Rheumatoid Arthritis (RA) is a chronic disease characterized by severe inflammation that leads to degradation of articular cartilage and the formation of bony erosions. Currently, certain anesthesiologist-led pain management clinics have begun to take on a collaborative role in the treatment of patients with RA, as this progressive disease impairs work capacity due to chronic pain. We present three clinical cases in which platelet-rich plasma (PRP) was used for the treatment of RA in patients seeking a new therapy for pain control and improved range of motion, specifically in certain joints of the hand. The Patient Activity Scale II was employed as a standardized method to assess RA disease severity, recorded on the day of injection, at one month, at three months, and at six months. All of the included patients, ages 49, 60, and 63, had an established diagnosis of RA affecting the proximal interphalangeal and metacarpophalangeal joints of the hand. Over the course of six months, two out of three patients reported a 20% reduction in pain from the initial visit and a 30% improvement in overall well-being. The third patient noted a 50% decrease in pain from the initial visit and a 50% improvement in overall well-being. PRP treatment consistently resulted in functional improvement for each of the three patients treated, while also reducing long term pain and inflammation. Initial clinical and laboratory studies have shown that autologous plasma rich in platelets serves as a source of an abundance of growth factors once activated. The multitude of these growth factors injected into and around the diseased joints improves functionality in patients with RA indicating PRP may be a safe and beneficial therapy in patients with RA primarily affecting the joints of the hand. Rheumatoid Arthritis (RA) is a chronic disease characterized by severe inflammation that leads to degradation of articular cartilage and the formation of bony erosions. A patient with RA primarily presents with significant swelling in the wrists, metacarpophalangeal, metatarsophalangeal, and proximal interphalangeal joints. Unfortunately, this condition affects about five in 1000 individuals worldwide, with a peak incidence in the sixth decade of life. Notably, women are two to three times more likely than men to develop RA over the course of their lifetime [Therapeutic approaches today primarily consist of disease modifying antirheumatic drugs (DMARDs). These agents have been noted to be key components in managing a patient’s RA immediately after the initial diagnosis . HoweverToday, anesthesiologist-led pain management clinics have started to take a more active role in the management of patients with chronic pain as this progressive disease impairs work capacity, leads to disability, and impacts a patient’s psychological state due to chronic pain ,5. The uWe present three clinical cases in which PRP was used for the treatment of RA in patients seeking a new therapy to control their chronic disease. Moving forward we believe that PRP therapy can serve as an additional treatment option, in which the body can use inherent physiologic tools to heal itself after the direct infusion of platelet-rich plasma.MethodsThree patients presenting with RA were treated with activated PRP. At the bedside, peripheral venous whole blood was drawn into 12 mL tube and PRP was created using a Juventix centrifugation systems  protocol by spinning at 3500 revolutions per min for eight minutes, to concentrate the platelets within the tube. Processing allows the visible gel separator within the tube to isolate the platelet-rich plasma clearly above the red blood cells and granulocytes for easy extraction. Next, a 32-gauge meso needle is placed at the top of the vial. An 18-gauge draw needle is then attached to a 10 mL syringe to withdraw the sample, directing the needle directly above the gel separator, thus extracting the entire platelet component.Patients were positioned in a manner that made their injection sites readily accessible for the administration of serum. For injection into the joint, a 7 mL sample of PRP was mixed with 1 mL of lidocaine into a syringe and attached to a 25-gauge needle. Each patient received a standard 0.5 mL dose intra-articularly and a 1.5 mL dose peri-articularly in each affected joint.In addition to clinical examination, the Patient Activity Scale II (PAS-II) was employed as a standardized method to assess RA disease severity. The PAS-II has been studied to be an effective and appropriate generic self-report indicator to assess active rheumatic disease .The survey was recorded on the day of PRP injection, at one month, at three months, and lastly, at six months. The following two questions were primarily used to determine disease severity throughout the course of this report: “How much pain have you had because of your illness in the past week on a scale of 0 to 10?” and “Considering all the ways that your illness affects you, rate how you are doing on the following scale of 0 to 10.” The goal of each of these questions was to serve as an effective assessment tool based on the patient’s mobility and functional capacity to quantify disease activity using patient reported outcomes. The numerical scores were evaluated and compared at each of the four time points.ResultsCase 1A 49-year-old male diagnosed with RA in 2019 presented to the clinic after previously declining initiation of DMARD therapy to treat his condition and subsequently struggled with significantly decreased range of motion, primarily in his hands, for one year before seeking pain management therapy. The patient came to the office in November of 2020 seeking therapeutic treatment of persistent inflammatory RA of the right fourth and fifth metacarpophalangeal joints. At his initial visit, the patient was given a PAS-II survey to complete. He noted “some difficulty” upon standing from a chair, doing outside work, and moving/lifting heavy objects, and reported he could complete the remaining activities “with no difficulty” such as opening car doors and reaching for objects. He reported 7/10 pain with his illness in the previous week. Additionally, he reported feeling at a level of 6/10 when asked about the effect of his illness on his daily functional capacity. On physical exam, the aforementioned joints were visibly swollen and tender to palpation. Per our methods, the patient received 0.5 mL intra-articularly and 1.5 mL peri-articularly.After one month, the patient was re-evaluated and objectively reported increased range of motion and diminished pain in the areas treated with PRP therapy. At three months, using the PAS-II scale, the patient reported only 3/10 pain with his illness and 4/10 overall, in terms of his illness. By six months, the patient felt as though the procedure gave him 100% relief and he rated on PAS-II scale being at 2/10 for pain and at a 1/10 as a whole, in light of the illness. Overall, the patient reported a 50% decrease in pain compared to his initial visit and overall well-being regarding the scope of his RA.Case 2A 60-year-old female diagnosed with RA in 2018, who had declined DMARD therapy with her rheumatologist, was seen in the pain management office in November of 2020 for treatment of her continued pain and inflammation primarily affecting the right third proximal interphalangeal (PIP) joint . At the initial visit, the patient was given a PAS-II survey to complete. She noted “much difficulty” with grasping and moving heavy objects. She reported 6/10 pain from her RA within the past week and again a 6/10 overall rating for her illness. Per our methods, the patient received 0.5 mL intra-articularly and 1.5 mL peri-articularly.After one month, the patient was evaluated again and objectively reported a mild decrease in her pain level, though still with significant restriction in her full range of motion. At three months, using the PAS-II scale, the patient reported 5/10 pain level and 5/10 overall, in terms of her illness. By six months, her PAS-II scale ratings were a 4/10 in terms of pain, and a 3/10 rating for overall daily functional capacity with her disease. Overall, she reported a 20% decrease in pain compared to her initial visit and 30% improvement in overall well-being in the scope of her RA.Case 3A 63-year-old male was diagnosed with RA in 2020 and was referred from his primary care physician to a rheumatologist for management of his condition. He was initially prescribed meloxicam for pain relief and then further sought therapy at our pain management clinic. He was seen in the office in November of 2020 for PRP administration in his afflicted joints - right third metacarpophalangeal (MCP) and right fifth PIP joints. At the initial visit, the patient was given a PAS-II survey to complete. He noted “some difficulty” with opening car doors and doing outside work such as yard work. He reported 4/10 pain from her RA within the past week and again a 4/10 overall illness rating. Per our methods, the patient received 0.5 mL intra-articularly and 1.5 mL peri-articularly into the affected joints.After one month, the patient was re-evaluated and objectively noted an improvement in his range of motion, with only a minor reduction of pain. At three months, using the PAS-II scale, the patient reported 3/10 pain level and 3/10 overall illness rating. By six months, his PAS-II scale ratings were a 2/10 in terms of his pain and a 1/10 regarding the effect the disease had on his overall well-being. Overall the patient reported a 20% decrease in pain compared to his initial visit and 30% improvement in overall daily, functional capacity in terms of his RA.Over the past decade, the application of PRP has substantially grown as a biological treatment for healing and regeneration of damaged tissues. Its effective pathophysiologic response has the potential to mitigate the significant damage caused by RA. Activation of the fibroblast-like synoviocytes (FLS) leads to the formation of “pannus,” a hyperplastic synovial lining that invades the periarticular bone leading to erosions and cartilage degradation . AdditioCurrent treatment options are aimed at the reduction of pain and inflammation to improve the quality of life of these patients, as this disease significantly affects activities of daily living. Since early diagnosis and treatment initiation halts the progression of joint damage in 90% of patients with early RA, a timely diagnosis and effective intervention is critical . PRP hasThe benefits of PRP in the pathogenesis of repair and regeneration in the setting of RA has been largely evaluated in laboratory, preclinical studies. Tong et. al. administered PRP in human rheumatoid FLS cells and found that it effectively altered the production of inflammatory mediators and enhanced neovascularization, which likely accelerates the healing process. PRP also regulates key factors in the P13K/AKT pathway, which is significantly involved in the progressing pathogenesis of the disease . Most noMuch of the clinical data supporting the use of therapeutic PRP has attempted to shed light on the benefits of PRP in treating patients with Osteoarthritis (OA), which shares some similarities in pathogenesis compared to RA, in regards to the pathophysiology of cartilage matrix degradation and progressive joint remodeling , 22. KeyThis report focuses on the use of PRP in RA patients seeking treatment to improve joint pain and inflammation. We present these cases to support the idea that PRP should be considered as an additional therapeutic option in the treatment of both the major biochemical and clinical effects of RA. In our experience, 0.5 mL of intra-articular PRP and 1.5 mL of peri-articular PRP resulted in significant functional improvement six months after injection with promise of sustained improvement. These results were independent of the duration of disease and past or ongoing treatment for these patients. Additionally, no adverse reactions were noted over the six-month follow-up period in the three patients who received PRP treatment. There are very few serious adverse events reported for PRP in the literature, likely due to the autologous nature of the treatment ,26. LimiIn conclusion, the precise mechanism of action of platelet-rich plasma shows promise as an effective agent for the management of RA in patients seeking an adjunct or alternative treatment to DMARD therapy. Initial clinical and laboratory studies have shown that autologous plasma rich in platelets serves as a source of an abundance of growth factors once activated. The multitude of these growth factors directly injected into the diseased joint accelerates healing and improves functionality in patients with RA. PRP is likely to be a safe and beneficial therapy in patients with any stage of RA. Intra-articular and peri-articular administration of PRP in outpatient settings is an easily adoptable treatment strategy, with growing emergence in our Board Certified Pain-Medicine practices. Overall, we believe that PRP should be further evaluated in clinical trials to outline the long-term clinical benefits in the improvement of joint structure and composition, as well as to evaluate the significant improvement expected in quality of life in patients with RA.


The amount and duration of opioids necessary after anterior cruciate ligament reconstruction (ACLR) are inadequately defined. This study sought to prospectively (1) define the amount and duration of opioid consumption, (2) investigate the relationship between preoperative pain expectation and postoperative satisfaction with pain management, and (3) identify risk factors for increased opioid use after ACLR.One hundred eight patients undergoing primary ACLR with hamstring graft were prospectively analyzed for preoperative pain expectation, using visual analog scale (VAS) rating, and postoperative satisfaction with pain management. Univariate and multivariate analyses were done to identify patient characteristics associated with satisfaction and/or amount and duration of opioid use.P = 0.0265) and longer duration (P = 0.0212) of opioid consumption. Baseline opioid users took opioids for twice as long postoperatively  and consumed twice as many tablets  compared with opioid-naive patients.Mean duration and cumulative intake of opioid consumption after ACLR were 5.3 days and 15.3 tablets, respectively. Patients expected moderate postoperative pain: mean preoperative VAS = 68.9. The preoperative VAS rating was associated with a significantly greater amount (This study demonstrated on average 15.3 opioid tablets over 5.3 days provided satisfactory pain management after ACLR. Risk factors for increased opioid consumption included preoperative opioid use. With orthopaedic surgeons ranking the third-highest prescribers across all medical specialties,9 the orthopaedic literature10-12 has increasingly called for minimizing leftover opioid medication and transitioning to multimodal, primarily non–opioid-based postoperative analgesia regimens. Although the development of standardized institutional protocols has been shown to mitigate opioid overprescription after surgery,13-15 there is a paucity of evidence to formulate these for many orthopaedic procedures.Oral opioid medications are frequently prescribed for postoperative pain control after common ambulatory orthopaedic procedures. However, their extended use has not only been shown to increase the risk of short-term and long-term medical complications but also the potential for dependency, abuse, and overdose.17 Recent studies have heightened awareness of opioid consumption after arthroscopic knee procedures. Adolescents and young adults undergoing knee arthroscopy and ligament reconstruction or tibial tubercle osteotomy consumed only one-third of the 51 opioid tablets they were on average prescribed, with 11% requiring no opioids at all and only 1% requesting a refill at 3 weeks.18 The median amount of opioid medication taken after knee arthroscopy is seven tablets, with over 80% of the patients consuming 20 tablets or less.19 ACLR ranked second-highest in opioid prescription duration and highest in prescription refill rate at 7.4 days and 39.3%, respectively, among eight common orthopaedic and general surgical procedures reviewed in a large data repository.20 One goal of newer surgical techniques, such as all-inside ACLR, is to reduce pain and postoperative opioid requirements associated with bone-tunnel drilling. A randomized controlled trial of 150 patients comparing all-inside versus full-tunnel ACLR with allograft found no difference in opioid consumption at 1 week . Conversely, in a recent study, median postdischarge opioid consumption after ACLR with autograft (hamstring or patellar bone-tendon-bone) or allograft was only seven tablets, and 71% of the patients had stopped using opioid medications after 1 week,21 encouraging rethinking of opioid-prescribing regimens.Anterior cruciate ligament reconstruction (ACLR) is one of the most common orthopaedic procedures, with approximately 200,000 operations done in the United States every year.The purpose of this prospective study was to define the amount and duration of opioid and nonopioid medications used and assess patient satisfaction 2 weeks after ACLR with a multimodal analgesia regimen incorporating nonopioid medications and a limited opioid prescription. Our expectation was that these findings could alter opioid-prescribing practices and inform the standardized prescribing guidelines. Our specific goals were to (1) assess preoperative patient expectation of postoperative pain, (2) measure postoperative patient satisfaction with their pain management, (3) quantify the typical amount and duration of opioid consumption, and (4) identify whether preoperative expectation or patient characteristics is associated with postoperative satisfaction or opioid consumption. The a priori hypothesis of this study was that greater than 80% of the ACLR patients would be satisfied with a multimodal pain management regimen incorporating a limited opioid taper.From January 2017 to October 2020, a consecutive cohort of 110 adult patients undergoing primary arthroscopic ACLR with hamstring autograft or allograft were prospectively enrolled at a single academic medical center after institutional review board approval. Exclusion criteria included age younger than 18 years, incomplete follow-up data, open approach, bone-patellar tenon-bone graft, quadriceps tendon graft, revision surgery, and/or multiligament surgery. Informed consent was obtained in clinic for patient participation in the study. Participants completed an electronic questionnaire in clinic. Demographic information and patient-reported outcome scores were collected. In addition, the survey included the Patient Health Questionnaire-2 to screen patients for baseline symptoms of depression and the Pain Self-Efficacy Questionnaire-2 to determine the patient's ability to accomplish daily goals and tasks while experiencing pain. Using a 100-point visual analog scale (VAS), the participants were asked to preoperatively rate their anticipated pain 48 hours after surgery. A score of 0 represented no pain, whereas a score of 100 represented the worst possible pain. Patients again rated their pain on the first postoperative day and at the 2-week postoperative visit. Satisfaction with pain management was assessed with two survey questions asking whether patients believed that their pain was (1) well-controlled and (2) properly addressed by hospital staff. The survey queried patients regarding the preoperative use of opioid medications having a strength equivalent to codeine or greater in morphine-equivalent units.At the 2-week postoperative visit, patients reported opioid and nonopioid consumption for the type of medication used, duration of use, interval and cumulative dose (milligrams), and quantity of tablets used. Satisfaction with pain management was measured on a four-point Likert scale  in response to the following two survey questions: (1) “In the time after surgery, how often was your pain well-controlled?” and (2) “In the time after surgery, how often did the hospital staff do everything they could to help with your pain?” They also completed the Patient Health Questionnaire-2 again at this visit. Patient-reported data were collected in REDCap , which is a browser-based electronic data capture system and subsequently stored in Surgical Outcome System , which is a Health Information Portability and Accountability Act-compliant global registry database.All participants received a preoperative ultrasound-guided adductor canal block and an intra-articular injection of 20 cc of 1% bupivacaine without epinephrine at the conclusion of the procedure. All patients underwent arthroscopic ACLR using an all-inside technique with cortical button fixation done by a single surgeon (E.G.M.). Hamstring autograft or allograft was used in all cases. Meniscal and chondral pathology was simultaneously addressed if present. After surgery, all patients were placed into a cryotherapy cuff, constrained knee brace locked in extension with weight-bearing as tolerated and initiated on a standardized, evidence-based postoperative rehabilitation protocol. Postoperatively, patients received nonopioid prescriptions for acetaminophen and a nonsteroidal anti-inflammatory drug, namely, either ibuprofen or naproxen. They were also prescribed a 20-tablet opioid supply of either oxycodone (5 mg) or tramadol (50 mg), without refills, to use for severe pain only if needed.P values less than 0.10 in bivariate analysis were advanced to multivariable models. Owing to the skewed distribution of the number of tablets and the number of days of opioid medication use, we used a square root transformation in the linear regression model. Satisfaction was analyzed with multivariable logistic regression. All P values less than 0.05 were considered statistically significant. All statistical analyses were done using SAS version 9.4 .Using a convenience sample of 110 subjects, this study was powered to detect between-group differences of approximately 0.54 SD; in other words, if the SD of total tablets of opioid medication was 14, there would be >80% power to detect differences of approximately 7.5 tablets. For continuous variables, this study was powered to detect correlation coefficients of approximately 0.27. Means, SDs, and medians are presented for continuous variables. Number and percent are presented for categorical variables. The associations between continuous outcomes (number of tablets and number of days) and continuous predictors were analyzed with the Spearman correlation coefficient and between continuous outcomes and categorical predictors using the Wilcoxon rank sum test. The associations between categorical outcome (satisfaction) and continuous variables were analyzed using the Wilcoxon rank sum test and between categorical outcome and categorical predictors using the Pearson chi-square test or Fisher exact test. Variables with 2 , no demographic or clinical characteristics were associated with postoperative satisfaction with pain management. Notably, preoperative pain expectation was not predictive of postoperative satisfaction, with an average prospective VAS rating of 72.2 in the “sometimes” or “never” satisfied group versus 67.6 in the “always” or “usually” satisfied group (P = 0.1984)  in response to how often pain was well-controlled after ACLR Table . AlthougMost patients used a combination of nonopioid and opioid medications to manage their postoperative pain. One hundred two patients (94.4%) took acetaminophen, ibuprofen, and/or naproxen after surgery. One hundred patients (92.6%) took at least one opioid tablet, whereas eight patients (7.4%) required no opioid medication.P = 0.0280). Preoperative pain expectation (P = 0.0265), age group , and male sex (P = 0.0418) were also significantly associated with higher opioid tablet consumption in the univariate analysis, although these were not independently predictive in the multivariate analysis (Table P = 0.0340) and preoperative opioid use (P = 0.0480).The mean duration of opioid consumption was 5.3 ± 4.1 days with a mean cumulative intake of 15.3 ± 13.9 tablets. Preoperative opioid users consumed twice as many opioid tablets as their opioid-naive counterparts  and preoperative opioid use (P = 0.0149) were each significantly associated with a longer duration of opioid consumption . Baseline opioid users remained on opioids for twice as long after surgery compared with those who were opioid-naive (10.0 versus 5.0 days).Preoperative pain expectation  define the required amount and duration of opioid consumption, (2) investigate the relationship between preoperative pain expectation and postoperative satisfaction with pain management, and (3) identify risk factors for increased opioid use over a 2-week follow-up period in a cohort of patients undergoing ACLR.This prospective study defined a mean opioid requirement of 15.3 tablets over a mean duration of 5.3 days for patients undergoing primary all-inside ACLR with hamstring autograft or allograft. Patients typically expected moderate postoperative pain, with a mean preoperative VAS score of 68.9. Although preoperative VAS scores had no bearing on postoperative patient satisfaction, they were markedly associated with greater amount and longer duration of opioid consumption. We also found that baseline opioid users remained on opioids for twice as long after surgery and consumed twice as many opioid tablets than their opioid-naive counterparts. Additional risk factors for prolonged duration or increased amount of opioid consumption included age group , male sex, and prior surgery.22 Preoperative opioid use exists in two-thirds of the patients undergoing orthopaedic surgery, which is more pervasive than in any other surgical subspecialty.23 It has been previously associated with higher postoperative opioid consumption in patients undergoing knee arthroscopy for meniscal repair, partial meniscectomy, débridement, chondroplasty, or loose body removal.19 Recently, preoperative opioid use was found to predict markedly prolonged postoperative opioid use and poorer functional outcome scores 6 and 12 months after ACLR.24Preoperative opioid use has previously been shown to confer a greater than sixfold risk of filling an opioid medication prescription 1 year after ACLR.The results of this study have the potential to change clinical practice, minimize the retention and/or circulation of unused opioid tablets, and reduce downstream complications and healthcare costs. They can guide the formulation of procedure-specific opioid-prescribing guidelines, potentially stemming the wave of opioid overconsumption and misuse. They also serve as an impetus for further, similarly designed research studies that aim to define opioid requirements for common outpatient procedures. Our findings also highlight the need for patient-targeted counseling, education, and/or cognitive-behavioral interventions before surgery to gauge, assuage, and, in some cases, redirect patient expectations about the nature and severity of pain they expect to experience after surgery.25 The study group consumed markedly less opioid medication at 6 and 12 weeks, and baseline opioid users were 6.8 times more likely to stop using opioids. Other studies have shown preoperative counseling, modifications to default electronic medical record order sets, and/or pocket reminder cards for clinicians markedly reduce postoperative opioid use after orthopaedic procedures.26-28 As far as prescribers are concerned, multiple studies have shown that relatively few patients recovering from knee or shoulder arthroscopy request a refill after completing their initial prescription.29 Therefore, prescribers should err on the side of minimizing unused tablets because this is not likely to generate a high number of refill requests. Our opioid usage data are consistent with a recent recommendation for a maximum of 20 opioid tablets for 1 week for patients undergoing ACLR.21Our findings are clinically applicable in light of building evidence that preoperative opioid education and expectation-setting can markedly reduce postoperative opioid consumption. A randomized controlled trial of patients undergoing arthroscopic rotator cuff repair at the Rothman Institute recently assessed the efficacy of a formal preoperative education program, which described recommended postoperative opioid use, adverse events, and potential for addiction and dependence.30 Incorporation of patient characteristics may eventually allow for individualized prescribing based on predictive modeling.There are noteworthy limitations to this study. Our study solely included the use of hamstring autografts or allografts, and it is conceivable that patients undergoing autograft harvest with a bone plug might have greater postoperative opioid requirements. Data such as amount and duration of opioid consumption were patient-reported and subject to reporting or recall biases, although the latter is minimized given that data were collected 1 day and 2 weeks after surgery. The Hawthorne effect, which dictates that study participant behavior may be altered because of the awareness of being observed, was minimized by electronically collecting bulk data for multiple arms of this prospective study without specific identification of the study hypothesis. The follow-up period was short-term by design, to define early postoperative opioid requirements, but cannot necessarily be extrapolated to later-term pain management as rehabilitation progresses. Although the identification of independent risk factors for increased opioid use was not the chief goal of this study, our multivariate analysis was underpowered to draw meaningful conclusions.31Strengths of this study include its prospective design, 100% follow-up rate, control of the prescription amount, and standardized technical characteristics, including regional anesthesia, graft and fixation technique, intraoperative anesthetic injection, rehabilitation protocol, and oral analgesic regimen, improving the reliability of our findings and limiting the influence of confounding factors. Furthermore, our interpretation of postoperative pain in the context of a preoperative baseline, which may markedly vary between individuals, achieves normalization and minimizes selection bias.In summary, pain after ACLR can be effectively controlled with a multimodal analgesia regimen incorporating a limited opioid taper of 15 tablets for 5 days, without compromising patient satisfaction. Enumeration of the opioid requirement by well-designed research studies, and increased recognition by both clinicians and patients, is critical for establishing and enacting sound procedure-specific opioid-prescribing guidelines for ACLR. Preoperative interventions involving patient education and expectation-setting should be targeted to at-risk groups. These include patients with heightened preoperative pain expectation and baseline opioid users, the latter of whom consume markedly more opioid medication for a markedly longer duration after ACLR than opioid-naive patients.http://links.lww.com/JG9/A183).In conclusion, this study demonstrated that, on average, 15.3 opioid tablets over a mean of 5.3 days provided satisfactory pain management after ACLR. Risk factors for increased opioid consumption included preoperative opioid use (


Ankylosing spondylitis (AS) is most common in adolescents and the ultimate result is disability, which places a huge burden on patients and society. Therefore, the key to improve the prognosis of AS is the early diagnosis of hip injury. To examine if AS patients whose hip pain is either absent or minimal might already have observable MRI and X-ray hip changes. Clinical and imaging hip data were systematically analyzed in 200 healthy controls (HC) and 300 AS with varying degrees of hip pain. Forty-four patients with early hip osteoarthritis (OA) served as positive imaging controls. In MRI images, BME lesions in the STIR sequence were much more frequent in AS (62%) compared to HC (2%) (p < 0.0001). Most importantly, 42% of AS with no or minimal hip pain had one or more MRI lesions. This was much more frequent compared to the 2% in HC (p < 0.05). These lesions in AS were observed singly or in combination in the trochanters (8%), femoral heads (12%), and acetabula (13%). Parallel finding that X-ray changes were present in patients with minimal or no hip pain was also observed with X-ray. Based on the normal hip width of HC, joint space narrowing was observed in 94.3% of the entire AS cohort, and importantly 56.7% of AS patients with no or mild hip pain. In these latter patients, functional activities of the hips such as walking were normal. At least 40% of AS patients with minimal or no hip pain might already show MRI and X-ray changes. Axial spondyloarthritis consists of two groups of entities, ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis, and non-radiographic axial spondyloarthritis (nr-axSpA). Radiographic sacroiliitis is present in AS but not in nr-axSpA . In the Hip lesions have been reported in 25 to 35 percent of AS patients , 13. TheOne of the major objectives of this project is to examine if patients with minimal or no hip pain might already have X-ray and MRI changes. Investigators can then test if the progression of arthritis can be arrested by more aggressive medical therapies.Two hundred healthy control (HC), 300 outpatients with AS with or without hip pain, and 44 patients with early OA of hips were recruited from the clinics of the Department of Clinical Rheumatology at Xijing Hospital, Xi’an, China. All AS patients fulfilled the 1984 modified New York criteria. Their spondylitis was regarded as being clinically active. None of them were on biologics at the time of evaluation. We follow three steps. The first step is to identify among a list of clinical parameters, the one which by itself is most useful for assessing hip involvement. The second is to identify X-ray parameters that might appear in early hip involvement. The third is to identify corresponding MRI changes. As for comparisons, we also investigate patients with moderate and severe hip pain. For positive controls, we used early hip osteoarthritis.None of AS patients had experienced hip injury or showed non-Spondyloarthritis causes of hip arthritis. Patient with psoriasis or inflammatory bowel disease were excluded from the study. The study and the informed consent have been approved by the ethics committee of the Xijing Hospital of Fourth Military Medical University (ID: 20110303-7).X-rays were taken with subjects in the supine position with the targeted hip(s) at the center of focus. They were instructed to extend their lower limbs, and to rotate them so that the two big toes would touch one another. The upper margin of the image included the superior iliac crests. The lower margin included the upper third of the femurs. Quantitative hip joint width (HJW) measurements were assessed on images in a DICOM viewer. Three sites were measured: superomedial, superolateral, and the point of narrowest part of each hip space. For each patient, the narrowest side of the three measurements was used for comparison to other patients. The team of readers consisted of two radiologists and two rheumatologists. Readers were blinded to the clinical data. In our own cohort, the X-rays of the hips of OA patients were assessed systematically for the following three features: osteophytes, subchondral sclerosis and femoral head deformity.MRI examinations were performed using standard protocols for T1W1 and STIR sequences using a 1.5-T machine . Patients were placed supine with the hip joint in a neutral position. The parameters for T1-weighted images were TR/TE 715/9.5ms, for coronal short-tau inversion recovery (STIR), repetition time was 3550, echo time 51, and inversion time 145ms. Slice thickness was 4 mm. Both hips were included in the same image. Formal readings were preceded by a learning session. In the learning session, MRIs of a randomly selected subset of subjects were read separately by the four experienced readers. We divided the intense STIR signals into the following categories: subchondral acetabular, subchondral femoral head, cysts in acetabula, cysts in the femoral heads, enthesitis at greater trochanter, enthesitis at lesser trochanter. The readers were blinded to the clinical data. Afterwards, the four readers reviewed their scores together and discussed about the discrepancies. This learning session was followed by formal reading of all MRI. Disparities were reviewed together to arrive at a consensus.Analyses were performed using the SPSS 19.0 software . Because the distribution was non-parametric, the Mann-Whitney U test was used for intra-group comparisons. In descriptive analysis, quantitative parameters were expressed as means and standard deviations. Qualitative parameters were expressed as percentages. Principal component analysis (PCA) was used to assess the percent contribution of each of different parameter. Kruskal-Wallis test was used for comparing samples of different sample sizes. Spearman’s rank correlation test was used to evaluate the degree of correlation. The threshold statistic significance was set at p < 0.05.In We first used the parameters in the Harris Score as a clinical tool to assess hip joint disease activity and function. These parameters included hip pain, three separate hip ranges of motion , function, and walking distance. The Harris scores of both AS (77.5 ± 8.7) and OA (81.2 ± 6.4) were significantly lower than those of healthy normal controls (94.1 ± 3.6) (p < 0.0001). In AS, correlation analysis showed that among the variables in the Harris score, a strong correlation was observed only between pain and walking distance . This showed that each parameter was relatively independent of the others. In AS, Harris score did not correlate with age, disease duration, BASDAI, BASMI, BASFI, ASDAS, CRP or ESR (p > 0.5). The lack of correlation to those parameters indicated that for AS, the Harris score was an independent evaluation tool. We used PCA to calculate the percent of contribution of each of the variable within the Harris score to the final score. PCA showed that pain accounted for at least 50% of the total variables. The contribution of the other parameters was relatively even and much less than that from pain. Harris Score divided the intensity of pain into three categories: minimal/none, moderate and severe. For hip pain, in our cohort, 33% of patients reported minimal/no pain, while 28% reported moderate pain, and 39% severe pain. In the OA cohort, 73% reported minimal/no pain, while 21% reported moderate pain, and 6% severe pain.Results are of X-ray features of the hips were tabulated in We systematically evaluated the STIR images of the OA hips for BME lesions in trochanters, superficial subchondral BME lesions in the femoral heads, superficial subchondral BME lesions in the acetabula, deep subchondral BME lesions in the femoral heads, deep subchondral BME lesions in the acetabula, cysts in the femoral heads, and cysts in the acetabula. The lesions designated as cystic were distinguished from the BME lesions by their very distinct outline. Results are tabulated in Hip X-rays were systematically evaluated to determine the following characteristics: osteophytes, subchondral sclerosis and femoral head deformity. The upper half of In the healthy controls, the percent of hips with BME lesions in trochanters, superficial subchondral BME lesions in the femoral heads, deep subchondral BME lesions in the femoral heads, superficial subchondral BME lesions in the acetabula, deep subchondral BME lesions in the acetabula, cysts in the femoral heads, and cysts in the acetabula were observed in only 0%, 1%, 1%, 0%, 0%, 0% and 0%, of all the hips. The corresponding values for AS were 14%, 56%, 38%, 29%, 13%, 0%and 10% respectively Table 3.All parameters except cysts in the femoral head were statistically more frequent in AS than those in the HC group . Interestingly, some of the BME lesions appeared to extend inward from the areas where the femoral heads engaged the labrum Figure 2When we confined our focus on the group of AS patients with minimal or no pain, we observed three differences from the HC group. Firstly, there were 8% in AS with BME lesions in trochanters. Secondly, 36% of AS showed subchondral BME lesions, and 4% of AS showed cystic lesions. All three MRI lesions were practically non-existent in the HC group. Overall, 42% of those with minimal or no pain in the hips showed one or more MRI lesions. Specifically, we did not observe any fat metaplasia.For X-ray features, we first focus on joint width. The lowest width in the HC group is 3.0 mm. If we consider the lowest 95% Percentile, the lowest limit is 4.0 mm. In the group of patients with minimal/no hip pain, 44% have width less than 3.0 mm and 88% have width less than 4.0 mm. When we examine for MRI changes, 58% show at least one MRI change, 39% show more than one MRI changes. The MRI changes and clinical parameters are shown in the accompanying AS places a huge burden on both patients and society. Inflammation of hip joint can eventually lead to bone damage, which result in decreased physical function and psychological disorders such as anxiety and depression. This further results in the need for help at work, increased sick leave and even incapacity. In addition, patients still need to spend a high amount of medical resources. It is important to note that the burden of disease increases with the course of the disease. Acute inflammatory findings on MRI can predict bone structure changes on late radiographs. Patients with early, typical presentation of AS may not have definite X-ray abnormalities, but further MRI examination may reveal early inflammation. Therefore, early diagnosis and treatment are crucial to improve prognosis.Hip involvement has been recognized to be present in 19% to 47% of AS patients in several studies , 19. TheWe know from sacroiliitis that MRI has the potential of showing pathologies before obvious radiographic changes. Two studies are promising in showing that more than 70% of AS patients with clinical hip involvement showed MRI abnormalities , 21. TheWe need to examine if patients with minimal or no hip pain might already have MRI changes. To ensure that we could identify MRI lesions, we first used patients with OA as positive controls. This is because MRI changes have been well described in OA, and typical examples are publically available. We then proceeded to study AS. In MRI images, BME lesions in the STIR sequence were much more frequent in AS (62%) compared to HC (2%) (p < 0.05 to 0.0001). Most importantly, 42% of AS with minimal or no hip pain had one or more MRI lesions. This was much more frequent compared to HC (p < 0.05). These lesions were observed singly or in combination in the trochanters (8%), femoral heads (12%)and acetabula (13%). For X-ray images, the most significant finding is that there was a high correlation between the joint width of the involved hips with hip pain . Using the HC to set the lower limit of normal, narrowing was observed in 94.3% of the entire AS cohort, and importantly 56.7% of AS patients with no or mild hip pain. To our knowledge, narrowing of hip joint width with minimal or no hip pain has not been reported before.In AS, overall disease activity in many patients can be controlled by TNF inhibitors, IL-17 inhibitors or Janus Kinase inhibitors. For TNF inhibitors, early treatment is often considered able to retard radiological vertebral progression. However, this has not been studied in hip studies. Part of the difficulty is that there are no markers for early hip disease. The present study offers several promising parameter for future investigation. Since it is not practical to subject every AS patients to MRI of the hips, we studied the X-ray changes in detail. Our results suggest that some AS patients with no or minimal pain might already show joint width narrowing on X-rays. Our results also showed that some of them might have normal acute phase reactants and low disease activity. In clinical practice, it would be reasonable to submit those patients with narrowed joint width to MRI evaluation of their hip joints. This indicated the joint width is a potentially very cost-effective objective imaging parameter to assess for both the presence as well the severity of hip involvement in AS.The present MRI study adds to the existing information because the cohort is much larger, and because we use healthy control as negative control, and OA as positive control. Further, we categorize patients into groups of symptoms severity.The present study has several shortcomings. The definitions of X-ray and MRI lesions were arbitrarily chosen because there is no standardization available. The method of measuring joint width might vary depending on how the X-rays are taken. In our study, all X-rays were taken with the same protocol. The presence of joint width narrowing in AS is not totally unexpected. What is unexpected is that there is considerable number of patients with joint width narrowing even when they have minimal or no hip pain. Similarly, the presence of MRI changes described is not unexpected. What is unexpected is that they can be present in patients with minimal or no hip pain. Another shortcoming is that we did not detect significant MRI changes with the T1 sequence. This might be partly because we were using a low-resolution machine. Another shortcoming is that the OA we report were used as positive controls. Our OA cohort consisted those with early OA. Any differences between the AS and the OA we observed do not reflect general differences between the two diseases. The most important shortcoming is that this is a cross-sectional study. Any changes we observed might theoretically be transient. However, the study provided parameters which we can use in the future in longitudinal studies.Hip involvement, which occurs in at least 20% of patients with AS, is associated with a high degree of disability. In current clinical practice, accurate diagnosis relies on X-ray, which is usually used only when there is hip pain and probably misses the early cases. This study discovers that AS patients with minimal or no hip pain might already have silent X-ray and MRI changes. Studies are needed to test whether AS patients with X-ray and MRI signs of early hip arthritis should be treated with aggressive medical therapies. The current research provides those X-ray and MRI parameters.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study and the informed consent have been approved by the ethics committee of Xijing Hospital of Fourth Military Medical University (ID: 20110303-7). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.QH and PZ contributed to the conception of the work and completed the first draft and final version of the manuscript. QH, ZZ, KZ, JD, and XB contributed to the design of the work. QH, ZZ, KZ, JD, and XB contributed to the data acquisition and analysis. QH, ZZ, KZ, JD, XB, and PZ contributed to interpretation of data. All authors were involved in the manuscript revision and agreed with final approval of the version, and ensured the accuracy of investigation.This study was funded by the National Basic Research Program of China (2015CB553704) and the National Nature Science Foundation Key Research Project of China (2017YFC0909002).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Due to the lack of normal standards of anorectal manometry in Brazil, data used are subject to normality patterns described at different nationalities. To determine the values and range of the parameters evaluated at anorectal manometry in people, at productive age, without pelvic floor disorders comparing the parameters obtained between male and female. Prospective analysis of clinical data, such as gender, age, race, body mass index (BMI) and anorectal manometry, of volunteers from a Brazilian university reference in pelvic floor disorders. Forty patients were included, with a mean age of 45.5 years in males and 37.2 females (p=0.43). According to male and female, respectively in mmHg, resting pressures were similar ; squeeze pressures  and total squeeze pressures . Men presented significantly higher values of anorectal squeeze pressures, as well as the average length of the functional anal canal . Normal sphincter pressure levels in Brazilians differ from those used until now as normal literature standards. Male gender has higher external anal sphincter tonus as compared to female, in addition a greater extension of the functional anal canal  It is an important examination and used in research centers, clinics or specialized hospitals searching for anorectal disorders1,3,10,18.Anorectal manometry can objectively be focused on the following data: resting and squeeze pressures, functional anal canal length, coordination of muscle relaxation during defecation, as well as the ability to sustain the sphincter contraction, the recto anal inhibitory reflex, rectal sensitivity (minimum volume to induce sensation of evacuation) and maximum rectal capacity (or maximum tolerable volume) ,Due to the lack of studies that demonstrate normal anorectal manometry parameters in our country, the data found in the Brazilian population are subject to normality patterns described by studies of different nationalities,,, Approximately 60% of patients with symptoms of anal incontinence may present normal manometric valuesThis research aimed to determine anorectal manometry values and range in patients, at productive age, without pelvic floor disorders, previous anorectal surgeries or parity, comparing the parameters obtained between the male and female.o. 513190. It is a prospective analysis of clinical data, such as gender, age, race, body mass index (BMI) and anorectal manometry, of volunteers from the outpatient Department of Digestive System Surgery, Hospital das Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil.This study was approved by institutional ethics committee under n2, without known pelvic floor disorders and women without obstetrical history, with normal anal continence and without any ROME III13 criteria for constipation were included in the study. Non-inclusion criteria were patients with diabetes mellitus or who did not consent to perform anorectal manometry or participation.From October 2015 to January 2018, persons of both genders with BMI between 18.5 and 29.9 kg/mThe preparation for anorectal manometry consisted of an evacuation enema at least 2 h before the exam. Volunteers were placed in the left lateral decubitus position (Simms position) with the lower limbs semi-flexed and the head resting on a pillow in a quiet and comfortable environment. The technique used for the anorectal manometry was stationary, in which the catheter was inserted up to 6 cm from the anal merge and traction distally every centimeter to zero.® fluid perfusion manometer, respective software and anorectal catheter with eight radial channels and one distal channel coupled to a balloon (Alacer Biomédica®). The values of all the following parameters were obtained: mean rest pressure, functional anal canal length, mean external anal sphincter contraction pressures and total voluntary contraction in the functional anal canal, retoanal inhibitory reflex, sensitivity (minimum volume to induce sensation of evacuation) and the capacity (maximum tolerable volume) of the rectum according to gender, race and age group to obtain limits and to observe this sample population standard.Anorectal manometry was performed using a Multiplex 2®).Variables descriptive analysis was performed. Quantitative ones were presented in terms of their central (mean) and dispersion (standard deviation and error) values. We adopted as values within normality the average plus or minus 2 standard errors. To compare the male and female, the t test was used and the level of significance was 5%. The statistical software used was SPSS 22.0 for Windows . The mean BMI was 25.46±3.66, been 25.48 for men and 24.43 for women. Regarding race, 90% were white, 5% black and 5% mixed race. The mean values found in the studied population of anorectal manometric parameters are shown in When comparing the genders, it was verified that, according to Analyzing the length of the functional anal canal between genders, this was significantly lower in women compared to men . The lenThe mean rectal sensitivity and capacity did not present statistically significant differences between the genders . There wThe performance of standardized studies in the Brazilian population, either by the selection and exclusion of patients, or by the technique used to perform anorectal manometry, is scarce in our country. Therefore, the Brazilian population adopt reference parameters established in populations quite different from the Brazilians, having no reference of patients without pelvic floor disorders.,,,Analyzing the anorectal manometry data in healthy Brazilian volunteers, without pelvic floor disorders, fecal incontinence or constipation, obesity, obstetric history and previous history of orthopedic and/or colorectal surgeries, it can be verified that the parameters obtained were, in general, different from those considered the international standard by world literatureMorgado et al,,,Lombardo et alLee et alLikewise, in the present study, mean total contraction pressures  and isolated external anal sphincter pressures  were significantly higher in men when compared to women. Among other factors, the greater density of muscle mass and contractile force in male individuals could justify the higher contraction pressuresIn a recent study, Carrington et alRegarding the significant variety of the anorectal manometry test, standardization of technique and results in that same studyThe evaluation of protocols and technical analyzes in different centers of different nationalities shows numerous disparities, which could make even more complicated the use of an anorectal manometric standard established in one country, based on data from other countries. Therefore, in addition to the population limitation, which differs from one nationality to another, there is also a technical limitation to the examination, depending on the protocol adopted by each institution and even on the brand and generation of the equipment used.Based on data collected in the present study, it is verified that the information obtained on anorectal manometry in this sample of the Brazilian population analyzed in a large national institution may explain cases previously considered incontinent in the clinic, but with pressure indexes previously presented as normal, based on data of literature. In addition, the population was controlled to include only non-elderly and non-obese patients, which could influence manometric values,,,,,,It should also be noted that, similarly to the literatureAmong the limitations of the study, we can mention the restriction of the sample, and the use of conventional anorectal manometry apparatus, in detriment of the high resolution. However, it should be emphasized the difficulty of recruiting volunteers for the study and the greater availability of conventional anorectal manometry devices nowadays in Brazil. In addition, the analysis was performed in a homogeneous group of healthy patients, with similar age and body mass index in a single specialized service with high volume of exams.The pressure levels found in a group of controlled people and without pelvic floor disorders are different from those used until then as standards of normality of the literature applied to patients throughout the country. The national standards of anorectal manometry need to be modified and adapted to our reality, so new limits of normality like those obtained in this study are suggested. Male have higher external anal sphincter tonus as compared to female, in addition to the greater extension of the functional anal canal.


Alveolar osteitis (AO) is the most common painful post‐operative complication after tooth extraction. The common modalities used in the management of AO are lavage, placement of medicated dressings, analgesics, and antibiotics. The present study was undertaken to compare platelet‐rich fibrin (PRF) and zinc oxide eugenol (ZOE) for pain relief in AO.t test, and Mann‐Whitney U test.All cases meeting the eligibility criteria received two different treatment modalities over a span of 18 months. At the analysis stage, the final sample size comprised 70 patients, with 35 patients appropriated in each group. Group A patients received ZOE and Group B received PRF. Pain scores were measured on “1st, 3rd, 5th, and 7th” days based on a visual analogue scale (VAS) and compared in both groups of patients. The collected data were analyzed using the chi‐square test, In patients treated with ZOE dressing, the average VAS scores observed were 7.4 ± 1.5, 5.1 ± 1.1, 3.4 ± 0.9, and 2.1 ± 0.7, respectively, on the “1st, 3rd, 5th, and 7th” follow‐up days. In patients treated with PRF, the average VAS score observed were 4.1 ± 1.2, 2.6 ± 0.9, 1.7 ± 0.9, and 0.8 ± 0.8 respectively.Both ZOE and PRF were effective in pain control during the follow‐up period. However, the pain intensity measured as a pain score using VAS was, lower in the PRF group than in the ZOE group on all follow‐up days. Blum defined dry socket as “postoperative pain in and around the extraction site, which increases in severity at any time between 1 and 3 days after the extraction, accompanied by a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis” while, excluding other possible causes of pain in the region.A multifactorial etiology has been suggested for the dry socket which includes oral anaerobic microorganisms, anatomic location, traumatic extractions, immoderate use of irrigating agents at the surgical site, curettage of the extraction socket, mechanical dislodgement of blood clot, fibrinolysis of blood clot, smoking, oral contraceptives, immune suppression, female gender, and vasoconstrictors.The emergence of AO as a common postoperative sequela of extraction has prompted surgeons to explore various treatment options, focusing on optimal healing and control over pain. It is fair to argue that the primary aim in the management of AO should be pain control until normal reparative processes are initiated.Platelet‐rich fibrin (PRF) is a second‐generation platelet concentrate developed by Choukroun et al in 2001.The definitive management of dry sockets remains inconclusive. It has been felt that a meaningful study must be carried out to evaluate the relative effectiveness of two different modalities used for pain management in AO. The present study aimed to compare ZOE and PRF for pain relief in AO.21. Study designThe design of the study was single‐blinded prospective study.2. Sample selection procedureAll cases meeting the eligibility criteria received two different treatment modalities over 18 months. The methods of screening, grouping, interventions, follow‐up, and analysis are summarized in the flow diagram . σ = SD.5. Estimation of sample sizeIn this study,σ) = 0.495.Pooled SD of VAS score at seventh day (Mean différence in VAS score on seventh day between methods (Δ) = 0.33AgeGenderPain based on visual analog scale (VAS)6. Outcome measures2.1Intense throbbing pain in relation to the extraction socket often radiates in nature and tends to increase in severity for a period between 1‐ and 3‐days post‐surgery.Extraction socket denuded the blood clot with or without halitosis.The following features were clinically diagnostic of AO.Group A patients received ZOE and Group B received PRF as the treatment modality. Pain score was measured on “1st, 3rd, 5th, and 7th” days based on a VAS and compared in both groups.In group A patients, ZOE was used as an intra‐alveolar obtundent dressing . .Copious irrigation of the extraction socket was undertaken using a mixture of isotonic saline and povidone‐iodine solution, to clear the socket of any remnants of disintegrated blood clots and debris. A thin paste of ZOE was soaked in a gauze piece and placed in the extraction socket, adhering to aseptic measures. The dressings were changed on “1st, 3rd, 5th, and 7th” days.2.1.1Samples were collected in an autoclavable test tube without anticoagulant and immediately centrifuged at 3500 rpm for 15 minutes until a thick, viscous, fibrous gel was obtained  Figure . CentrifIn all group B patients, local anesthesia was administered using 2% lignocaine with adrenaline at a 1:200,000 concentration. Thorough irrigation of the extraction socket was performed using a mixture of isotonic saline and povidone‐iodine solution. PRF was then placed in the unhealed socket, and the surgical site was closed using a 3‐0 black silk suture. PRF‐treated wounds on seventh post‐operative day demonstrated satisfactory wound healing Figure .2.2t test, chi‐square test, and Mann‐Whitney U test, and a P value <.05, which was defined as the level of statistical significance. SPSS Inc. Released 2007. SPSS for Windows, version 16.0. Chicago. SPSS Inc.The data were entered into Microsoft Office Excel 2007 version and the data were analyzed using SPSS for Windows, Version 16.0.* Qualitative variables are expressed as means, frequencies, and percentages. Qualitative variables were analyzed using the 3The study was approved by the Institutional Ethics Committee, Government Dental College, Thiruvananthapuram, Kerala, India . Informed consent was obtained from all the participants.4The results are summarized in Tables In the present study, among 35 patients in group A, 8 (22.9%) were men and 27 (77.1%) were women. In group B, 9 (25.7%) patients were men and 26 (74.3%) were women. The incidence of AO was more common in females among the treatment groups. There was no significant difference in the number of male and female patients treated in either group. Hence the two study groups were homogenous in terms of sex.P < .01)  Figure .P < .01)  on day 5  on day 7  have been explained.


Video-assisted thoracoscopic surgery (VATS) has been widely used as an alternative for thoracotomy, but the reported incidence of chronic postsurgical pain (CPSP) following VATS varied widely. The purpose of this study was to investigate the incidence and risk factors for CPSP after VATS.We retrospectively collected preoperative demographic, anesthesiology, and surgical factors in a cohort of patients undergoing VATS between January 2018 and October 2020. Patients were interviewed via phone survey for pain intensity, and related medical treatment 3 months after VATS. Univariate and multivariate analysis were used to explore independent risk factors associated with CPSP.P = 0.011), female , education level less than junior school , preoperative pain , consumption of rescue analgesia postoperative , consumption of sedative hypnotic postoperative , and history of postoperative wound infection  were independent risk factors for CPSP development.2348 patients were included in our study. The incidence of CPSP after VATS were 43.99% (n = 1033 of 2348). Within those suffering CPSP, 14.71% (n = 152 of 1033) patients reported moderate or severe chronic pain. Only 15.23% (n = 23 of 152) patients with moderate to severe chronic pain sought active analgesic therapies. Age < 65 years , 2021/04/24 Chronic postsurgical pain (CPSP) is defined as chronic pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, i.e., at least 3 months after the surgery or tissue trauma by International Classification of Diseases-11 (ICD-11) . As trauThe aetiology of CPSP after VATS is multifactorial and may involve both patient- and treatment-related factors. Although some studies have examined perioperative risk factors for the development of CPSP after VATS, most of them focused on a limited number of variables –7. SinceBased on the above reasons, the primary aim of this study was to investigate the incidence of CPSP after VATS in a large sample of patients. The second aim was to identify independently predictors of CPSP from a comprehensive evaluation of demographic, anesthesiology, and surgical factors in a retrospective cohort.This retrospective, observational study was approved by the Institutional Review Board (IRB) for Clinical Investigations at Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School (2020-297-02) and retrospective requirement for written informed consent was waived. This study was registered at Chinese Clinical Trial Registry (ChiCTR2100045765). Patients who underwent VATS between January 2018 and December 2020 at our institution  were identified. Study inclusion criteria were as follows: (1) age ≥ 18 years; (2) American Society of Anesthesiologists(ASA) I–III grade; (3) non-emergency VATS surgery. The exclusion criteria were as follows: (1) patients with previous thoracodorsal surgery; (2) patients underwent bilateral surgery or converted to thoracotomy; (3) patients who developed III/IV/V complications according to Clavien-Dindo grade system; (4) patients with inadequate medical records perioperatively.Data on demographics, medical history, anesthesia/surgery related parameters, perioperative pain-related parameters were collected from an electronic medical records retrieval system.Total intravenous anesthesia protocol was performed. No premedication was administered before surgery. Anesthesia was induced by intravenous midazolam 0.05 mg/kg, 1% propofol 1–2 mg/kg (or etomidate 0.3–0.5 mg/kg), fentanyl 3–8 μg/kg, vecuronium bromide 0.08–0.12 mg/kg. Double-lumen endotracheal intubation was performed under visual laryngoscope. Anesthesia was maintained with continuous infusion of propofol 4–12 mg/kg/h, remifentanil 0.05–0.2 μg/kg/min, cisatracurium 1–3 μg/kg/min. Intravenous patient-controlled analgesia consisted of a combination of sufentanil 1 µg/mL, ondansetron 8 mg, and dexmedetomidine 10 mg at a continuous infusion rate of 2 mL/h and a bolus of 0.5 mL with a lockout interval of 15 min. Based on the anesthesia record sheet, whether using nerve block, dexmedetomidine, and sevoflurane, dosage of fentanyl and remifentanil per kilogram, and intraoperative blood transfusion were collected.VATS was performed by a two-port technique, one port was used as an operating hole and the other as an observation hole. The location of the chest wall incision was selected by surgeons according to the clinical features of patient’s lesion. At the end of surgery, the chest tube was disposed for postoperative thoracic drainage. The etiology of the operation, duration of the operation, whether lymph node dissection was performed and the amount of intraoperative blood loss were collected according to the surgery records.If there were no contraindications, all patients received intravenous injection of propacetamol hydrochloride after operation routinely. If patients complained severe pain, surgeons choosed indomethacin, flurbiprofen axetil injection, codeine phosphate, pethidine or tramadol as rescue analgesics according to the patient’s pain severity. The use of rescue analgesics was extracted from the electronic medical system.Patients were contacted by telephone about whether CPSP developed after VATS. Our list of questions can be divided into two main parts:Did you feel any pain around the surgery scar or the surrounding issue 3 months after VATS?Did you feel pain before surgery? Was the pain 3 months after VATS the same as the preoperative pain?Was there any other cause for the pain ?Part 1. To confirm whether CPSP developed. The following questions were asked:If 0 represents no pain and 10 represents the worst pain you can imagine, which number will reflects your most severe pain 3 months after VATS appropriately?Did you adopt any measure to solve the pain, such as having a rest or reducing daily activity, taking medicine on yourself, asking help from doctors or none ?Part 2. To evaluate the intensity of CPSP and record the patients’ pain relief methods. The following questions were asked:If CPSP was confirmed by part 1, further understanding of the patient's CPSP characteristics could be obtained through part 2. Numerical Rating Scale (NRS) was used to evaluate patients’ pain intensity and the most severe pain could be induced when rest, coughing, moving or others. Pain score ≥ 1 were diagnosed as CPSP .Data were analyzed using SPSS 19.0 . The results were expressed as means ± standard deviation for continuous variables or as number and percentages for categorical variables. The independent t test or Mann–Whitney U-tests were used for between-group testing, depending on the distribution of the variables. Chi-square test tests or Fisher’s exact tests were applied for categorical variables.P-value indicates good calibration. A significance level of 5% (P < 0.05), and confidence intervals of 95% were used [Univariable logistic regression analysis was applied to examine predictors of CPSP after VATS, and candidate covariates were chosen based on statistical significance or possible clinical importance. Multivariate model was developed using a stepwise forward approach. The discriminatory power of the multivariate model was evaluated by using the area under the receiver operating characteristic curve and its 95% confidence interval (CI). The calibration of the multivariate model was evaluated using the Hosmer–Lemeshow goodness-of-fit statistic, where a high ere used .Of 3147 patients who were screened for inclusion, 2738 met the inclusion criteria. When we attempted to contact these patients and assess their postoperative pain, 348 patients were excluded due to unanswered phone calls/refusal to answer, and 42 were excluded due to death. Finally, 2348 patients were included in our analysis .Sociodemographic and medical history of patients were presented in Table P < 0.05).Data about surgery and anesthesia were summarized in Table P < 0.25 in the univariate analysis were entered in the multivariate model. As showed in Fig. P = 0.011), female , education level less than junior school , preoperative pain , consumption of rescue analgesia postoperative , consumption of sedative hypnotic postoperative , and history of postoperative wound infection .Based on statistical significance or possible clinical implication, variates with X2 = 4.956, P = 0.665.The predictive model for CPSP after VATS yield the area under the receiver operating characteristic curve of 0.622 (95% CI 0.599–0.644) Fig. , and theAlthough VATS alleviates some iatrogenic injuries, it is still controversial whether this technique can reduce the risk of CPSP. The reported rates of CPSP after VATS varies widely, such a difference between studies may be related to the methodology , perioperative analgesia regimen and CPSP definition. Additionally, “risk factor” has been a hot spot in the field of CPSP research in recent 10 years . SurgicaIn this study, we investigated the incidence of CPSP after two-ports VATS in 2348 patients. Our study showed that the incidence of CPSP was 43.99%. Most CPSP were mild and bearable, and the incidence of moderate-severe CPSP were 14.71%. The results of multivariate logistic regression analysis showed that age < 65 years, female, education level less than junior school, preoperative pain, consumption of rescue analgesia postoperative, consumption of sedative hypnotic postoperative, and history of postoperative wound infection were risk factors of CPSP.Previously published meta-analysis reported the incidence of CPSP after thoracotomy was 57%, but data about the risk of developing CPSP after VATS were not sufficient to summarize , 15. TheN-methyl-d-aspartic acid receptor or P2X3 receptor, μ/κ subtype splits in the endogenous analgesic system, and brain structure and function between men and women are related to the mechanism of sex differences in pain perception [In terms of demographics data, age < 65 years, female and education level less than junior school were independent risk factors for CPSP. These results were consistent with previously published, known risk factors for CPSP in a variety of surgical procedures, including thoracic surgery , 14, 16.rception . And frorception . Associarception . Anyway,rception .As for perioperative pain-related parameters, our findings revealed that preoperative pain, the consumption of rescue analgesics and sedative hypnotic after surgery were independent predictors for CPSP. The association between preoperative pain and CPSP has been reported in several clinical trials , 13, 22.Postoperative use of rescue analgesics is an important indicator of postoperative pain intensity, especially when pain scores are performed only once or twice a day, the need for rescue analgesics helps in revealing the true level of postoperative pain intensity . ConsistFor surgery related parameters, the history of postoperative wound infection was strongly associated with the occurrence of CPSP. On the one hand, nociceptor neurons themselves can detect pathogens and their related molecular ligands to mediate pain, on the other hand, immune cells secrete multiple cytokines during infection which can lower the threshold of action potentials of nociceptor . In addiGuidelines recommend intravenous use of dexmedetomidine during VATS and a number of studies have found that intraoperative use of dexmedetomidine can reduce pain within 24 h after VATS without significant adverse events , howeverOur study has strengths, including the large sample size and adequate range of risk factors collection. However, the results should still be interpreted cautiously for some reasons, mostly related to its retrospective design and the telephone interview. To solve these, We made a data acquisition table in advance to collect comprehensive and standardized data before, during and after surgery for each patient. During the telephone interview, we assessed patients’ CPSP according to a pre-formulated list of questions, which ensured the homogeneity of the follow-up process. Besides, due to the long follow-up time of CPSP, other authors often use telephone follow-up to obtain relevant data , 35. AddOverall, our study found that the incidence of CPSP after VATS was 43.99%. Although the majority of patients reported mild pain, such a high incidence suggests that CPSP after VATS remains an important challenge that cannot be ignored. In addition, our study found that younger age, female, low education level, preoperative pain, postoperative consumption of rescue analgesics and sedative hypnotic and postoperative wound infection were important predictors of CPSP, which suggested that clinicians should conducted a throughout evaluation perioperatively in order to identify high-risk groups of CPSP as soon as possible and tailor individualized pain prevention and treatment strategies for them.


The treatment of chronic inflammatory and degenerative diseases by low dose radiation therapy (LDRT) is promising especially for patients who were refractory for classical therapies. LDRT aims to reduce pain of patients and to increase their mobility. Although LDRT has been applied since the late 19th century, the immunological mechanisms remain elusive. Within the prospective IMMO-LDRT01 trial (NCT02653079) the effects of LDRT on the peripheral blood immune status, as well as on pain and life quality of patients have been analyzed. Blood is taken before and after every serial irradiation with a single dose per fraction of 0.5Gy, as well as during follow-up appointments in order to determine a detailed longitudinal immune status by multicolor flow cytometry. Here, we report the results of an interim analysis of 125 patients, representing half the number of patients to be recruited. LDRT significantly improved patients’ pain levels and induced distinct systemic immune modulations. While the total number of leukocytes remained unchanged in the peripheral blood, LDRT induced a slight reduction of eosinophils, basophils and plasmacytoid dendritic cells and an increase of B cells. Furthermore, activated immune cells were decreased following LDRT. Especially cells of the monocytic lineage correlated to LDRT-induced improvements of clinical symptoms, qualifying these immune cells as predictive biomarkers for the therapeutic success. We conclude that LDRT improves pain of the patients by inducing systemic immune modulations and that immune biomarkers could be defined for prediction by improved patient stratification in the future. Chronic degenerative and inflammatory diseases, such as osteoarthritis have an increasing prevalence in western countries over the last decades. As the prevalence of these diseases is closely connected to rising mean age in the population, incidence will further increase in the future . The terAs chronic degenerative and inflammatory diseases are heterogeneous, the possible treatment options are very broad and depend on the specific diagnosis and stage of disease. As those diseases are progressive, the therapeutic intervention primarily aims to decelerate the destructive and inflammatory processes and to reduce the pain. Depending on the diagnosis, patients can profit from non-pharmacological treatment strategies, such as orthoses, physiotherapy or a weight reduction. Nonetheless, these options often fail to induce a sufficient pain relief. Therefore, pharmacological interventions with non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), injections or even surgical interventions are considered in advanced stages . Even thEspecially for those patients with insufficient therapeutic responses, low dose radiation therapy (LDRT) is a promising alternate therapy. For over 100 years, LDRT is well-known for the pain relieving effects in joint diseases that can last at least for up to one year . LDRT isEven though the analgesic effects of LDRT are well known, the molecular mechanisms are not yet characterized in detail. As pain is often closely connected to inflammatory processes, a modulation of the inflammatory reaction is very likely a central mechanism of action of LDRT. Indeed, numerous preclinical studies focus on the immunological modes of action of LDRT. In general, it was found that LDRT downregulates preexisting inflammatory and bone degrading processes. Up to today, various immune-modulating mechanisms have been found in preclinical models that support this hypothesis. In leukocytes, LDRT increases the apoptosis rate and reduces the adhesion of the immune cells to the endothelium. Moreover, the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α, as well as chemokines is downregulated and the secretion of anti-inflammatory cytokines, such as TGF-β is enhanced. Especially macrophages seem to be modulated by LDRT, as they reduce the secretion of reactive oxygen species and enhance the clearance of apoptotic cells. In summary, an anti-inflammatory microenvironment is formed by LDRT in the affected tissue –16. In lin vitro studies. On the other hand, a plethora of patient studies are being conducted on the effectiveness of LDRT  was initiated in 2015. This prospective, observatory study aims to unravel the immunological mechanisms underlying LDRT, as well as proving the pain-relieving effects. Informed consent was obtained from all subjects involved in the study.After enrollment, patients undergo a serial irradiation with six fractions of a single dose per fraction of 0.5 Gy delivered over three weeks with at least 48 hours between the fractions. If the patient is not subjectively satisfied with the therapeutic outcome, a second radiation series is applied three months later according to the same scheme as before. Radiation therapy is applied using an orthovoltage technique. In detail, an X-ray device  was used with 180kV and 10mA, a 0.2 mm Cu filter and a focus skin distance of 50 cm. Three months after the completion of LDRT a follow-up visit is performed. As immunological modulations by LDRT are examined in this trial, a detailed immune status was analyzed from peripheral blood. Therefore, patients underwent blood withdrawals at indicated time points before and after every irradiation series, as well as for the follow-up appointment Figure 1The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the Friedrich-Alexander Universität Erlangen-Nürnberg .Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.For this planned interim analyses, 125 out of planned 250 patients suffering from chronic degenerative and inflammatory diseases have been enrolled. All patients received alternative treatments before being referred to the Department of Radiation Oncology of the Universitätsklinikum Erlangen for LDRT. The detailed patient characteristics are listed in In order to determine a detailed immune status from peripheral blood, immunophenotyping was performed. Therefore, whole blood samples were analyzed within three hours after the blood withdrawal by multi-color flow cytometry. Immunophenotyping (IPT) was executed as described in our previously published IPT protocols –24. FigIn order to quantify the pain-relieving effects of LDRT patients filled out a detailed questionnaire on their pain level in different daily situations and times, health status, as well as their quality of life. The pain level (and the morning stiffness) were scored on a visual analog scale (VAS) ranging from 10 = worst pain imaginable to 0 = no pain. As most patients experienced a pain reduction that lasted until the follow-up appointment, patients were asked to score their pain level again retrospectively at least six months after the follow-up appointment, in order to determine long-lasting therapeutic effects.Microsoft Excel was used for data management and GraphPad Prism 9 and IBM SPSS Statistics 24 were used for the statistical analysis.The Wilcoxon test was applied to evaluate the differences in the scoring of the retrospective pain level, the absolute immune cell numbers and the activation status of the immune cells. A p-value of < 0.05 was considered statistically significant.A Spearman’s rank order correlation was performed to analyze the relationship between the pain level and the study time points, as well as the relationship between the immune cell numbers and the pain level. A p-value of < 0.05 was considered as statistically significant. Afterwards, a simple linear regression was performed. For the graphical illustration the mean values of the pain levels Figure 3In order to prove and quantify the pain-relieving effects of LDRT, the patients filled out a questionnaire on their subjective pain level, as well as their health status and quality of life. A more detailed understanding of the pain level was generated by asking for the quality of pain or the pain level in different situations, such as the pain at rest, the pain at night or the morning stiffness. Indeed, differences in the pain level in these different situations were detected. The most prominent findings on the pain level are summarized in The general pain level . This means that with increasing numbers of mDCs in peripheral blood, patients report a reduced pain level . The patients/participants provided their written informed consent to participate in this study.Conceptualization, UG, RF, OO, and BF. Methodology, A-JD, IB, TG, and TW. Software, A-JD, IB, BMF, and MD. Formal analysis, A-JD, BMF, MD, and LM. Investigation, A-JD and TW. Writing—original draft preparation, A-JD. Writing—review and editing, IB and UG. Visualization, A-JD. Supervision, UG and BF. Project administration, BF. Funding acquisition, UG and BF. All authors contributed to the article and approved the submitted version.This work is funded by the Bundesministerium für Bildung und Forschung .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer KL declared a past co-authorship with authors UG and BF to the handling editor.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pain is affecting acceptance of supportive periodontal therapy and primary periodontitis prevention. Our objective was to evaluate the efficacy of a 1-week pre-treatment use of dentinal-hypersensitivity-reducing mouth-rinses (DHM) in periodontal maintenance (SPT) or dental prophylaxis patients.n = 52), arginine (n = 52), or herbal extracts (n = 51). At baseline and reassessment, procedural pain was assessed by visual analogue scale (VAS) and verbal rating scale (VRS). Self-reported efficacy was documented.One hundred fifty-five participants attending for professional mechanical plaque removal (PMPR) were randomly assigned to use a mouth-rinse twice daily for 1 week prior to their next PMPR. Rinses were containing either potassium oxalate (p < 0.05).No inter-group differences were estimated between both test groups and the control for baseline and reassessment means . In the SPT group, VAS reduction and self-reported efficacy were found  contains supplementary material, which is available to authorized users. The medical benefits of professional mechanical plaque removal (PMPR) are well documented for primary and secondary prevention of periodontitis –4. FocusA source of discomfort or pain during PMPR is the mechanical irritation of the dentin-pulp complex. The pain origin is similar to dentine hypersensitivity—the hydrodynamical theory . In the Therefore, the aim of this study was to evaluate the efficacy on procedural pain during PMPR of a 1-week use of two mouth-rinses designed to relieve dentin hypersensitivity prior to PMPR on pain or discomfort in patients ongoing primary or secondary periodontal prevention. Primary outcome was procedural pain during PMPR measured by VAS and VRS, and secondary outcomes were self-reported efficacy and safety.This was a randomized, clinical, single-blind, controlled, parallel-group, investigator-initiated trial conducted in Germany to evaluate the impact of a 1-week pre-operative use of two mouth-rinses designed for dentine hypersensitivity  on pain or discomfort caused by PMPR in maintenance patients . All examinations were carried out at the Department of Operative Dentistry and Periodontology at the University of Cologne. The study was approved by the local ethics review board of the University of Cologne (no. 16-257) and registered (DRKS00010811). All participants gave written informed consent before study-related procedures were carried out.Participants were individually instructed in the use of the mouth-rinses, and written instructions were also provided. The participants were instructed not to use any other kind of mouth-rinse and continue the use of their pre-study dentifrice, toothbrush, and interdental cleaning routine.A study of a continuous response variable from independent control and experimental subjects with one control per experimental subject was planned. In a pre-study, the response within each subject group was normally distributed with standard deviation 1. If the true difference in the experimental and control means is 0.5, 64 experimental and 64 controls are needed to reject the null hypothesis that the population means of the experimental and control groups are equal with the power 0.8. The type I error probability associated with this test of this null hypothesis is 0.05. A priori, an interim analysis was planned after 12 months duration of recruitment and at least 50% of participants included.After the ethical and organizational tasks were fulfilled, the screening began in September 2016. Participants were recruited in the Department of Operative Dentistry and Periodontology at the University Hospital Cologne. Inclusion criteria were (1) risk-based periodontal maintenance or dental prophylaxis patient , (2) recall frequency twice a year (or more), (3) recall appointment third or more, and (4) adult patients (> 18 years old). Exclusion criteria were (1) presence of acute dental pain, pulpitis, or other acute dental infections; (2) caries lesions with invasive treatment need; (3) antibiotic therapy (up to 7 days prior to the study appointments); (4) history of allergic or undesirable reactions to the test products or ingredients; (5) long-term medication with analgetics, (6) diseases or medication influencing inflammation or the immune system (including anti-inflammatory drugs); (7) abuse to alcohol; and (8) pregnant or lactating women.https://prod.tenalea.net/zkskoeln/dm/). Allocation concealment was achieved by having a person not involved in clinical examination (L. V.) distributing the mouth-rinses and giving instructions for use. Examiners were blinded regarding the mouth-rinse used.Block randomization (strata: self-reported pain sensitivity and diagnosis) into three groups was provided by the Institute for Medical Statistics, Informatics and Epidemiology, University of Cologne  and plaque index (PI) were obtained as described in detail elsewhere , 16. PMPParticipants started to use the assigned mouth-rinse 1 week prior to the second PMPR appointment twice daily—in the morning and the evening—for 1 min directly after toothbrushing. The amount of mouth-rinse per use followed the application instructions of the manufacturers . Participants were instructed not to use any other kind of mouth-rinse and continue the use of their pre-study dentifrice, toothbrush, and interdental cleaning routine. They were asked to complete a rinsing diary and document each use of the mouth-rinse including time of use and amount. The diaries were collected and checked for completeness after second study appointment to ensure adherence to the study protocol.Indices and PMPR were proceeded as prescribed above. Additionally, intra-oral soft tissue examination was performed (safety protocol). Again, all participants filled in a questionnaire regarding their self-reported efficacy of the assigned mouth-rinse and the procedural pain via VAS and VRS.p values ≤ 0.05 were considered to indicate statistical significance. Data were typed twice to minimize data entry mistakes. Missing data (drop out) were handled by the last-observation-carried-forward method (LOCF).Between groups differences  were evaluated for baseline, study appointment, and the treatment effect by one-way ANOVA. Within group analysis of the treatment effect was performed by Wilcoxon signed-rank test. Pearson’s chi-square test was used for dichotomous parameters. Additionally, subgroup analyses dividing the groups by initial diagnosis were performed as described above. All analyses were carried out at participant level  using SPSS Statistics 24 Software . A total of 155 participants  completed the trial  in contrast to arginine and control (p > 0.05). Pointing out the responder analysis, dipotassium oxalate showed the highest amount of responders and the lowest amount of non-responders compared to arginine and control group , accompanied by the largest VAS reduction  and a superior intra-group treatment effect (Wilcoxon signed-rank test p = 0.001) in periodontitis patients. None of these effects was found in the gingivitis group . Subgrouping by diagnosis revealed the same results for gingivitis and periodontitis patients . In gingivitis patients, no differences were shown  quit using the assigned mouth-rinse because of bad taste.To our knowledge, this randomized controlled trial is the first to evaluate the efficacy of a 1-week use of mouth-rinses designated for dentinal hypersensitivity as pretreatment to control pain and discomfort during professional mechanical plaque control in patients undergoing primary or secondary periodontal prophylaxis. Even if the dentinal-hypersensitivity-reducing mouth-rinses were not able to achieve a predictable impact on discomfort during PMPR for all patients, dipotassium oxalate proved a pain reduction ability overall and in the periodontitis group but not for gingivitis patients.Focusing VAS responder-analysis, all groups showed around 50% responders, but the dipotassium oxalate users showed noticeable fewer non-responders with 6% than the others . In patients undergoing periodontal supportive therapy, both test groups showed a higher amount of VAS responders which was not found in gingivitis patients.Also, both test groups showed a higher amount of self-reported efficacy, and again the dipotassium group pointed out with the best results. Despite the fact that a predictable impact on pain experience measured by VAS was not found, the subjective efficacy was reported by more than 50% of the participants in the test groups. Thus, our hypothesis was not supported by the primary outcome but proved for self-reported efficacy. Again, this effect was quantifiable for periodontitis patients but limited in the gingivitis group. Even if the measurable pain reduction could not be found, this patient-reported outcome (PRO) is a very valuable information as it reflects the individual perception of the participants. The recent EFP position paper focusing on endpoints of active periodontal therapy demands PROs to be included in studies additional to clinical measurements . PatientThe overall analysis and subgrouping by diagnosis revealed a higher efficacy of the mouth-rinse pretreatment in the periodontitis-group, especially for DPOX. As expected, the occlusion-based active ingredients proved a higher impact on pain reduction in periodontal patients. This may be explained by the already experienced attachment loss accompanied by a higher amount of open dentine tubules. No quantifiable effect could be found for gingivitis patients. For them, procedural pain during PMPR may rather be soft tissue-associated or caused by pain peak sites with dentine hypersensitivity. The prevalence of dentine hypersensitivity is high and affects around one-third of the patients, even in young adults , 21. OneDuring PMPR both—hard and soft tissues—are stimulated and therefore both may be a source of experienced discomfort with individual distribution. As intrapocket anesthesia is a well-documented option to overcome soft tissue pain in a non-invasive manner, hard tissue–related sensations are predominantly controlled by invasive injection anesthesia or in-office use of medical products –25.A meta-analysis focusing the use of desensitizing mouth-rinses to control dentin hypersensitivity was performed in 2017 . Due to We have also carried out a gender-specific subgroup analysis . Both test products belong to well-known brands from the healthcare sector. This may have triggered a positive expectation in patients, which may have been reflected in an overly good evaluation of self-reported efficacy.Based on the sample size calculation, we needed 64 participants per group and included 10% more for drop-outs. During the study, every fifth participant dropped out. That may be attributed to long period between the PMPR appointments with 3 to 6 months depending on risk-based recall frequency ESM 2(DOCX 15 kb)ESM 3(DOCX 11 kb)