Severe pain and impairments in functioning are commonly reported for youth with juvenile fibromyalgia. The prevalence and impact of pain in other diseases commonly managed in pediatric rheumatology comparatively have been rarely systematically studied. The objective of the current study was to determine the extent to which high levels of pain and functional limitations, and the strength of their association, are unique to youth with juvenile primary fibromyalgia syndrome/JPFS) relative to other pediatric rheumatic diseases.Using data from 7753 patients enrolled in the multinational Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry, we compared the levels and association of pain and functional limitations between youth with JPFS and those with other rheumatic diseases.M = 6.4/10, SD = 2.4) and lowest for juvenile dermatomyositis , with pain significantly higher in the JPFS group than any other pediatric rheumatic disease (effect sizes = .22 to 1.05). Ratings on measures of functioning and well-being also were significantly worse for patients with JPFS than patients with any other rheumatic disease (effect sizes = .62 to 1.06). The magnitude of association between pain intensity and functional disability, however, generally was higher in other rheumatic diseases than in JPFS. Pain was most strongly associated with functional limitations in juvenile dermatomyositis, juvenile idiopathic arthritis, and mixed connective tissue disease.Pain levels were rated highest among youth with JPFS (JPFS is unique among conditions seen in pediatric rheumatology with regard to ratings of pain and disability. However, pain appears to be comparably or more highly associated with level of functional impairment in other pediatric rheumatic diseases. Pain in childhood rheumatic disease thus would benefit from increased prioritization for research and treatment. The pprovider –7. Reducprovider . Thus, aFor other medical conditions commonly managed in pediatric rheumatology, levels of impairment in functioning and well-being also can be substantial. For example, children with juvenile dermatomyositis (JDM), systemic lupus erythematosus (SLE), or juvenile idiopathic arthritis (JIA) have significantly reduced scores on measures of health-related quality of life (HRQOL) relative to healthy peers –12. The Multi-site patient registries offer an optimal means of comparing clinical data across conditions. Registries use observational study methods to collect high quality data in naturalistic clinical settings . Data elFor the current study, we used data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry to achieve the following aims: (a) to quantify the occurrence and intensity of pain across a representative sample of pediatric patients diagnosed either with a chronic idiopathic musculoskeletal pain condition (JPFS) or another rheumatic disease; and (b) to determine if the strength of relationship between pain and functioning is unique to JPFS or comparable across diseases seen in pediatric rheumatology. We hypothesized that levels of pain and disability, and the magnitude of their association, would be uniquely high among youth with JPFS relative to youth with other rheumatic diseases.The study was an observational study comprising a retrospective review of data. Data were originally obtained as part of the CARRA Legacy Registry for patients who enrolled and had an initial assessment visit between May 2010 and May 2014 (the time period of active registry recruitment for the CARRA Legacy Registry). The CARRA Legacy Registry is the largest multi-site clinical database of children and adolescents with a rheumatic disease. Data from this registry thus are regarded to be generalizable and ideal for comparing disease characteristics and/or outcomes across diagnoses.Patients from 56 pediatric rheumatology centers in North America contributed data to the CARRA Legacy Registry. Conditions represented in this registry and included for the current study comprised Juvenile Primary Fibromyalgia Syndrome (JPFS), mixed connective tissue disease (MCTD), SLE, JDM, JIA, and central nervous system vasculitis. To be eligible for the registry, patients had to be under the age of 18 years at the time of symptom onset and under the age of 21 years at the time of giving consent to participate. For the current study, we included children and adolescents who were between the ages of 5–21 (inclusive) at the time of consent. For JPFS, patients needed to meet American College of Rheumatology (ACR) criteria (if age 18 and above) or Yunus and Masi criteria –17. EstaRecruitment of patients to participate in the registry was conducted by site research coordinators during new or follow-up outpatient rheumatology visits. Written informed consent and assent (for those above 9 years old) was obtained for all patients agreeing to enroll in the registry. Standardized case report forms were used for data collection at each site. Data sources included medical chart review, physician assessment, and physician/parent/patient completion of subjective measures. Data recorded on the case report forms were manually entered into local databases by site coordinators. Entered data were integrated into a centralized i2b2 data warehouse from which approved registry investigators could request deidentified databases for study analyses . ProceduInformation on patient- or parent-reported demographics , diagnosis, date of symptom onset, date first seen by a pediatric rheumatologist, body mass index, and family history of fibromyalgia and autoimmune disease was recorded on standardized case report forms at the index visit.Patients ages 10 and above were asked to rate the average intensity of pain associated with his/her condition over the past week using a 0–10 numeric rating scale, with 0 being “no pain” and 10 being “very severe pain.” The numeric rating scale is considered a well-established measure for measuring the presence and intensity of pain in pediatric populations . For chiThe Childhood Health Assessment Questionnaire was completed by patients or caregiver proxies (for children younger than 10) as a measure of impact of disease on daily functioning over the past week . This quThe physician global assessment of disease activity (MDGA) was used to quantify disease activity on a 0–10 numeric rating scale, with “0” representing “inactive disease” and “10” representing “very active disease.” d formula. Fisher’s r-to-z transformation was used to compare disease groups on the correlation between pain and functional measures. SPSS® software (IBM) version 24.0 was used for all analyses.Descriptive statistics  were used to summarize data from index visits on patient characteristics, pain intensity, and indices of functional disability across all conditions. Differences in baseline patient characteristics as a function of group (JPFS versus other rheumatic diseases combined) were evaluated using correlations, chi-square analyses, or independent samples t-tests as applicable. Omnibus general linear models were used to compare groups (JPFS versus other rheumatic diseases combined) on pain severity and on each of the functioning measures. In these models, age and MDGA were specified as covariates. If the overall test was significant, the JPFS group was compared to each of the individual rheumatic diseases included in the combined group. Effect sizes for group differences are reported based on Cohen’s M = 13.0, SD = 4.0). Of these, 201 were diagnosed with JPFS and 7552 were diagnosed with another rheumatic disease (Table M = 15.5 versus 13.0), at the time of reported symptom onset (M = 12.1 versus 8.3), and at the time of the first visit to a rheumatologist (M = 13.7 versus 9.2). A significantly higher proportion of females were represented among patients with JPFS (84%) than in other rheumatic diseases (72%). A significantly higher proportion of patients with a reported family history of fibromyalgia or autoimmune disease were represented among patients with JPFS  than in other rheumatic disease . Patients with JPFS on average had significantly greater body mass index (M = 24.2 versus 21.2). There were no other significant differences in measured patient characteristics between the JPFS cohort and other rheumatic disease cohort.Data on patient characteristics for the cohort are presented in Table 2 = 72.15, p < .01. Reported intensity of pain was significantly higher on average for patients with JPFS than for patients with other rheumatic diseases  = 167.9, p < .01. effect size = 1.49). Regardless of diagnosis, the mean pain intensity scores reported at the index visit spanned the entire range from 0 to 10. All conditions also had at least some patients rating pain in the severe range (> 7/10). The proportion of patients reporting severe pain was significantly greater for those in the JPFS cohort relative to the other rheumatic diseases group (54.7% versus 11.7%), χ2 = 324.6, p < .01. Lowest pain ratings were observed for the group of patients diagnosed with juvenile dermatomyositis .Table M = 5.0 vs. 2.5, F  = 66.79, p < .01, effect size = .87), the CHAQ  = 18.68, p < .01. effect size = .72), ACR functional class index  = 49.68, p < .01, effect size = .58), and the HRQOL measure  = 50.90, p < .01, effect size = .92).Table rs = .44–.59). The relationship between pain and ACR functional class scores was significantly stronger for patients with JDM and JIA (r = .44 and r = .36) than for those with JPFS (r = .24). For HRQOL, scores were significantly more strongly related to pain level for youth with JIA and MCTD (r = .51 and r = .55) compared to youth with JPFS (r = .40). Finally, relative to youth with JPFS, there was a significantly stronger relationship observed between pain and well-being ratings for JIA .Table Patients with JPFS were found in this study to reliably report both higher levels of pain and more impairment in functioning than children with any other rheumatic disease. The degree to which pain is associated with impairment in functioning and well-being, however, was found to be variable across rheumatic conditions. Results suggested in particular that the occurrence and level of pain in patients with JIA, JDM, SLE, and MCTD is robustly linked to indicators of greater impairments in functioning.This study further confirms that severe pain and impairment in functioning is typical in youth with JPFS who are seen in pediatric rheumatology clinics. This is a common observation in research on youth with idiopathic chronic musculoskeletal pain , 25, 26.The ability to compare the relationship between pain and indicators of functioning in the current study facilitated some unique findings. Pain in JPFS has a relatively well-established moderate association with functional limitations . PatientUse of data from the CARRA Legacy Registry enabled an evaluation of clinically relevant research questions that otherwise would have been difficult and costly to conduct. This registry provided the infrastructure for secure collection, storage, and sharing of uniformly collected data from multiple informants for over 9000 pediatric rheumatology patients . Cross-cResults of the current study further confirm that pain and impairment in indicators of functioning often are severe in youth with JPFS but may be even more connected with one another in patients with other rheumatic diseases including JIA, JDM, SLE, and MCTD. Pain appears to reliably relate to perceived impairments in typical daily functioning and overall well-being across these conditions. Historically pain has been less routinely assessed or targeted for treatment in many pediatric rheumatic disease relative to more objective indicators of disease activity. Pain and optimal approaches to minimize its impact also have been rarely studied in several of the pediatric rheumatic diseases. However, more routine incorporation of pain and other patient-reported outcomes into patient registries in part is helping to address this –31. Our


We used Analysis of Variance, aChi-Square test and a Likelihood Ratio test. the average age was 42.1 years (17.8); 59.9% were women; the green (58.9%)and yellow (22.7%) risk classification prevailed and hypertension (18.3%)was the most common Comorbidity. The most frequent pain intensity wasmoderate (25.9%). In the red category, patients presented a higherpercentage of absence of pain; in the blue, mild pain; and in the green,yellow and orange categories, there was a greater percentage of intense pain(p < 0.0001). among the patients who presented pain, the majority reported moderateintensity. Regarding risk categories, most patients in the red category didnot report pain. Those who were classified as green, yellow and orange,reported mostly intense pain. On the other hand, patients in the bluecategory reported predominantly mild pain. The demand for these services has increased due to highrates of urban violence, accidents and aging populations with a consequent increaseof chronic diseases,The reception of patients with Risk Assessment and Classification (RRAC) wasimplemented to improve care in Emergency Services and consists of a system ofinitial evaluation of patients’ complaints with the main objective of providing careaccording to the level of severity, and no longer on a first-come, first-servedbasisThe RRAC performed by nurses is a tool to recognize patients who must be assistedwithin the shortest time possible. In the 1990s, several countries adopted andimproved scales to classify patients’ risk. The most recognized international scalesare: the Emergency Severity Index (ESI), the Australasian Triage Scale (ATS), theCanadian Triage Acuity Scale (CTAS) and the Manchester Triage System (MTS). In 2004,the Ministry of Health (MOH) created the QualiSUS Program and the NationalHumanization Policy (PNH), initiating the RRAC in Brazil as based on the Manchesterprotocol. The RRAC scales are different from each other and are often adapted to theplaces where they are used; yet, most of them rank patients into five riskcategories, each category corresponding to a time interval which the patients canwait to receive medical attention, according to the severity of their situationAmong the health professionals authorized to conduct the risk classification process,after proper training, are the nurses. In a brief nursing consultation, thesituation of the patient is evaluated through a physical examination focused on thecomplaints, personal history, and vital signs based on established protocols. Afterthis process, the patient is informed about the estimated waiting time. When thecomplaint is painful, the intensity of the pain should be evaluated according to theprotocol adopted at the institutionPain is a symptomatic response of the organism, being a relevant sign at the momentof the evaluation. The search for emergency services is motivated by painfulcomplaints which can be perceived in different ways. Thus, nurses must be aware ofthe time of their evaluation to provide the best carePain is defined by the American Pain Society as the fifth vital sign, and should beassessed along with temperature, respiratory rate, pulse and blood pressure. Itsevaluation helps to diagnose the problem presented by the patientsPain in the ES, in most cases, is acute and may be related to trauma or inflammatoryprocessesSome obstacles have been identified in the evaluation of painful complaints ofpatients in Risk Classification, including the patients’ impaired ability toreliably report pain due to altered emotional state, anxiety due to the affectedphysical and mental state, and the type of approach by the professionals, becausetechnical language sometimes makes it difficult for the patients to understand whatis said. In addition, in ESs, there are many tasks to be performed in a short periodof time as a result of the excessive flow of patients and need for fast caremeasures that can lead to an impaired evaluation of pain as a vital signThe management of pain in Emergency Services is complex because of its subjectivity,and still remains a challenge. The quality of safe and effective care can avoidcomplications resulting from prolonged pain, as well as provide the patient withgreater comfort in the care in these placesThe objective of this study was to correlate the risk classification categories withthe level of pain of patients in an emergency service. The secondary objective wasto correlate the degree of pain with sociodemographic variables, comorbidities,medical specialty, and signs and symptoms presented by patients who sought emergencycare.This is a cross-sectional study with quantitative analysis carried out in the sectorof Risk Classification of the Emergency Service of the Hospital of São Paulo (HSP),a public university institution of high complexity located in the South Zone of SãoPaulo.RRAC works 24 hours a day, seven days a week and is performed by nurses who make abrief nursing consultation in which the patients are classified and given colorsaccording to severity categories. The RRAC protocol used at the Hospital of SãoPaulo was developed at the institution and is based on the protocol of the Ministryof Health, but uses five severity categories (colors)The sample consisted of 611 digitized records of the patients over 18 years of ageattended at the RRAC during the months of April to June 2014, as part of a master’sproject approved under the CAEE: 05739412910015505. Inclusion criteria were allrecords of patients over the age of 18 attended in the proposed period. Incompleteor illegible records were excluded. Considering that this study was observationaland the collection of patient data was done by means of electronic medical records,not causing any type of interference in the sector or on patient care, the study wasexempted from the need to request informed consent forms, when the project wasapproved. Access to data took place through the Hospital Management System of theInformation Technology Department - HSP, after authorization. The patient dataanalyzed were age, sex, comorbidities, duration of the complaint, medical specialty,signs and symptoms, outcome, color attributed in the risk classification and paingrade according to a numerical scale (NS) varying as follows: without pain (0); mildpain (1 - 4); moderate pain (5-7) and severe pain (8-10)The software used for analysis was the Statistical Package for Social Sciences(SPSS), version 19. Descriptive analysis was used for sociodemographiccharacterization, color attributed in the risk classification, duration of thecomplaint and comorbidities. For the continuous variables, we calculated the mean,standard deviation, median, minimum and maximum and for categorical variables,frequencies and percentages. Analysis of Variance (ANOVA) was used to compare painintensity with age. Pain intensity was correlated with sex, signs and symptoms,history of cancer, category of risk classification and medical specialty using theChi-Square test and when necessary the Likelihood Ratio test. A significance levelof 5%  was adopted.Among the 611 patient records analyzed in this study, the mean age was 42.1 (17.84)years; the majority were women 366 (59.9%); and the duration of complaint to receivecare ranged from 1 to 365 days. Patients were classified in risk classificationcategories as follows: green (58.9%); yellow (22.7%); orange (7.9%); blue (5.9%) andred (4.6%). Most of them were attended by medical specialties of medical clinic(37.3%), orthopedics (16%) and surgery (13.4%); the majority was discharged (91.5%).The prevalent comorbidities were hypertension (18.3%) and diabetes mellitus (7.1%).The more prevalent symptoms were respiratory symptoms (14.4%) and pain (46.3%).Patients who were asked about pain reported no pain (37.6%), and mild (12.1%),moderate (25.9%) and intense (24.4%) pain.Patients with no pain had a significantly higher age than those with moderate pain,with men presenting a higher percentage of absence of pain while women had moreoften intense pain .Patients classified in the red category had a higher percentage of absence of pain,whereas patients classified as green, yellow and orange had severe pain and those asblue had mild pain .Patients attended by psychiatry presented a higher percentage of absence of pain andthose attended by orthopedics, of intense pain .In relation to signs and symptoms, patients with respiratory symptoms had a higherpercentage of absence of pain, while those without these symptoms had a greaterpercentage of intense pain .Patients who were not able to move their bodies and those with psychiatric andneurological symptoms had a higher percentage of absence of pain, while those withan inability to move part of the body had a higher percentage of moderate andintense pain .Patients who reported nausea had a higher percentage of intense pain, and thosewithout nausea had a higher percentage of absence of pain and moderate pain .Patients with neoplasias (n = 25) had a higher percentage of absence of pain  and intense pain  (p = 0.0372).The demand for urgent care has increased and most patients report pain at the time ofRRAC. Based on this complaint, resources are used to classify and organize thepriorities of these patients. Pain is one of the main reasons that can generateinabilities and cause human suffering, impacts the quality of life, and can generatepsychosocial and economic repercussionsIn this study, women predominated in the demand for Emergency Service in relation tomen Some factors that may explain this is the resistance of men to seek health caredue to societal taboos and gender-related sociocultural factors in which diseasesare considered a sign of fragility and the search for medical services, ademonstration of weaknessIn the risk classification categories, the majority of patients were classified asgreen (58.9%), followed by yellow (22.7%), orange (7.9%), blue (5.9% ) and red(4.6%), a similar result to another national study conducted in a public hospital inDiamantina, Minas Gerais, Brazil, in which low complexity patients were also themajorityHospital discharge (91.5%) was the most frequent outcome in this study, as well as ofanother study conducted in a public hospital in Minas Gerais that observed therelationship between risk classification, mortality and hospital stay. When the riskclassification category attributed to patients was less severe, the chance ofhospital discharge was greater-As for comorbidities, hypertension (18.3%) and diabetes mellitus (7.1%) predominated,reflecting the high prevalence of these diseases in the general populationIn the present study, the symptoms that most motivated the search for the servicewere pain (46.3%) and respiratory symptoms (14.4%). Similar results were found intwo other national studies evaluating patients’ complaints according to the riskclassification protocolRegarding the intensity of pain reported by the patients in this study, the majorityreported no pain (37.6%), and the rest, moderate (25.9%), intense (24.4%) and mild(12.1%) pain. A similar study performed in a public hospital in Aracajú foundprevalence of intense (53.7%) and moderate (36.6%) pain, concluding that painintensity was related to the main reason for seeking emergency careParticipants in this study who did not present pain were significantly older thanthose with moderate pain. A study carried out in an Emergency Service in Aracajúshowed that patients with moderate pain complaints were younger than those who didnot present pain, corroborating the results of the present studyMale patients had a higher percentage of absence of pain, while female patients had ahigher percentage of intense pain. Pain is a personal and subjective experience, notonly resulting from characteristics of tissue injury, but also integratingindividual emotional and cultural factors.Furthermore, it is common for severe patients to present altered consciousness, whatprevents pain assessmentThe patients in this study classified in the red category did not complain of pain.This is due in part to the fact that patients classified as red are at high risk ofdeath and their pain assessment may be impaired due to prioritization of care, whichis started even before the patient is registered in the hospitalPatients classified as green, yellow and orange had a higher percentage of intensepain. The process of pain recognition informed at the moment of assessment issubjective and individual and may influence the risk category attributed to thepatientPain is a common symptom presented in ESs. Although it is often underestimated,poorly assessed and treated, priority judgment often may not be appropriate in thatsituation. The nurses’ ability for not to interfere in the report of the painintensity is still an obstacle to be faced. The application of a protocol for theadequate management of pain by the nurses can avoid delays in the treatment withanalgesics and improve the quality of patient carePatients attended by the medical specialty of psychiatry had a higher percentage ofabsence of pain. This result can be explained by the fact that pain evaluationinvolves the identification of the disease, etiologic factor, onset, duration,distribution, triggering and attenuating factors, quality and intensity of pain, aswell as sensorial tests. In patients with an altered mental status, such conditionmay influence the evaluation of other signs and symptoms, requiring a differentiatedassessment and individualized treatment, often difficult to perform in the ES due tothe imminent risk situationIn this study, patients with respiratory symptoms had a higher percentage of absenceof pain, while those who did not present respiratory symptoms presented a higherpercentage of intense pain. Respiratory problems are frequent reasons for seekingESs, are often not associated with significant pain symptoms; and determinesituations of imminent risk of death. In these cases, the patients’ perception ofpain may be impaired by respiratory discomfort and sometimes by the need foranalgesia and sedation to obtain a patent airway and make it possible the use ofmechanical ventilationThe absence of pain was more frequent in patients who did not present inability tomove part of the body, while those with disability had a higher percentage ofmoderate and intense pain. Persistent pain and impaired mobility and function areconditions commonly associated with musculoskeletal problems. There is a closerelationship between painful musculoskeletal conditions and inability or reducedability to move or perform some kind of physical activity resulting in functionaldecline, loss of independence and poor quality of life. For these individuals, notonly the usual analgesic treatment should be adopted, but also an individualizedrehabilitation programPatients with psychiatric and neurological symptoms presented higher percentage ofabsence pain while individuals without psychiatric and neurological symptomspresented moderate and intense pain. Physical, mental, psychological, behavioral andeven social problems can play an important role in the perception of pain and thereactions before it, interfering in the central neuro-modulation of afferentstimuli. Different approaches, including psychological ones, have a great impact onthe understanding and treatment of these individuals. Such patients often requirefurther evaluation and therapy to obtain better results, as these disorders mayexacerbate or adversely affect pain perception and therapeutic responsePatients with nausea presented, in most cases, severe pain. This finding may berelated to the malaise that nausea causes, often leading to puke, causing themuscles in the abdominal wall and chest to contract, and consequently producingpain. These symptoms, too, may accompany a complex variety of gastrointestinalorganic disorders and systemic diseases that may have pain as a consequencePain in cancer patients ranged from absence (48%) to severe (40%) intensity. Thiscomplaint may vary according to the stage of the disease, and studies show that 90%of patients in advanced stages of cancer feel more intense painThe limitations of this study were its realization in a single center, collection ofdata from medical records which were often incomplete and illegible and use of RRACprotocol with adaptations to the needs of the Institution limiting the comparisonwith other studies.This study may contribute to practice insofar as its findings demonstrate theimportance of professionals working in RRAC to be able to use pain intensity scalesbecause this symptom is an individual and subjective experience, and itsidentification may influence the category of severity attributed and the experienceof the patients regarding the quality of care received.Since pain is one of the main reasons for seeking ESs, it is paramount that nurseshave knowledge about it. In most cases, nurses are the professionals responsible forthe first care measures and they define the flow of the patients in the service. Allpatients have the right to express their pain and receive treatment for thiscomplaint, and the nurses and the multiprofessional team must implement effectivestrategies to relieve pain avoiding deleterious effects resulting from this symptomand providing patients with humanized care.In this study, the pain intensity reported by patients was most frequently ofmoderate intensity. The association of pain with the risk classification categoriesshowed that patients classified in the red color showed, in most cases, absence ofpain; those classified in the blue color had mild pain; and those classified in thegreen, yellow and orange colors had severe pain.


Introduction: Erector spinae plane block (ESPB) is a novel regional anesthesia technique used in postoperative pain and chronic neuropathic pain of the thoracoabdominal region. There are no previously published large case series. This retrospective review aimed to report the indications, levels of block, success of block and complications, and also to evaluate the effect of ESPB on postoperative/chronic pain.Methods: We retrospectively evaluated the charts and medical records of 182 patients who had ESPB in the last one year. All records were collected in the postoperative recovery room, ward, and pain unit.Results: ESPB performed at several different levels and for several different indications led to effective postoperative analgesia when part of a multimodal analgesia plan. Few complications were noted.Conclusion: ESPB is an interfascial plane block with many indications. The possibility of complications must be considered. Ultrasound-guided erector spinae plane block (ESPB) is an interfascial plane block described by Forero et al.  for the Anatomical dissections and imaging studies aimed at revealing the mechanism of the effect of ESPB have reported differing results ,12,13. TIn this retrospective review, we report the indications, levels of block, success of block, and effect of ESPB on postoperative analgesic effect.Study designclinicaltrials.gov (NCT03739086), a patient chart review was performed. Prospectively collected data were retrospectively analyzed. Patients undergoing ESPB in our center between 01.07.2017 and 01.10.2018 were included in the study. Patients who underwent a peripheral block in addition to ESPB were not included in the study.After local ethical committee approval and registration at Data collectionA standard peroperative and postoperative analgesia plan is applied to all patients who undergo a regional anesthesia technique at our institute and a standardized regional anesthesia data collection form is used to collect all patient data. All patients undergoing regional anesthesia techniques give informed consent for all procedures and the use of their data in medical studies.The following data were collected for all patients undergoing ESPB: age, gender, weight, height, surgical procedure, surgical time, patient-controlled analgesia (PCA) (tramadol) data, use of routine and rescue analgesia, and numeric rating scale (NRS) at 1st, 3rd, 6th, 9th, 12th, 18th, and 24th hours.Additionally, descriptive data were noted from data collection forms. In patients undergoing ESPB, the level of ESPB, unilateral or bilateral application, volume applied, concentration and LA content, time of block , block application time, complications, and any additional descriptive data the patient provided during follow-up was noted. While there is no standard bupivacaine concentration for our block application, in patients undergoing ESPB for short-lasting surgical procedures (less than one hour) or ESPB after completion of surgery, the LA included 0.4%-0.5% lidocaine in addition to bupivacaine. Maximum of 150 mg or 2.5 mg/kg bupivacaine and maximum 200 mg or 3 mg/kg of lidocaine was used. ESPB was performed under ultrasound guidance and generally using the out-of-plane technique.Standard perioperative analgesia included paracetamol 1 gr and tenoxicam 20 mg. However, in patients undergoing major surgical procedures such as thoracotomy, laparoscopic hysterectomy, hip surgery or laparoscopic/open nephrectomy, 0.05 mg/kg morphine (max 3.5 mg) was added. Our postoperative analgesia plan included paracetamol application every eight hours as standard. However, if the NRS value was <2 and the patient did not request analgesia, paracetamol doses were skipped or delayed. Additionally, tramadol PCA  was also standard and commenced in the recovery room. If despite these analgesics the NRS value was >3, rescue analgesia was performed using intramuscular diclofenac and, if required, meperidine 50 mg. All analgesics and their application times were noted in detail in patient files.Patients with NRS values ≥6 within the first hour or those requiring rescue analgesia within the first six hours were considered as block failure/lack of efficiency. Also, patients with an NRS value <4 within the first 24 hours who do not meet the criteria for block failure or who reported reflected pain were considered as “inadequate spread for surgical procedure”.In addition to data of the patients undergoing ESPB for postoperative pain control, data of the patients undergoing ESPB for chronic pain were also obtained from the patient files.The data of 182 patients undergoing ESPB between 01.07.2017 and 01.10.2018 were included in the study. ESPB was performed for postoperative analgesia in 173 patients and chronic pain in nine patients. The average age of the patients was 58.8 years (range 8 y-88 y) and the average body mass index was 27.9 (16.2-42.9). The American Society of Anesthesiology (ASA) physical status rating of patients undergoing ESPB for postoperative analgesia were '1' for 41 patients, '2' for 101 patients, and '3' for 31 patients.We found that 15-30 ml of local anaesthetic was used per side and level. The maximum applied LA volume was 60 mL. While 88 patients underwent bilateral ESPB, 94 underwent unilateral ESPB. When considering bilateral and bi-level blocks, a total of 296 ESPB applications were performed.ESPB was performed using the in-plane technique in only 14 patients; the remaining underwent ESPB using the out-of-plane technique. In a majority of patients, lidocaine was added to the LA and bupivacaine was used in 0.25% concentration.ESPB for postoperative analgesiaBlock application levels, local anaesthetic concentrations and applied volumes, surgical procedures, average paracetamol use, and tramadol requirements in the first 24 hours as well as the first 24-hour average NRS scores are shown in Tables In patients undergoing laparoscopic/open upper or lower abdominal, urological or gynaecological procedures, 68 underwent single level ESPB between Th6-Th9 and two underwent bi-level ESPB between Th9-L2 (thoracolumbar) levels. ESPB was performed from the low thoracic vertebral levels Th10-11) in 17 patients undergoing abdominal surgeries. ESPB was performed from the lumbar vertebral levels in 43 patients undergoing urological, gynaecological, hip, and knee surgeries. The details of surgical procedures and descriptive data are given in Tables 0-11 in 1When postoperative 24-hour analgesia requirements were analyzed, 41 patients (23%) required rescue analgesia, 15 (9%) of whom required rescue within the first 12 hours. The average paracetamol and tramadol use per patient was 2.33 gr (0-3 gr) and 99.33 (0-300) mg, respectively. The average NRS score in the first 24 hours was 1.86 . The analgesic use, rescue analgesia requirement, and NRS score distributions are shown in Tables ESPB for chronic painFive patients underwent ESPB from Th2-Th3 for frozen shoulder, three from Th4 for myofascial pain, and one patient from L4 for postoperative pain. The average NRS scores were 7.11 range 5-8) before ESPB, and following ESPB, the average NRS decreased to 1.22 (0-2) at the 1st hour, 1.44 (0-3) at the 24th hour, and 2 (0-3) at the 72nd hour. The patients reported a high degree of satisfaction on the third day. ESPB application details are given in Table -8 beforeBlock failure/lack of efficiency and inadequate spread for surgical procedureESPB failure/lack of efficiency was seen in 12 patients (6.5%). There was no common denominator of these patients with regards to surgical procedures, application level, applied LA volume or concentration. Surgical procedures in these patients were thoracotomy in three, laparoscopic hysterectomy in three, hip surgery in two, and sleeve gastrectomy, shoulder arthroscopy, laparoscopic Nissen fundoplication, and open inguinal hernia repair in one patient each. Prolonged surgery time for thoracotomies may have led to a decrease in or loss of ESPB effect.In 10 patients (5.5%) ESPB provided effective analgesia but patients reported mild to moderate pain in a section of the surgical field or reflected pain and therefore the block was considered to be “inadequate”. While two patients undergoing mastectomy and axillary dissection did not report breast pain, they reported mild to moderate pain over the axilla. In seven patients undergoing Nissen fundoplication, all seven reported left shoulder pain but no pain in the surgical field. One patient undergoing Nissen fundoplication reported both shoulder pain and mild to moderate mid abdominal pain.ComplicationsComplications were seen in four (0.22%) patients. In a 29-year-old female undergoing C/S and myomectomy, bilateral ESPB  was performed from Th11 following completion of surgery. In this patient bilateral quadriceps muscle weakness was observed for 14 hours. The patient had no previous history of neurological disease. Bilateral ESPB was performed from Th9 under general anaesthesia following completion of surgery in a 56-year-old female patient who underwent laparoscopic hysterectomy. Transient apathy and aphasia was observed for three hours, possibly due to ESPB or the effects of general anesthesia.A 38-year-old female underwent ESPB from Th3 for myofascial pain. Following ESPB, perioral numbness, lisp, and dizziness were observed. These symptoms fluctuated until complete resolution after 1.5 hours. This was probably a vascular complication of lidocaine. A 76-year-old female patient who underwent laparoscopic umbilical hernia repair underwent bilateral ESPB from Th9 preoperatively without sedation. Following ESPB, the patient was observed to have loss of general muscle tonus and consciousness. Following airway control and O2 support, the patient was unconscious until the third minute and the Glasgow coma scale (GCS) was 15 after 10 minutes, after which the surgery was successfully completed. We believe this is possibly a minor neurological complication of the LA. No treatment was required.These complications were considered to be due to the spread of the LA to the lumbar plexus in the first case and probable LA toxicity in the remaining cases. In the second patient, atropine-related anticholinergic syndrome could not be ruled out.Herein we reported a total of 182 patients undergoing ESPB from 13 different level/combinations of which nine were thoracic, two were separate lumbar, and two were bilevel. While most ESPBs were performed for postoperative analgesia, we also report a limited number of patients undergoing ESPB for chronic pain.The use of ESPB for postoperative analgesia has increased in popularity with new indications continuing to be reported ,6,10,16.While ESPB has been reported for use in frozen shoulder and myofascial pain, we report its first time use from L4 in neuropathic pain following hip surgery. ESPB was performed in 34 different surgical procedures and three different causes of chronic pain.We report ESPB performed from different levels or a combination of levels depending on the required dermatomal blockage for the surgical field. For example we report laparoscopic Nissen fundoplication with ESPB from Th6, Th8, and Th10 levels and laparoscopic hysterectomy from Th9, Th10, and Th11 levels.LA spread both cephalad and caudally is more extensive in ESPB when compared to other peri-paravertebral blocks . We therBlock success and effective analgesia are dependent on many factors and we are not able to explain the exact mechanism and sensorial coverage in ESPB. While there are differences in the spread of the LA in thoracic and lumbar vertebral applications, there are also differences reported within thoracic applications . AlthougWe took into account the dermatomal coverage of the surgical field in determining the volume and generally applied 20-30 mL LA in thoracic and 30-40 mL in lumbar areas. When we compared applied volume and block success, we were unable to determine any causative relationship. However, it is probable that high volume and concentration increase the success rate of ESPB.Understanding the anatomy of the fascia between the erector spinae muscle and the transverse process may be the key to increasing block success. When applying LA in ESPB to the interfascial plane, presuming that there are two overlapping layers in which LA is applied between may lead to increased failure. We must consider that the deeper fascia that ESPB targets is multi-structured and that increased spread between these structures will lead to better block success and coverage . We usedUltrasound-guided ESPB is a new and popular block technique and only two complications have been reported. One of these was pneumothorax and the second, from our institute, was motor weakness when ESPB was performed from a lower thoracic level ,9. PneumLocal anaesthetic systemic toxicity (LAST) is typically manifested as central nervous system (CNS) toxicity  or cardiovascular toxicity . The dose capable of causing CNS symptoms is typically lower than the dose and concentration result in cardiovascular toxicity. This is because the CNS is more susceptible to local anaesthetic toxicity than the cardiovascular system ,24. We oThe classical teaching that vascular absorption of LAs is highest with intercostal blocks followed by epidural and brachial plexus injections corresponds to clinical data demonstrating that the highest incidence of LAST occurs with paravertebral blocks, followed by upper extremity and trunk/lower extremity blocks . The risNone of the patients with complications had a history of spinal surgery. The LA in two consisted of 0.25% marcaine-0.5% lidocaine, one consisted of bilaterally applied 20 mL / 20 mL of 0.25% bupivacaine. It is noteworthy that no complications were observed in the group of patients in whom 60 mL of 0.375% marcaine was applied, yet complications occurred at lower concentrations of the LA. In our experience, concentrations of the LA did not exceed 2.5 mg/kg for bupivacaine and 4 mg/kg for lidocaine.The rate of LAST in our series is 1.6%, which we consider to be relatively high. However, we did not observe any major LAST complications such as seizures or cardiac arrest. Complications defined herein are suspicious cases of minor LAST complications which may be due to the volume/concentration of the LA used. Literature reports very few cases of LAST after interfascial plane blocks. We believe that this complication is underreported as the symptoms may be mild  and masked as sedation precedes the induction of general anaesthesia that immediately follows awake intubation or as the block is performed under anaesthesia. Larger case series and meta-analysis are required to determine the exact rate of LAST in ESPB.Another analysis in this study was the rate of “block failure/lack of efficiency” and “inadequate spread for surgical procedure”. We must firstly clarify these definitions. Unlike peripheral nerve blocks it is impossible to directly determine block failure in interfascial blocks. For example, the radial nerve is either blocked or not blocked following brachial plexus block from the axillary region; therefore, the patient either has pain in the area innervated by the radial nerve or not. However, the evaluation of interfascial blocks includes many components and evaluation of the dermatomal spread is generally not adequate for the determination of block success ,27. WhilHow can the success of ESPB be evaluated when the mechanism of action is yet to be understood? Dermatomal spread is far from being the answer. Can we say that sensorial/somatic blockage of the surgical area leads to effective analgesia? Or can we expect ESPB to lead to a complete block of a hemithorax or hemiabdomen ?We determined to also use lack of efficiency as a definition apart from block failure. Therefore, our definition of block failure/lack of efficiency was NRS >6 in the first hour or requirement of rescue analgesia when ESPB is used as a component of multimodal analgesia. We observed that 12 patients had block failure/lack of efficiency (6.5%). These patients underwent varying procedures from shoulder to hip surgery and therefore had ESPB performed for differing indications. Further studies are required to analyze block failure/lack of efficiency as well as sensorial spread not only of the surgical field but of the back, side, and anterior.We determined that 10 patients (5.5%) had inadequate spread for surgical procedure. In these, two patients undergoing mastectomy and axillary dissection had mild pain in the axilla. When considering that the sensorial innervation of the axilla comes from branches of the cervical plexus, this may be expected. In seven patients undergoing laparoscopic Nissen fundoplication, one had both moderate (NRS <6) left shoulder and mid-abdominal pain, which was accepted as inadequate spread for surgical procedure. It is noteworthy that while eight of these patients had “inadequate spread for surgical procedure” none required rescue analgesia.Our study has several limitations. Firstly, the study was designed as a single-center, retrospective chart review. Therefore some block failures, etc. may not have been recorded or may have been overlooked. Another limitation is that sensorial evaluation of patients undergoing ESPB was not routinely performed. Also, nearly all ESPB were performed under general anaesthesia or sedoanalgesia meaning that some neurological findings of LAST may not have been observed.Our experience has demonstrated that when used as part of a multimodal analgesia plan, ESPB is an effective and safely performed interfascial plane block with a large range of indications. More experience must be reported to better understand the complication rates, mechanism of action, and factors that affect block failure/lack of efficiency.


Pain control during and after any surgical procedure, is extremely essential for the comfort of patients. Pain killers used routinely act by inhibiting cyclooxygenase to control pain and inflammation. Cox-1 is constitutively expressed in most cell types, including platelets, whereas Cox-2 is absent from most healthy tissues but is induced by pro-inflammatory or proliferative stimuli. Cox-1 plays a role in the production of prostaglandins involved in protection of the gastric mucosal layer and thromboxanes (TX) in platelets. Cox-2 generally mediates elevations of prostaglandins associated with inflammation, pain, and pyresis. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are generally nonselective inhibitors of Coxs. This lack of selectivity has been linked to their propensity to cause gastrointestinal side effects. The new Cox-2 selective inhibitors, or coxibs, show the same anti-inflammatory, analgesic, and antipyretic effects as nonselective NSAIDs but are supposed to have reduced side-effect profiles. This study evaluates whether rofecoxib (50 mg) given one hour pre-operatively or the same drug given one hour post-operatively is more effective in controlling the pain and swelling in mandibular third molar surgery. Excellent pain control in dentistry is essential for the delivery of optimal dental care and for the well being of the patient. It is now known that high levels of cyclooxygenase -2 (Cox–2) are expressed at the sites of tissue inflammation leading to the synthesis of prostaglandins that mediate pain and inflammation.Prostaglandin synthesis in humans is catalyzed by two distinct isoforms of cyclooxygenase (Cox-1 and Cox-2). Cox-1 is constitutively active throughout the body, whereas Cox-2 expression is markedly upregulated by a variety of inflammatory mediators. These distinct expression patterns have led to the proposal that prostaglandins produced by Cox-1 are largely responsible for physiological functions, while Cox-2 derived prostaglandin mediate pathophysiological and inflammatory processes including pain.Cox-2 inhibitors like rofecoxib act by specifically blocking Cox-2 activities without blocking the other isoform of cyclo-oxygenase, namely Cox-1, which is responsible for gastric mucosal protection and vascular homeostasis. So we did a comparative study on the efficacy of rofecoxib, a Cox-2 inhibitor by administering the drug preoperatively for one group of patients and postoperatively for the other group.The study group comprised of those patients who came to the department of oral and maxillofacial surgery, Mahatma Gandhi Dental College and Hospital, Pondicherry for the surgical removal of impacted mandibular third molar. A total of 38 patients, that is, 19 patients in each group were included in the study. A randomization table was prepared manually and a randomly allocated number was given to each patient using this table. A proper clinical and radiologic evaluation was done preoperatively. The patients underwent the treatment under local anesthesia .The inclusion criteria were as follows:1.All types of impaction were taken up for the study.2.Patients of age 18 – 35 were included.3.Both sexes were included.4.Only patients willing to give an informed consent were made to participate in the study.The exclusion criteria were as follows:1.Hypersensitivity to analgesics.2.Patients who have taken tricyclic antidepressants, sedatives, analgesics, antibiotics, antihistamines, or corticosteroids in the last one month.3.Medically compromised patients.4.Pregnant ladiesThe two groups in the study were:Rofecoxib 50 mg orally, once daily and it was given 1 hour pre-operatively. A placebo was given 5 minutes after the surgery.For the patients in this group, the placebo was given one hour preoperatively. rofecoxib 50 mg orally, once daily was given five minutes post operatively.The patients in both the groups continued taking rofecoxib 50 mg (once daily) for another five days.In this triple blind study, the drugs were given to the patients by a post graduate teacher/staff nurse in the department who was neither the operator nor the observer.The following details were recorded preoperatively:Name of the patient, age, sex, address, date, randomization number, informed consent, tooth number, operator’s name and experience, type of impaction, and split/elevated.After giving inferior alveolar nerve block using 2% lignocaine hydrochloride containing 1:80,000 adrenalines, ward’s incision was placed in relation to the impacted third molar. The flap was raised and the tooth was removed either by splitting or elevation after bone removal. The wound was closed with 3-0 black braided suture.The surgical procedure was done by post graduates in the department. The operators were requested not to prescribe any pain killer or other drugs after the surgery. The operators were unaware of which drug was given preoperatively and post operatively.The patients were asked to assess their pain intensity at 5, 7, and 24 hours after surgery. The subjects were asked to record their pain Intensity (PI) on a 100 mm visual analog scale (VAS) by placing a mark on the line to indicate the magnitude of their pain.The subjects were asked to assess their pain intensity on a four-point categorical scale in the graph drawn above. The scoring scale was as follows:Score 0 – No pain.Score 1 – Mild pain.Score 2 – Moderate pain.Score 3 – Severe Pain.The patients were recalled 48 hours after the administration of the drug and they were asked about the pain relieving effect of the drug by a single observer who was unaware of the drug given. The graph was also seen by the observer.However, patients were advised to take a rescue medication (one Paracetamol tablet) if pain developed before the time at which rofecoxib was supposed to be taken. If the patient had taken the rescue medication, the pain intensity (PI) just before taking the rescue medication had to be marked on the graph by the patient himself/herself.The following details were recorded postoperatively:1.Duration taken for surgery.2.Pain intensity, after 5, 7, and 24 hours as marked in the visual analog scale.3.Whether patient has taken rescue medication.4.CRP test was done after 48 hours to assess the inflammatory response.C-reactive protein is one of the family of acute phase proteins found in the blood of both humans and animals. It is found in concentrations of less than or equal to 5 µg/ml in the serum of healthy persons. However, during an inflammation or infection, the levels may increase by as much as one thousand fold and can be detected as early as 5–10 hours after tissue damage. The increase in CRP levels in serum appears to be a non specific phenomenon but the change can be used to monitor the course of certain diseases and their treatment.Elevated level of CRP can be demonstrated in cases of acute myocardial infarction, rheumatoid arthritis, bacterial and viral infections, acute rheumatic fever, and several types of malignancies.In our study, we have assessed the CRP level of the patients both qualitatively and semi quantitatively using the ‘SPAN’ CRP test kit.Analgesics are routinely used after dental and oral surgical procedures. But the NSAIDs which are usually prescribed, though effective in controlling inflammation, have some undesirable side effects. So, we decided to evaluate the efficacy of coxibs (rofecoxib 50 mg) in controlling the inflammation after removal of impacted mandibular third molar by comparing two groups – one receiving the tablet 1 hour preoperatively and the other receiving the tablet 5 minutes postoperatively. The patients in both groups continued taking the tablet for a total period of 5 days.The mean age of patients in our study was 26.5 years, ranging from 18 years to 35 years. The number of males and females were 15 and 23, respectively, with a ratio of 1:1.5. For 31 patients the tooth was removed by splitting and for the other seven patients the tooth was removed by elevation. The type of impaction was mesioangular in 27 cases, distoangular in 10 cases, and horizontal in one case.The patients reported for follow-up after 48 hours and then after 1 week following surgery. One patient had numbness in the lower lip on the operated side and six patients had postoperative infection. These complications were managed conservatively.The maximum pain score as assessed using the visual analog scale was ‘1’ in the postoperative group and ‘2’ in the preoperative group, twenty four hours after surgery. The C-reactive protein level 48 hours after surgery ranged from <6µg/ml-96 µg/ml in the postoperative group and <6 µg/ml-48 µg/ml in the preoperative group.Two patients in the postoperative group and four patients in the preoperative group had taken rescue medication once after surgery. One patient in each of the group had taken rescue medication twice after surgery.A comparison was done between the two groups based on CRP level and the number of patients who required rescue medication. There was no statistically significant difference between both the groups in the level of inflammation after surgery .Development of the coxibs, a new group of anti-inflammatory drugs, represents a response to the unsatisfactory therapeutic profile of NSAIDs. Although NSAIDs are the most commonly used analgesic agents in ambulatory patients, their long term use is limited by gastrointestinal effects such as dyspepsia and abdominal pain and, less often, gastric or duodenal perforation or bleeding.In the recent past, the analgesic efficacy of coxibs had been compared with NSAIDs in the dental pain model. Malmstrom K., et al., compared the analgesic efficacy of rofecoxib with celecoxib and ibuprofen in patients experiencing pain after third molar surgery. They found that rofecoxib had superior analgesic effect and longer duration of action than celecoxib and ibuprofen, respectively.In our study we had assessed the efficacy of the cox-2 inhibitor rofecoxib based on the timing of its administration unlike most of the studies which had either compared its efficacy with another cox-2 inhibitor or a NSAID.Swan et al., by comparing the effects on renal function in patients receiving rofecoxib, indomethacin, and placebo concluded that rofecoxib has effects on renal function quite similar to nonselective NSAIDsThe ‘CLASS’ trial which lasted for 13 months concluded that there was no statistically significant difference between celecoxib and NSAIDs like ibuprofen and diclofenac in the incidence of upper gastrointestinal bleeding or gastric perforation.However, Claire Bombardier established a statistically significant difference in the upper gastrointestinal events by comparing rofecoxib with naproxen in patients with rheumatoid arthritis.Francesca Catella – Lawson had demonstrated that the concomitant administration of rofecoxib did not affect the pharmacodynamics of aspirin in patients with both arthritis and vascular diseases. However, we have excluded medically compromised patients from our study group.Muhammad. Mamdani did an observational cohort study over a period of 1 year to compare the rates of upper gastrointestinal hemorrhage in patients treated for arthritis with either cox-2 inhibitors or NSAIDs and concluded that there is a lower short term risk of upper gastrointestinal hemorrhage for selective cox-2 inhibitors compared with non-selective NSAIDs.Apart from control of inflammation and pain associated with it, the antiangiogenic activity of cox-2 inhibitors provides an additional rationale for the use of cox-2 inhibitors in severe painful conditions like rheumatoid arthritis. James. M. Woods demonstrated that rofecoxib acts directly on human dermal microvascular endothelial cells and inhibit their chemotactic and tube forming ability.The cox-2 inhibitors are believed to be associated with an increased risk of myocardial infarction and congestive cardiac failure. ,34 Hyon Muhammad Mamdani (2004)  suggesteGizzarelli compared the efficacy of preoperative administration of rofecoxib with ibuprofen in third molar extraction. The results showed that at 6 hours rofecoxib group had significantly better pain relief than ibuprofen group.Kyle.S. Christensen in a randomized placebo-controlled trial on patients experiencing moderate or severe pain within 4 hours after multiple third molar extractions showed that valdecoxib had a significantly faster onset of action and superior analgesic effect than rofecoxib.There are studies ‘for’ and ‘against’ the use of cox-2 inhibitors as an alternative to NSAIDs in patients who develop adverse drug reaction to NSAIDs. However, in our study we had not been confronted with a situation in which an allergic reaction to rofecoxib occurred.This study group comprised of those patients who came to the department of oral and maxillofacial surgery, Mahatma Gandhi Dental College and Hospital, Pondicherry for the surgical removal of impacted mandibular third molar. The study group comprised of one group for which rofecoxib 50 mg was given one hour preoperatively and the other for which the same drug was given 5 minutes postoperatively.Five patients in the preoperative group and three patients in the postoperative group required rescue medication despite taking rofecoxib 50 mg once daily for five days including the day of surgery. No significant statistical difference was observed in the CRP level between both the groups.Our study concluded that the timing of administration of drug (preoperatively or postoperatively) does not have any significant difference in controlling the pain and swelling in mandibular third molar surgery.The authors confirm that there are no conflicts of interest.


TRPA1 was shown to influence pain sensitivity, we asked if the expression of TRPA1 is dysregulated in patients suffering from Crohn’s disease.Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract associated with abdominal pain and diarrhea. Pain caused by Crohn’s disease likely involves neurogenic inflammation which seems to involve the ion channel transient receptor potential ankyrin 1 (TRPA1). Since the promoter methylation of TRPA1 promoter region were determined from DNA derived from whole blood samples of Crohn patients and healthy participants. Quantitative sensory testing was used to examine pain sensitivities.The methylation rates of CpG dinucleotides in the TRPA1 promoter. This effect was more pronounced in female compared to male Crohn patients. Similar results were found for mechanical pain thresholds. Furthermore, age-dependent effects were detected. Whereas the CpG − 628 methylation rate declined with age in healthy participants, the methylation rate in Crohn patients increased. Pressure pain thresholds increased with age in both cohorts.Pressure pain thresholds were lower in Crohn patients as compared to healthy participants, and they were also lower in females than in males. They correlated inversely with the methylation rate at the CpG − 628 site of the TRPA1 promoter methylation appears to be dysregulated in patients suffering from Crohn’s disease, and this effect is most obvious when taking gender and age into account. As TRPA1 is regarded to be involved in pain caused by neurogenic inflammation, its aberrant expression may contribute to typical symptoms of Crohn’s disease.The  Inflammatory bowel diseases (IBD) including Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract resulting from multiple factors that seem to trigger an abnormal activation of the mucosal immune system through commensal microflora. Studies employing animal models on IBD reported that sensory neurons innervating the gastrointestinal tract are likely to be involved in these disorders –10. ActiTRPA1 gene was reported to be associated with paradoxical heat sensations in neuropathic pain patients [TRPA1. The promoter methylation of TRPA1 was initially reported to be strongly associated with thermal pain thresholds [TRPA1 promoter also seems to predict pressure pain thresholds in healthy individuals as well as neuropathic pain symptoms in patients suffering from chronic pain [TRPA1 promoter with regard to pain sensitivity.TRPA1 was demonstrated to mediate pain-like behavior in rodent models of visceral pain, and also visceral hyperalgesia developing in models of IBD was reported to be mediated by TRPA1 , 35–38. patients . Here, wresholds . We and nic pain , 43. HypP = 0.052). Comparison between female and male Crohn patients by calculation with Mann-Whitney U test (random sample selection) revealed only significant differences for HPT (P = 0.020) and PPT (P = 0.039), with females showing lower thresholds as compared to males.Mean values for QST parameters and postoperative morphine consumption of female and male Crohn patients are shown in Table U, p < 0.001, Fig. U, healthy participants: p < 0.001, Crohn patients p = 0.039). The mean PPT in healthy subjects was 73.2 N for females and 104.1 N for males, and the corresponding values in Crohn patients were significantly lower with 40.6 N for females and 53.9 N for males.The measurement of PPT via algometer revealed significant differences between healthy participants and Crohn patients  and females (R2 = 0.050), the corresponding linear regression for Crohn patients reveals a strong predictive potential for female (R2 = 0.250) as compared to male patients (R2 = 0.008) as well as to the healthy volunteer group.Unfortunately, PPT was the only QST parameter measured in both cohorts, enabling a comparison between healthy subjects and Crohn patients. The linear association between CpG − 628 methylation and PPT is illustrated in Fig. R2 = 0.187, R2corr = 0.155, F(2) = 5.970, p = 0.005) included gender and CpG − 628 methylation as significant predictors . In case of MPT, the best fitting model  = 2.901, p = 0.064) included only CpG − 628 methylation as significant predictor . Calculation of the linear regression of the MPT reveals differences between female (R2 = 0.122) and male patients (R2 = 0.006). The predictor age did not reach significance level . To analyze if the observed effect of BMI is gender-related, we calculated a regression separately for both genders, including age, CpG − 628 methylation and BMI as predictors and PPT as the dependent variable. CpG − 628 methylation in female subjects was found to be the only significant predictor for PPT . When calculating a stepwise multiple linear regression (using the BACKWARD method) with the same predictors and dependent variable, the best fitting model for female patients for PPT  = 5.676, p = 0.009) included only CpG − 628 methylation as significant predictor . Again, the predictor age did not reach the significance level . For male patients, none of the predictors was significant. Therefore, BMI was not considered a relevant factor, but rather a gender-related side effect.We next calculated a stepwise multiple linear regression of Crohn patient data using the BACKWARD method. We included age, gender, and CpG − 628 methylation as predictors and separately for each analysis values for PCA and QST Table  as well R2 = 0.183), it increases in Crohn patients (R2 = 0.078). In contrast, PPTs seem to be unaffected by this circumstance .We next investigated age-related effects and found oppositional results for CpG − 628 methylation in healthy subjects and Crohn patients Fig. a. WhereaTRIM39-RPP21, which regulates the type I interferon pathway and is therefore important for viral immunity [TRAF6, mediating signal transduction downstream of the tumor necrosis factor receptor superfamily and the interleukin-1 receptor/Toll-like receptor superfamily [Several studies are dealing with genetic factors contributing to the susceptibility of IBD and additional environmental factors triggering the onset of the respective disease . A familimmunity , is hypoimmunity . In conterfamily  is hypererfamily .TRPA1 promoter methylation with regard to pain sensitivity. Evaluation of patient-controlled analgesia (PCA) and quantitative sensory testing (QST) of Crohn patients revealed significant differences between genders for heat pain threshold (HPT) and pressure pain threshold (PPT), with females showing higher sensitivity than males. Gender-biased pain thresholds have been indeed reported in several studies. As mentioned previously [TRPA1 mRNA was found to be significantly upregulated in response to inflammation in mouse and human colon. The authors propose a protective role of TRPA1 since in a murine model for colitis the disease activity index and the histological score were lower in TRPA1 expressing mice than in the knockout mice after 10 days of dextran-sulfate treatment. This theory was further supported by the TRPA1-mediated downregulation of proinflammatory neuropeptides and cytokines under these serious inflammatory conditions [TRPA1 promoter. Unfortunately, PPT data were the only QST data measured in healthy subjects. In both cohorts, the threshold is significantly lower for females than for males. Crohn patients may exhibit an altered regulation of pain perception, which can be caused by the inflammatory condition itself as well as by the medication Crohn patients receive. Reactive oxygen species, which are capable of activating TRPA1 [TRPA1 promoter for Crohn patients. Due to this fact we concentrated further analyses on CpG − 628 since this CpG site showed a superordinate role regarding pain thresholds in healthy individuals in previous studies [TRPA1 promoter methylation seems to have a higher influence on PPT in female than in male patients, these results might suggest that different pain treatments for female and male Crohn patients are reasonable and possible. Hence, broader studies should be carried out to verify the previous results in order to specify gender-dependent treatment options. Furthermore, CpG − 628 methylation rate was found to be a significant predictor not only for PPT but also for MPT. Similar to PPT, the effect of CpG − 628 methylation rate seems to also have a greater influence on females than on male patients for this parameter .Aging is known to be a factor influencing the methylation status. The methylation rate can even be used to predict the age of different tissues and cell types . We comppatterns , and glupatterns . In patipatterns , 76. HowA limitation of our study is the usage of DNA from whole blood cells for methylation analysis. It would have been more accurate to use TRPA1 expressing nociceptive neurons for methylation and expression analyses, but due to the inaccessibility of the tissue, we were limited to blood cells. Although in some cases variations in DNA methylation have been observed to be tissue-specific , in otheTRPA1 promoter methylation seems to be dysregulated in Crohn patients in an age-dependent manner.We found lower PPT for Crohn patients than for healthy participants and detected differences regarding the correlation between CpG − 628 methylation and PPT in the different genders, with a high correlation in female patients compared to the other groups. In Crohn patients, similar results were obtained for MPT, confirming the PPT results. Therefore further investigation of gender-dependent treatment options should be considered. Since we only found a significant effect regarding the correlation between CpG − 628 methylation and PPT in female patients, other mechanisms have to be involved in the altered pain perception in Crohn patients. Furthermore, After approval by the local ethics committee and informed written consent from all volunteers, blood sampling of 75 healthy participants  and 55 patients suffering from Crohn’s disease  was conducted at the University of Erlangen-Nuremberg. In all patients, Crohn’s disease was histologically proved, they had no history of surgery within the last 3 months and did currently not take any pain medication. EDTA-blood was frozen at − 80 °C directly after sampling. Characteristics such as gender and age were documented for all subjects. Disease duration defined as years between diagnosis and blood sampling, extraintestinal manifestations, as well as BMI, were documented additionally for Crohn patients  was conducted as described previously . Postope2 over the thenar muscles. PPT was determined with 3 series of ascending stimulus intensities until the subjects expressed pain. Mean values were used for statistical analyses.Somatosensory profiles in Crohn patients were estimated via quantitative sensory testing (QST) as described previously , accordiDNA for methylation analysis of both cohorts was extracted from blood. The cleanup of genomic DNA from healthy participants was performed using the Nucleo-Mag® Blood 200 μl DNA Kit . Genomic DNA from Crohn patients was extracted according to standard procedures with an automated chemagic MSM I system . Bisulfite conversion and DNA purification were conducted via the EpiTect® 96 Bisulfite Kit . DNA concentrations were determined via a Nanodrop 1000 spectrophotometer . A Biomek® NxP  was used for pipetting, transferring and purification steps.TRPA1 promoter target sequences of the purified bisulfite-converted DNA was conducted in 2 different fragments, as described previously [TRPA1 was amplified using the forward primer 5′-GTTTGTATTAGATAGTTTTTTTGTTTG-3′ and the reverse primer 5′-TCCTACAAACCTATATTTCCCAC-3′, the second fragment via the forward primer 5′-GGGGTAGGGTAAGGGGTTTT-3′ and the reverse primer 5′-TACACACACCCCAAAACTTACAAC-3′, using touchdown PCRs [Amplification of eviously . The firown PCRs  with staTRPA1 gene (from − 734 bp to + 335 bp of the first exon). Products of the sequencing PCR were purified using Agencourt CleanSeq® XP magnetic beads , afterward sequencing was performed on a 3500XL genetic analyzer from ABI Life Technologies  according to the manufacturer’s instructions.Amplification products of touchdown PCRs were purified using the Agencourt® AMPure® XP magnetic beads . Sequencing PCRs of the target fragments were performed using the Big-Dye® Terminator v3.1 Cycle Sequencing Kit . Oligonucleotides used for sequencing PCR were 5′-GTTTGTATTAGATAGTTTTTTTGTTTG-3′ (first fragment) and 5′-CTACCCCCAAAAAAACCTCCAAC-3′ (second fragment). For amplification of the first fragment, cycling conditions apply as follows: 1 min 96 °C, 28 × . For the second fragment, cycling conditions for AT-rich sequences were applied according to manufacturer recommendations: 1 min 96 °C, 26 x . The amplified fragments covered 55 CpG sites within the promoter region of the Sequence analysis and determination of methylation rates for each CpG site were conducted using the Epigenetic Sequencing Methylation (ESME) analysis software . The metp value of < 0.05 was considered significant.Sequence quality was assessed via Sequence Scanner v1.0 software . Only sequences with a Quality Value > 20 for Trace Score in the Quality Control Report were included for further analyses . All statistical calculations were performed using the Statistical Package for the Social Sciences . We used GraphPad Prism for Windows 5.03 for data illustration . Single CpGs with less than 95% sequencing success among the samples were excluded, which applied to CpG − 161, − 40, and − 38 ahead of the first exon, as well as CpG + 147, + 333, and + 335 of the first exon. Samples with less than 95% sequencing success of overall CpGs, which applied to 6 samples, and CpG sites with less than 5% inter-individual variability, which applied to CpG − 480, + 13, + 15, and + 191 were also not further analyzed. After applying the criteria for data exclusion as mentioned previously, the remaining number of samples dropped from 147  to 130 , the number of analyzed CpGs dropped from 55 to 45. Methylation levels for individual CpG sites are provided in Fig.


This study is a prospective, assessor-blinded, parallel-group, randomized controlled pilot trial to explore the effectiveness of 12-week adjuvant moxibustion therapy for arthralgia in menopausal females at stage I to III breast cancer on aromatase inhibitor (AI) administration, compared with those receiving usual care.Forty-six menopausal female patients with breast cancer who completed cancer therapy will be randomly allocated to either adjuvant moxibustion or usual care groups with a 1:1 allocation ratio. The intervention group will undergo 24 sessions of adjuvant moxibustion therapy with usual care for 12 weeks, whereas the control group will receive only usual care during the same period. The usual care consists of acetaminophen administration on demand and self-directed exercise education to manage AI-related joint pain. The primary outcome is the mean change of the worst pain level according to the Brief Pain Inventory—Short Form between the initial visit and the endpoint. The mean changes in depression, fatigue, and quality of life will also be compared between groups. Safety and pharmacoeconomic evaluations will also be included.t test or Wilcoxon rank-sum test between the adjuvant moxibustion and usual care groups. Adverse events will be analyzed using the chi-square or Fisher exact test. The statistical analysis will be performed by a 2-tailed test at a significance level of .05.Continuous variables will be compared by an independent  However, patients receiving AIs commonly develop arthralgia related to AIs, which affects their adjuvant cancer therapy, and also their quality of life (QoL).Postmenopausal women with hormone receptor-positive breast cancer receive adjuvant aromatase inhibitors (AIs) for 5 years Patients usually complain of symmetric arthralgia, especially in the hands or wrist joints. The incidence of AIA varies between 5% and 35%. AIA is highly suspected to substantially lead to nonadherence of AI therapy, which could significantly affect breast cancer recurrence.,4Aromatase inhibitor-induced arthralgia (AIA) is defined as joint pain which initiates or worsens after AI administration. The joint pain improves or resolves within 2 weeks after AI cessation, but comes back on re-administration of AIs. Acupuncture therapy for AIA has also been investigated. A systematic review showed acupuncture therapy has potential benefits in relieving pain in AIA patients. However, standard treatments for AIA are not yet defined.Physicians are encouraged to inform patients before initiating AI therapy that they may experience joint pain during AI administration. Exercise, weight loss, vitamin D supply, or selective serotonin reuptake inhibitor administration has been suggested for mild arthralgia, whereas prednisolone or nonsteroidal anti-inflammatory drugs are prescribed for moderate to severe arthralgia in clinical practice.–7 Another randomized controlled trial (RCT) showed that moxibustion improved anorexia in patients with metastatic cancer. These previous studies imply a possible benefit in administering moxibustion for AIA in breast cancer patients.Moxibustion is a noninvasive procedure in traditional Korean medicine (TKM), which burns moxa (dried mugwort) directly or indirectly on acupoints to alleviate symptoms. It has been widely used in clinical practice for various conditions including rheumatic diseases, dyspepsia, hot flush, and fetal breech presentation. Clinical research shows that moxibustion could improve pain or QoL of knee osteoarthritis patients.This pilot study aims to evaluate the effectiveness and safety of adjuvant moxibustion therapy for postmenopausal female patients with breast cancer stage I to III who complain of joint pain associated with 3 months or more of AI administration.2 and Standard Protocol Items for Clinical Trials with Traditional Chinese Medicine 2018: Recommendations, Explanation and Elaboration (SPIRIT-TCM Extension 2018).This trial protocol conforms to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement,2.1This study aims to primarily to explore the effectiveness of 12-week adjuvant moxibustion therapy for arthralgia in menopausal females with stage I to III breast cancer under AI administration, compared with those receiving usual care. Further, we will assess how moxibustion therapy affects depression, fatigue, and QoL of AIA patients. Furthermore, the safety and economic evaluation of moxibustion therapy for AIA patients will be performed with this pilot trial.2.2This study is a prospective, assessor-blinded, parallel-group, randomized, controlled pilot trial. We will enroll 46 menopausal female patients (aged 40–65) diagnosed with stage I to III breast cancer who have completed cancer therapy and are receiving AIs for 3 months or more. The patients presenting with joint pain with 4 points or more on the Brief Pain Inventory—Short Form (BPI-SF) will be eligible to participate in this trial. After screening assessment and group allocation, they will receive 24 sessions of adjuvant moxibustion therapy with usual care for 12 weeks, whereas the control group will receive only usual care during the same period. The usual care consists of acetaminophen administration and self-exercise to manage AI-related joint pain.Eligible participants will be enrolled from among the outpatients in the Kyung Hee University Korean Medicine Hospital, Seoul, Republic of Korea. The trial will be advertised via web pages and notice boards for potential participants. Study coordinators will keep closely in touch with the participants to promote adherence.The flow chart following the SPIRIT statement is illustrated in Fig. 2.3The inclusion criteria are as follows:a)Females with amenorrhea, aged 45 to 65, who are without menstrual period for 1 year or more or with serum follicle-stimulating hormone of 45 mIU/mL or higher;b)Estrogen receptor-positive breast cancer patients of stage I to III, who have completed surgical procedures, chemotherapy, and/or radiation therapy and do not have active cancer treatment plans;c)Patients who are taking third-generation AIs such as anastrozole, letrozole, and so on for 3 months or more and are not supposed to cease the administration during the study period;d)Patients who develop continuing arthralgia in 1 or more joints after AI treatment is initiated;e)Patients who are assessed with more than 4 points of BPI-SF in terms of the maximum pain level at baseline; andf)Volunteers who sign the informed consent forms after obtaining all necessary information.The exclusion criteria are as follows:a)Patients who have primary or metastatic residual cancer or recurrent cancer;b)Patients who have had previous fracture or surgery in the painful joints within the past 3 months before enrollment;c)Patients experiencing moxibustion therapy for AIA within the past 3 months before enrollment;d)Patients who are receiving steroids or narcotic analgesics at baseline;e)Patients who elicit an allergic reaction to moxibustion, keloids, or any skin diseases on the targeted acupoints for moxibustion;f)Patients who are scared of moxibustion therapy; org)Patients who have participated in another clinical study within the past month prior enrollment.2.4The participants will be dropped out even after being allocated to a group if they turn out to have one of the following:a)If investigators find any violation of eligibility criteria after randomization;b)If participants withdraw consent or refuse moxibustion therapy after randomization;c)If investigators lose participants to follow-up;d)If participants cannot continue the study participation due to serious and unexpected adverse events or newly found or worsened concomitant disorders;e)If participants violate the study protocol including undergoing any prohibited treatments for AIA during study participation; orf)If participants miss 5 or more sessions of moxibustion therapy.2.5An independent statistician will generate random sequence numbers with the blockrand package (version 1.3) in R . The random number and allocated group will be delivered in sealed envelopes. After completing screening procedures, an investigator will open the sealed envelopes in consecutive order and allocate patients to either the moxibustion group or the usual care group at a 1:1 ratio, enabling complete concealment of group allocation.This study is an open-label trial; therefore, practitioners and participants cannot be blinded during the whole study. However, an independent outcome assessor will be blinded throughout the study to minimize study bias.2.6Participants allocated to the intervention group will receive moxibustion therapy twice a week for 12 weeks (24 sessions). Dried mugwort in a cone shape  and individually selected acupoints of the 2 joints with pain except for the cervical joint. If a patient complains of pain in more than 2 joints, only the 2 joints with the most severe pain will be selected for the moxibustion therapy. The prespecified acupoints for each joint are illustrated in Fig. ion Fig. .[13] The2.7Participants in the study will all receive usual care for AIA; the intervention group will receive both moxibustion therapy and usual care, and only usual care will be administered to the control group. The control group is set up to represent actual practice.We will educate the eligible participants with a brochure after their screening assessment, which includes a self-directed exercise program . Moreover, acetaminophen  will be prescribed at the initial visit and the patients will be advised to intake the medication appropriately as needed. They may take 1 tablet each time, up to 4 times a day. Because an on-demand policy of acetaminophen administration is planned, we will record how many tablets are consumed based on the number of prescriptions and returns. Furthermore, the patients will be advised to maintain a diary of the drug usage and submit it to the investigator.All other concomitant treatments for AIA will be strictly prohibited. These include steroid or narcotic analgesics for arthralgia , physical therapy , or other TKM treatments .2.8Data will be collected and recorded in case report forms. An independent monitor will regularly visit the study site for source data verification, investigator product management, protocol deviation check, and safety issue monitoring.2.8.1 The BPI-SF consists of 9 domains and evaluates the severity of pain and its impact on functioning. Patients respond to each question with a numeric rating scale of 1 to 10. A higher score defines more severe pain. The primary outcome is the mean change of the worst pain level in BPI-SF between the baseline (visit 1) and the endpoint (visit 24).The BPI-SF is widely used to evaluate joint pain in breast cancer patients with AIA.2.8.2The mean changes in the worst pain level in BPI-SF will be compared between visits 1 and 9, visits 1 and 17, and visit 1 and the follow-up visit (visit 25), respectively. Moreover, the least pain score, the average pain score, the present pain score, the relief level after treatment, and the level of interference to general activity, mood, walking ability, normal work, social relationships, sleep, or social functioning owing to joint pain obtained from BPI-SF assessments will be also compared between groups . The amount of acetaminophen administration will be investigated to evaluate the pain severity secondarily. More severe pain will be defined by increased consumption of the medication.,17The Beck Depression Inventory (BDI) will be used to evaluate the severity of depression based on 21 items . We will use the validated Korean version of the BDI for this study.The Multidimensional Fatigue Symptom Inventory—Short Form (MFSI-SF) is a 30-item patient-reported outcome tool to evaluate the severity of fatigue. This tool has often been used in cancer patients. The total fatigue score is calculated from 5 subdomains, which is the sum of the general scale score, physical scale score, emotional scale score, and mental scale score minus vigor scale score. EQ-5D consists of questions on mobility, self-care, usual activities, pain/discomfort and anxiety/depression, and a visual analog scale to evaluate QoL of the general population. This tool has been also validated in Korean.Furthermore, we will assess the changes of QoL in breast cancer patients affected by moxibustion therapy with the Functional Assessment of Cancer Therapy–Breast (FACT-B) and EuroQoL Five Dimensions (EQ-5D) questionnaires. FACT-B was developed to evaluate QoL in breast cancer patients and assesses physical, social/family, emotional, and functional well-being based on 36 components. The patients should select a score between 0 and 4 for each component. The Korean version of FACT-B is validated.The mean changes in BDI, MFSI-SF, FACT-B, and EQ-5D between visits 1 and 9, visits 1 and 17, visits 1 and 24, and visits 1 and 25, respectively, will be compared.2.8.3Adverse events will be reported throughout the study period. The frequency of adverse events will be used to assess the safety of adjuvant moxibustion therapy compared with the control group.2.8.4The incremental cost-utility ratio will be estimated with the quality-adjusted life-year (QALY), which will be deduced from the EQ-5D and cost data. The incremental cost-effectiveness ratio will also be estimated with BPI-SF scores and cost data. The cost data will be directly obtained from a cost survey of study participants and indirectly from national health insurance resources.The Work Productivity and Activity Impairment Questionnaire (WPAI) and iMTA Productivity Cost Questionnaire (iPCQ) will assess productivity losses related to health problems, particularly breast cancer in this trial. Patients will respond to 6 items in the WPAI recalling the previous 1 week, and 12 items in the iPCQ recalling the previous 4 weeks.2.9μinterventon = μcontrol, where μ denotes the mean change of the worst pain level in BPI-SF scores between the baseline and week 12. Because there was no previous study evaluating the effectiveness of moxibustion therapy for AIA in breast cancer patients, we used an acupuncture study assessing pain severity with BPI-SF for AIA in breast cancer patients. They showed a BPI-SF change of −3.7 ± 2.43 in acupuncture group, and −0.11 ± 3.15 in the sham group between the baseline and the endpoint. The optimal sample size has been calculated as 23 per group, assuming correlation coefficient of 0.1, dropout rate of 0.2, significance level of 0.05, power of 0.95, and a 2-sided test with PASS version 14.0.11 . Therefore, 46 eligible participants will be enrolled for the whole study at a 1:1 allocation ratio.The primary outcome is the mean change of the worst pain level in the BPI-SF score after 12 weeks of treatment. The null hypothesis is 2.10The primary analysis will be carried out with the full analysis set (FAS). The FAS is defined as the set of participants who receive 1 or more sessions of moxibustion therapy and assess their BPI-SF at least once. The per protocol set (PPS) will also be analyzed. The PPS is defined as the set of participants who complete all procedures planned in the study.t test or the Wilcoxon rank-sum test depending on the normality of the distribution to ascertain statistically significant differences between the intervention and control groups. Adverse events will be compared with the chi-square or Fisher exact test depending on the number of cells which contain values of 5 or less in the contingency table. The statistical analysis will be performed with R (version 3.5.2 or later) at a significance level of 0.05 (2-sided).Continuous variables will be compared by an independent 2.11https://cris.nih.go.kr/cris/en/, KCT0003698) on April 1, 2019. Any amendments of protocol will be published via CRIS after obtaining the approval of the Institutional Review Board at Kyung Hee University Korean Medicine Hospital.The study protocol and the informed consent form have been reviewed and approved by the Institutional Review Board at Kyung Hee University Korean Medicine Hospital, Republic of Korea (KOMCIRB 2017–08–029) on September 26, 2017 (Protocol V1.1) and registered in the Clinical Research Information Service (CRIS, The TKM doctors will explain the necessary information to participants and obtain written informed consent. The personal information of the participants will be protected by random numbers and their initials. Any personal information, including identification code and names, will neither be recorded in case report forms nor shared with others.The datasets used and/or analyzed after completing the current study will be available from the corresponding author under reasonable requests. The investigators will disseminate the study results and implications via publication.3This study is a prospective, assessor-blinded, parallel-group, randomized controlled pilot trial to explore the effectiveness of a 12-week adjuvant moxibustion therapy in menopausal females with arthralgia at stage I to III breast cancer on AI administration, compared with those receiving usual care. Forty-six menopausal female patients with breast cancer who have completed cancer therapy will be allocated to either an adjuvant moxibustion or usual care group with a 1:1 allocation ratio. The intervention group will receive 24 sessions of adjuvant moxibustion therapy with usual care for 12 weeks, whereas the control group will receive only usual care during the same period. The usual care consists of acetaminophen administration on demand and self-exercise education to manage the AI-related joint pain. These theories have led to many clinical research studies, particularly for knee osteoarthritis.,7,24 We expect this pilot study could find a clinical use for moxibustion therapy in treating AIA in menopausal patients with breast cancer.Moxibustion therapy has been widely used in East Asian countries. It is similar to acupuncture therapy in terms of the meridian system and acupoint theories. However, it is different from acupuncture therapy in that moxa is burned on acupoints. Moxibustion therapy is known to bring warmth back to the Yang and eliminate cold in the Yin in traditional theory, resulting in alleviating joint pain.Conceptualization: Seungwon Shin, Sun Kyung Baek, Deok-Sang Hwang.Data curation: Seungwon Shin, Deok-Sang Hwang.Funding acquisition: Deok-Sang Hwang.Investigation: Bo-Hyoung Jang, Seung-Hyeok Park, Jin-Wook Lee, Min Soo Chae, Namhoon Kim, Hae Sun Suh, Sola Han, Sun Young Min, Sun Kyung Baek, Yu Jin Lim, Deok-Sang Hwang.Methodology: Seungwon Shin, Bo-Hyoung Jang, Hae Sun Suh, Sola Han, Sun Young Min, Sun Kyung Baek, Deok-Sang Hwang.Project administration: Deok-Sang Hwang.Supervision: Deok-Sang Hwang.Writing – original draft: Seungwon Shin.Writing – review & editing: Seungwon Shin, Seung-Hyeok Park, Jin-Wook Lee, Min Soo Chae, Namhoon Kim, Hae Sun Suh, Sola Han, Sun Young Min, Sun Kyung Baek, Yu Jin Lim, Deok-Sang Hwang.Deok-Sang Hwang orcid: 0000-0001-9179-0797.