.05–0.1 mL/kg, an infusion rate of 0.004—0.008 mL/kg/hour, a bolus dose of 0.01–0.02 mL/kg, and a lockout time of 5–12 min. At the anesthesiologist's discretion, an additional antiemetic drug (5 mg of droperidol) was added to the PCA. Following surgery, an anesthesiologist regularly visited the patient and adjusted the infusion rate and bolus dose according to pain intensity and adverse events. The PCA was removed 72 h following surgery.Prior to wound closure, periarticular injection with 10 ml of 0.25% bupivacaine was administered around the knee joint. All patients had oral paracetamol 500 mg, 4 times/day and celecoxib 200 mg, 2 times/day after surgery.22. Patients with: (1) bilateral TKAs; (2) body mass index (BMI) > 30 kg/m2; (3) history of deep vein thrombosis or pulmonary embolism, and (4) varicose vein or stasis dermatitis, were included. This protocol consisted of: (1) an injection of low molecular weight heparin  immediately following surgery, and daily until postoperative day 3, then followed by; (2) low-dose aspirin  for 2 weeks, starting at postoperative day 4.The study followed a protocol for thromboembolism prophylaxisA standardized postoperative protocol was provided for all of subjects. Patients were permitted to ambulate and to bear weight without restrictions as soon as they were able. A continuous passive motion (CPM) device for range of motion (ROM) training was utilized four times a day, followed by ice compression over the surgical site for 15 min. CPM was started at 70 degrees and an additional 10 degrees was added at each session, if the patient could tolerate it. The indwelling Foley catheter was removed on postoperative day 1. The Hemovac drain was removed on postoperative day 2. Patients were discharged on postoperative day 4 or 5, as appropriate.To ensure the success of the assessor-blinded study design, an independent research assistant contacted patients by phone to evaluate pain intensity, at rest and with movement, using VAS scores at five postoperative time points: 6, 12, 24, 48 and 72 h. In determining the efficacy of the opioid-sparing effect the cumulative morphine consumption (mg) in both groups at postoperative 24, 48 and 72 h, was recorded. The maximum ROM, with CPM, that patients could tolerate postoperatively at 24, 48 and 72 h was noted.All drug related adverse events were noted postoperatively for 2 weeks, including: nausea/vomiting, dry mouth, dizziness, pruritus or skin rashes, constipation, dyspepsia or gastrointestinal bleeding, cardiovascular events such as angina or myocardial infarction, signs of fluid retention, e.g. lower leg edema, decreased urine output or urinary retention, respiratory depression, sedation or cognitive impairment. An overall satisfaction scale (0–100 points) was employed 2 weeks postoperatively, with regards to the efficacy and safety of the pain management protocol.23. The power was set to 95% to reduce the risk of type II error. Sample size was calculated in R 3.1.6 with the command pwr.t.test from the package pwr for the primary outcome. Assuming a 20% loss or drop off during the study and setting MCID = 22.6, SD = 20.3 , power = 0.95, and a level of significance of p = 0.05, a sample size of 56 patients, with 28 in each group was adequate to determine clinical significance.The study utilized a non-inferiority design. To estimate adequate sample size necessary to achieve clinical significance, the minimal clinically important differences (MCID) for postoperative VAS score after primary TKA was determined to be 22.6Data were entered and analyzed with SPSS software . Data were represented as mean, range and standard deviation for continuous variables, or number and percentages for categorical variables. Fisher’s exact test was used to compare differences between the two groups for each discrete variable. A value of P < 0.05 was considered statistically significant. The post-hoc power analysis (α = 0.05) of cumulative morphine consumption at different time points was performed using G*Power software .From March 20, 2020 to June 20, 2020, 65 patients who had undergone SBTKA procedures were initially considered for inclusion. Nine patients were excluded for: refusal to participate (N = 4), chronic kidney disease (N = 2), rheumatoid arthritis of the knee (N = 2), and history of CAD N = 1). The 56 patients who met all inclusion criteria were randomly allocated to either an opioid-sparing or opioid-based protocol , and American Society of Anesthesiologists score were similar between the two groups. Both groups had similar operation times and similar total blood loss Table .Table 1P23. VAS scores at all other time points were not significantly different between the two groups  and 72 h (3.50 ± 1.80 vs. 4.93 ± 2.23). However, this difference did not reach the MCID of VAS score for the TKA procedureThe cumulative morphine dose was significantly lower postoperatively in the opioid-sparing group, compared with the opioid-based group, at the three time points measured: 24 h (3.14 ± 2.62 mg vs. 20.99 ± 7.97 mg respectively); 48 h , and 72 h . The post-hoc power analysis revealed that the power was adequate to determine the difference of cumulative morphine dose between the opioid-sparing group and opioid-based group at postoperative 24, 48 and 72 h, with the power values all being 1.0. Patients in the opioid-sparing group had, on average, one dose of rescue morphine, with a cumulative morphine dose of 4.75 ± 4.33 mg at postoperative 72 h. In terms of ROM with CPM, no significant difference at any time point was found , we compared the efficacy of two multimodal pain management protocols which consist of preemptive analgesia, regional nerve block, periarticular infiltration analgesia and systemic administration of various medications. The opioid-sparing protocol was found to be capable of reducing perioperative morphine consumption while maintaining satisfactory pain scores that were similar to the opioid-based group. The postoperative VAS score with movement was lower in the opioid-sparing group compared with the opioid based group, at both times measured. At 24 h, the VAS scores for the opioid-sparing were lower than the opioid-based group . At 72 h, the scores for the opioid-sparing group were again lower than the opioid-based group . In neither case did the difference reach the MCID of VAS scores (2.26) following TKA procedure20. The efficacy of each multimodal pain management protocol can be difficult to assess. One method is to calculate the MME dosage to assess the efficacy of each protocol. Bian et al. conducted a RCT to compare single-dose, preemptive parecoxib versus placebo treatment in patients who had undergone unilateral TKA. The MME was not significantly different in the two Bain groups with parecoxib vs. placebo  trial noted the cumulative opioid dose at postoperative 72 h was lower in the parecoxib group compared with the placebo group . The parecoxib vs. placebo difference has been observed up to 6 weeks after surgery, with parecoxib lower than placebo 16. None of these studies specifically described the regional analgesia modality in their protocol, which is critical in a multimodal pain management protocol24. This could explain the difference in MME reported in these studies25. Sarridou et al. conducted a RCT to compare the efficacy of the combination of parecoxib and continuous femoral nerve block versus placebo after TKA. Cumulative morphine consumption at postoperative 36 h using this combination was less than 10 mg19. Kampitak et al. compared a combination of obturator nerve block and tibial nerve block in addition to a multimodal protocol which consisted of continuous adductor canal block and parecoxib. The cumulative morphine doses at postoperative 48 h in all of the groups were less than 10 mg25. All of the above studies included only patients who had undergone unilateral TKA procedures25. The population reported in this study consisted of patients that had undergone SBTKA, a procedure which normally requires dosages of narcotics up to 20% higher than unilateral TKA, in order to relieve pain15. The opioid-sparing protocol reported here consisted of preemptive analgesia, single-injection nerve block, periarticular infiltration analgesia and systemic administration of medications. In this trial, the cumulative morphine dose at postoperative 72 h in the opioid-sparing group was 4.75 mg, which is much lower than protocols that did not utilize modalities such as nerve block and periarticular infiltration analgesia (MME: 28.93–48.86 mg)20. The results reported here were comparable to protocols consisting of parecoxib plus continuous nerve blocks, in which MME: < 10mg25. Another advantage of this protocol was the utilization of an ultrasound-guided single-injection adductor canal block, which can be less stressful for the patient, as there are no retained catheters, such as the ones seen with PCA or continuous nerve blocks. In addition, the combination of neuroaxial anesthesia to general anesthesia can lead to reduced risk of mortality, pulmonary complications, gastrointestinal complications, acute renal failure and all-cause infections26.The efficacy of parecoxib for pain relief after total joint arthroplasty has been validated in several studies28. In comparison to unilateral TKA, the perioperative opioid dose can increase by up to 20% in a SBTKA procedure15. The goal of using parecoxib, an intravenous cyclooxygenase-2 inhibitor as a non-opioid analgesic in the multimodal pain management protocol is to reduce the incidence of opioid-related adverse events, including nausea and vomiting, dizziness, pruritus, constipation, urinary retention, sedation, impaired cognition, respiratory depression and possible death29. Most of the adverse events from the study reported here were minor with N = 5 in the opioid-sparing group and N = 10 in the opioid-based group.  Cardiovascular events, e.g. myocardial infarction and stroke, and gastrointestinal bleeding are two major adverse events associated with selective cox-2 inhibitors30. Although patients with a history of CAD or peptic ulcer disease are not contraindicated for the use of parecoxib, risk was minimized by excluding such patients from this study. The dose and duration of parecoxib  was also limited. Possibly as a result of this exclusion, no cardiovascular or gastrointestinal bleeding events were observed.Patients that had undergone SBTKA procedures were selected as the study population because of the established need for, yet the potentially adverse impact of, opioids following total joint arthroplasty33. In a review regarding sex differences in pain, there was a trend toward greater post-procedural acute pain in female patients34. Therefore, the efficacy of the opioid-sparing protocol with regards to pain scores and cumulative opioid consumption may have been influenced by the relatively high proportion of females. One significant uniform factor was that all the procedures were performed by a single surgeon with identical postoperative care and pain control protocol, except for the interventions using intravenous parecoxib or PCA.This study has limitations. First, the required number of subjects was calculated based on a non-inferiority design. The non-inferiority margin was set at 22.6 ± 20.3 mm of VAS score, α = 0.05, 1 − β = 0.95 and a loss or drop off rate of 20%. The sample size was adequate to determine a significant difference between the cumulative morphine doses at different time points but not for drug-related adverse events. Indeed, a number of adverse events in each group were recorded. Due to the relatively small sample size, a conclusion regarding adverse effects cannot be drawn, especially for rare adverse events such as respiratory depression or cognitive impairment. Second, it should be noted that the overlapping prescription of two types of COX-II medication in the opioid-sparing protocol does not lead to additional benefits but rather to a higher risk of adverse effect, such as renal impairment. Therefore, the overlapping prescription of two types of COX-II medication cannot be recommended as the standard of care, before adjusting the prescription of COX-II medication in the opioid-sparing protocol. Third, the access to opioids in the two groups was not equal, which could lead to biased results regarding opioid consumption. Fourth, patients were excluded if there was a history of peptic ulcer disease, chronic renal impairment, severe hepatic impairment or coronary artery disease, based on the potential adverse effect of parecoxib. According to the medication package insert, parecoxib is not contraindicated in patients with the above medical diseases but should be used cautiously [Supplementary file]. The generalizability of this study is limited by these exclusion criteria. Fifth, this study was an assessor-blinded design, in which the patient and the ward personnel were not blinded. Potential biases could have occurred with this setting. Sixth, although patients were not selected based on sex, there were more female than male patients included in this study (80.3%). This percentage is generally a higher than most of the current studies, in which the range is 52.8–65.5%Based on the finding of up to 85% reduced cumulative opioid consumption when using the opioid-sparing protocol, accompanied by few drug-related adverse events, and the finding that the opioid-sparing protocol was capable of reducing perioperative morphine consumption while maintaining satisfactory pain scores that were similar to the opioid-based group, it is concluded that an opioid-sparing protocol may be an effective alternative to opioid-based protocols.Supplementary Information.


Temporomandibular joint (TMJ) ‘closed lock’ is a clinical condition causing TMJ pain and limited mouth opening (painful locking). Recent studies suggest an increasing prevalence of degenerative joint disease associated with the onset of TMJ closed lock in adolescents and young adults. Early interventions are recommended, but the curative effect of standard therapies remains controversial. In this retrospective study, an alternative method of non-surgical treatment of TMJ closed lock is presented, and its long-term efficacy has been observed.Forty adolescents and young adults, aged 16 to 30 years old, with distinct combination of symptoms of TMJ closed lock, were enrolled. Patients received anesthetic blockages of the auriculotemporal nerve, then performed mandibular condylar movement exercise for 10 min, and subsequently received hypertonic dextrose prolotherapy in retro-discal area of TMJ. Clinical assessments at baseline and at follow-up  included intensity and frequency of TMJ pain, mandibular range of motion, TMJ sounds, and impairment of chewing.Cone beam CT images of the TMJs revealed joint space changes in all patients and degenerative bone changes in 20% (8/40) of the patients. The patients were diagnosed as having disc displacement without reduction with limited opening. Successful reduction of displaced disc had been achieved in the treatment. And pain at rest and pain on mastication had substantially decreased in all patients and mandibular function and mouth opening had significantly improved since 2 weeks’ follow-up. The overall success rate kept at a high level of 97.5% (39/40) at 6 months and 5 years’ follow-up.The technique combining mandibular condylar movement exercise with auriculotemporal nerve block and dextrose prolotherapy is straightforward to perform, inexpensive and satisfactory to young patients with TMJ closed lock. Temporomandibular joint (TMJ) closed lock is a clinical condition that is mostly attributed to anterior or anteromedial disc displacement without reduction (DDwoR). DDwoR can be a quite debilitating intra-articular disorder, causing significant pain and dysfunction that disturbs the patient’s quality of life with the potential for persistence of symptoms and degenerative joint diseases (DJD) –8. The pIn view of therapeutic effects, and risks and costs associated with more complex interventions, patients with symptomatic TMJ closed lock should be initially treated by the least invasive intervention focusing at speeding up the process of alleviation of pain and of improvement in mouth opening , 11–15. By contrast, in designing this study we scheduled anesthetic block of auriculotemporal nerve to numb TMJ area before exercise procedures. The regional anesthesia can reduce pain and protective muscle splinting, increase the mandibular range of motion, and assist in providing a more manageable treatment , 22. AftForty patients (16–30 years old) were enrolled between Jun 2014 and Jun 2015. All these patients had undergone conservative treatment before this procedure, but did not respond to the same. All the patients and/or their patients gave their informed consent for the treatment. They were assessed clinically and radiographically by a senior oral surgeon. The clinical diagnosis criteria for TMJ closed lock were: joint clicking followed by sudden onset of pain and limited mouth opening without clicking; joint pain and limitation in jaw opening severe enough to interfere with ability to eat; a painful locking duration over a week; history of recurrent lock. Cone beam computed tomography (CBCT) images of the TMJs were obtained and evaluated in consecutive slices. The exclusion criteria were: less than 16 years of age, inability to understand the treatment; history of psychoses; maxillomandibular developmental abnormality.Firstly, the patients received anesthetic blockages of the auriculotemporal nerve with injections of 2 ml 2% lidocaine without vasoconstrictor. The injection method was as follows: 1) mandibular condyle was palpated to find the condylar neck for introduction of anesthesia while patients were instructed to open and close the mouth; (2) then the patients were asked to close the mouth and keep in a resting position; (3) a 35-mm-long and 0.5-mm-diameter needle was inserted about 6 mm anterior to the junction of the tragus and lobule and directed to the lateral bone surface of the condylar neck to deposit 0.5 ml lidocaine; (4) the needle was penetrated around the backside of condyle and into the posterior periarticular tissues to a depth of about 25–28 mm where 1.0 ml lidocaine was deposited; (5) the needle was gradually withdrawn meanwhile the final 0.5 ml lidocaine was deposited. Figure  mandibulSecondly, the patients were guided to perform mandibular condylar movement exercise to achieve sufficient recovery of the mouth-opening in about 10 min. The exercise consisted of repetitive and incremental mouth opening and bi-lateral movement of the mandibular jaw. Patients could use their fingers to pull down on lower tooth while opening the jaw to the greatest extent, or exercise maximum mouth opening and maximum tongue protrusion. Successful reduction of displaced disc was indicated by returning of joint clicking during mandibular condylar movement exercise, and recovery of mouth opening up to 35-mm width. Figure Finally, the patients received injection of 2 ml 50% dextrose as proliferation therapy (prolotherapy) in retro-discal area. Because the auriculotemporal nerve runs around the mandibular condyle’s neck and passes through the retro-discal site of TMJ. The dextrose prolotherapy injection were designed to use the same method as described above in anesthetic blockages of auriculotemporal nerve. Patients were advised to use NSAIDs as well as local application of ice in following days for possible post-treatment pain.Clinical examinations and questionnaires were completed at baseline and at 2 weeks, 2 months, 6 months follow-ups, and a telephone survey was made at 5 years. The effectiveness of treatment was assessed using outcome measures recommended by the International Association of Oral and Maxillofacial Surgeons (IAOMS). Data collection included pain intensity and frequency, jaw range of motion, TMJ sounds, and mandibular function impairment . All comThe initial CBCT image of TMJs revealed joint space changes in all patients and degenerative bone changes in 20% (8/40) of the patients before the treatment. Patients were diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) as having disc displacement without reduction with limited opening (Axis I Group IIb), and DDwoR with concomitant degenerative joint disease (Group IIb/IIIb). The clinical characteristics of the study population are given in Table Under auriculotemporal nerve block, patients could have their displaced disc reduced by self-exercise in the treatment. Significant improvement of pain at rest and pain on mastication were reported two weeks after the treatment. Dull pain due to injection of hypertonic dextrose was reported and could be alleviated effectively by oral analgesics (0.8 ± 2.3 tablets/per patient) in the first two days. Slight numbness at the injection site was reported by 6/40 patients (15.0%) and recovered within a week.Analyses of IAOMS recommended outcome variables by time effect are shown in Table The follow-up CBCT images confirmed more ideal articular fossa-condyle relationship. The dominant location of affected condyles changed from a posterior position to a media position in all patients. Condylar repair was also observed in patients with degenerative joint disease. No progressed condylar bone destruction or condyle deformation were observed. Figure This study was designed to confirm the clinical efficacy of an alternative method of conservative treatments for TMJ closed lock in adolescents and young adults. We innovatively combined mandibular condylar movement exercise with auriculotemporal nerve block and dextrose prolotherapy to improve curative effects. The technique is unique, to the best of our knowledge, in that TMJ closed lock reduction and reinforced articular disc repositioning could be accomplished in one conservative treatment. The therapeutic process is greatly simplified and shortened.As the recommendations of the International RDC/TMD Consortium Network (2014), the episode of TMJ “closed lock” has good diagnostic validity for the disc displacement without reduction with limited opening  . DistincLei J, et al. reported that the prevalence of degenerative TMJ changes could be up to 59.30% in chinses adolescents and young adults with recent-onset disc displacement without reduction . Early dTMJ closed lock start from “mechanical” joint disorder, in which a displaced disc obstructs the forward condylar translation resulting in restricted mouth opening . TheoretAnesthetic block of auriculotemporal nerve can effectively numb TMJ and reduce protective muscle splinting , 22. SubWhen the disc is recaptured through excise therapy, a considerable number of cases will be re-dislocated , 26. We The technique combining mandibular condylar movement exercise with auriculotemporal nerve block and dextrose prolotherapy is straightforward to perform, inexpensive and satisfactory to young patients with TMJ closed lock. Limitations of this study include a relatively small sample size. Larger and randomized controlled trials are required to further determine whether all TMJ closed lock patients respond similarly to the treatment.