Clinical problems of the temporomandibular joint (TMJ) and the masticatory musculature are both included in the term temporomandibular disorder (TMD). The purpose of the present study was to examine the pathology of the joints of patients diagnosed with TMD utilizing the dedicated Piper MRI-based classification, and to link these pathologies with various symptoms while considering their severity. In total, 64 patients with clinical TMD were examined. Symptoms were recorded using a questionnaire. The clinical examination included diagnosing the occlusion in centric relation, which was followed by a standardized MRI. It was confirmed that, although they occurred in a high percentage in all classes, muscle pain and occlusal interference are not indicators of TMJ damage. The results indicate that the progressive degradation of the TMJ, represented by qualification to the higher Piper classes, is associated with an increase in TMJ pain only up to a certain stage. For the highest Piper classes, the joint pain occurs in a smaller percentage of patients, but sounds are more frequent. The typical reasons for visits to the dentist are dental caries, periodontal problems, or, more rarely, the loss of teeth . ClinicaTMD is considered a collective term for different symptoms, including pain in the TMJ, headache, teeth clenching, grinding, impaired mouth opening, clicking, crepitus in the TMJ, and masticatory tenderness . PatientTMD is considered to have multiple etiological factors. Although the research diagnostic criteria for temporomandibular disorder (RDC/TMD) has been established , patientThe purpose of the present study was to examine the pathology of the joints of patients diagnosed with TMD utilizing the dedicated Piper MRI-based classification, and to link these pathologies with various symptoms while considering their severity.In the study, 64 patients were included, and all patients provided their informed consent. All patients came for treatment in the private dental clinic Tollbugata in Bodø, Norway.-Painful TMD, with a diagnosis based on the previously published criteria for TMD ,20,42-Facial pain noted at least 3 months prior to the visit-Full dental arches -Orthodontic treatment was ended at least one year ago-General good health-At least 18 years of age-Fluent in Norwegian or English.-The exclusion criteria were as follows:-Undergoing or completed orthodontic treatment in the last 12 months-Previous craniofacial surgery and/or noted injuries-The patient was not willing to undergo MRI or not suited for MRI-Cognitive impairment-Psychiatric limitations that may affect the participation in the study assessmentsThe clinical examinations were conducted and considered the inclusion criteria of joint disorders ,20,42. TThe final patient group consisted of 15 men, 20–77 years old, and 49 women, 20–66 years old. The mean age of the total group was 38.9 years. In total, 128 joints were examined, of which 68 joints were classified as IVa class, 22 as IVb, 12 as Va, and 22 as Vb. In addition, for one patient, the joints were classified as class II and IIIa. Because it was a single case, it was not included in the presented study.The questionnaire/evaluation of symptoms was completed in the clinic with the examining dentist assisting the patient (the patients had previously received the questionnaire so they could be acquainted with the questions). During the visit, clinical interview was performed, and the symptoms were described. It was determined whether patients suffered pain (continuous or intermittent) from headaches, or their neck, jaw, ear, face, or another region. The painful regions were marked on a diagram showing the right and left profile schematically. It was determined how long the patient experienced the pain, whether it was constant or intermittent , and whether it occurred in the morning, afternoon, evening, or/and at night. It was determined whether the patient had sustained any injuries in the past, what made the pain better or worse, and whether the patient was using medications to improve the situation . It was established whether and in what situations the patient experienced pain . It was determined whether the patient’s jaw ever locked, and whether the patient noticed changes in the occlusion (front or back teeth), the profile, or the asymmetries in the maxilla/mandible. It was determined whether the patient had excessive tooth sensitivity, or had ear problems such as reduced hearing, ringing, dizziness, or other problems. It was determined if the patient had swallowing problems; if/when he/she had any TMJ-related treatment such as a splint, night guard, occlusal adjustment, or orthodontic treatment; and whether these treatments were effective. The muscles were palpated to determine which were painful. The dentist palpated the jaw muscles bilaterally to discover sore trigger points and sense the muscle tonus. Masseters were palpated with the fingers positioned over the angle of the mandible, the temporalis muscles were palpated along the temple with the jaw relaxed and clenched, and the pterygoid muscles were palpated intraorally along the medial aspect of the mandibular ramus between the tonsillar pillars . The subThe protocol followed the criteria of The Helsinki Declaration, ICH Guideline for Good Clinical Practice. The study was approved by the ethical committee of the University of Bialystok .The occlusal interference was diagnosed in centric relation (CR), defined as the most anterior superior position of the condyle disk assembly within the glenoid fossa. The CR was recorded by bimanual manipulation. The models were prepared, placed in this position, and mounted in an articulator . The occlusal interference was recorded on the model and on the patient utilizing articulating paper .The MR imaging was obtained with a GE Signa 1.5 T MR scanner , with a dedicated coil for a TMJ protocol. All MRI scans were read by the dentist and two experienced radiologists. The radiologists were blinded to the clinical data. The differences in the assessment carried out by specialists concerned only the details and did not affect the final diagnosis/qualification, which was the same in all cases. The following factors were determined as normal or abnormal: condylar translation , condyle cortex , condyle shape , condyle size , articular spacing , disk quality , disk posture , and occlusal interference.The TMJ MRI scan protocol was as follows: the sagittal slices should cut perpendicular to the line bisecting the medial and lateral poles; the coronal slices should be parallel to the line bisecting the medial and lateral poles; T1 ; sagittal slices were performed with closed-mouth CR, and when possible, with an open mouth (30 mm minimum); the coronal slices were obtained with a closed mouth; T2 ; the sagittal slices were performed utilizing the proton density .The examined TMJ stages were divided into five groups according to the Piper classification , which wStage I—Normal a. In a nStage II—Intermittent Click. The earliest soft tissue breakdown within the temporomandibular joint occurs at the lateral pole. Note that the disk is in normal alignment most of the time. Approximately 25 percent of the temporomandibular joints have lateral pole laxity, or Piper Stage II. This is by far the most common internal arrangement.Stage IIIa—Lateral Pole Click. There is a more chronic displacement of the disk from the lateral pole. Fibrosis begins to develop in the lateral part of the superior belly of the lateral pterygoid muscle. This results in chronic clicking because of the displacement of the disk from the lateral pole of the condylar head.Stage IIIb—Lateral Pole Lock. Stage IIIb is the locking phase of lateral pole disk disease. In this stage, the lateral 50% of the disk is dislocated from the condylar head. Therefore, there is no joint clicking. It is probable that as much as 15% of the global population has Stage IIIa or IIIb disk displacement. Because the medial pole is covered by the disk, these joints tend to be more comfortable when they are returned to centric posture (4).Stage IVa—Medial Pole Click b. Stage Stage IVb—Medial pole lock. Stage IVb is the locking phase in patients who have medial disk displacement. There has been significant deformation of the disk at the medial pole.Stage Va—Perforation with acute disk joint destruction (DJD).Stage Vb—Perforation with chronic DJD. These patients have chronic disk displacement and perforation of the retrodiscal tissues.n = 128). Considering that the obtained results for each of the patients were considered valid, we included them in the analyses. As a result, for tables 4 × 4 , the calculated power was 0.99, and for tables 4 × 2 , the calculated power was 0.82.Statistical analysis of the results was performed using the PQStat 1.8.0 software . The Pearson’s chi-square (χ2) test for categorical data or Fisher’s exact test (α = 0.05) was used. The sample size was calculated. The effect size  was assumed as medium (φc = 0.3) or large (φc = 0.5) . For 4 ×A total of 10 patients (16%) had additional medical disorders, and some patients had several disorders. The most prevalent disorder was medically treated hypertension in five patients (8%), while three patients had asthma and two had rheumatism. Individual cases of diabetes, cancer treatment, or occasional depression an intermittent dose antidepressant) were registered.In total, 24 patients suffered from headaches (38%), 28 felt neck pain (44%), 5 had problems with locking joints (8%), and 4 suffered from ear fullness (6%). It was also found that 52% of patients (33 of 63) could link TMD to previous trauma. MRI scans disclosed that all patients had changes in their TMJ, and all patients also had pathological changes corresponding to various degrees of disk displacement. All patients suffered from painful jaw muscles (left or right side or both sides). It was found that 58 patients (92%) of the patients complained of pain in the masseter muscle, 36 (57%) had temporal muscle pain, and 35 (55%) had other jaw muscle pain. Joint pain was noted for 14 (22%) patients, and 36 (57%) had joint sounds.p < 0.05) differences in the distribution of the symptoms were noted. These results may be analyzed together with the percentage of symptoms in the number of cases for the particular Piper classes (2b). For classes Iva–Va, muscular pain was the most frequently noted symptom, and the pain was noted for more than 85% of the joints in all Piper classes. However, in class IVb and Va TMD, joint pain was reported frequently, but for classes IVb and IVa, it was registered from four- to ten-times less often, respectively. At the same time, for class Vb, sounds from the joints were noted in 86% of cases. However, sounds from the joints were noted much less frequently in the other classes. Therefore, it should be noted that, for the Vb class, the most characteristic symptom was joint sounds without joint pain, but for classes IVb and Va, joint pain was the typical symptom.The analysis of the results depends on the side that the joint was located shown in . In Figup > 0.05).This corresponds well with the results presented in p < 0.05) differences in the distribution of symptoms in the classes. For the IVa class, the symptoms were not registered in the case of most of joints. However, for the other classes, the percentages of joints without symptoms were one-third lower. Joint pain was typical for classes IVb and Va, but rare for others. Popping joint sounds were frequently  noted for the Vb class.The impact of the Piper classification on temporomandibular joint symptoms is presented in p < 0.05)).The bone changes in TMJ intensified in the subsequent classes f. As theAn occlusal interference was registered in all patients. However, considering but the side of the particular joints, a CR molar occlusal interference was noted for nearly 60% of the joints , and itsThe disk changes and position are the key features that are diagnosed with MRI. Diagnosis depends on the technique to a large extent. An MRI at 3.0 T shows significantly better visibility and better overall image quality compared to 1.5 T ,45 becauIn the presented research, TMJs classified as Piper class IVa–Vb were analyzed due to the small number of joints assigned to classes II–III. In another study, the majority of joints were classified as classes IIIa–IIIb, but the number of joints classified as Piper II class was also small. Moreover, a much smaller number of joints were classified as Iva–Vb . This faGenerally, it should be assumed that a higher stage in the Piper classification would cause more frequent symptoms and more significant anatomical changes than bone tissue remodeling . For example, Larheim et al. found that TMJ pain patients generally had more severe joint changes compared to the asymptomatic control group . AnterioThe phenomenon of reducing the frequency of joint pain symptoms with the intensification of the destruction of joint structures and sounds from the joint can be explained by the progressive adaptation of the structures to the new  situation. In this state, significant damage to the adjacent structures occurs, but the situation becomes stabilized. The findings are in agreement with the results found by the authors of , who staOn the other hand, neuroimaging revealed that changes in the brain are associated with changes in the TMJ and MM regions and with TMD pain . Muscle We found occlusal interference in all patients, although these problems did not often occur on both sides—only about 60% of TMJ occlusal interference was recorded on the side of the analyzed joint without regard to the Piper class. The occlusal changes may be related to a change in the joint area because the medial part of the joint, which we examined by MRI, is the load bearing part of the joint, so occlusal changes would be expected. This can partially explain the term occlusal disease. However, it should be noted that only a couple of the selected studies have indicated a correlation between TMD and occlusal factors ,82. OnlyThe small size of the patient group was a limiting factor. The patients were treated in a private clinic from a geographic area with a low population density, which could have affected the results. Another limitation is that our work is retrospective, and the sample size was not determined prior to testing. The number of patients and the distribution of TMJ classified into a particular class will not necessarily be the same in other populations. In the future, a larger group of patients, including a control group of pain-free patients diagnosed according to the Piper classification, should be used. Another limitation is the fact that patients belonging to Piper classes I–III were not included. The number of people who came to the clinic was too small to include patients from classes I–III in the analyses.The presented results linking these pathologies with various symptoms, considering the severity of these pathologies, add to the discussion on this subject. The results of the research indicate that the progressive degradation of the TMJ, represented by the qualification to the higher Piper classes, is associated with an increase in TMJ pain only up to a certain stage (Va). Then, the joint pain occurs less frequently, but the sounds are more frequent. It was confirmed that, although they occurred in a high percentage in all classes, muscle pain and occlusal interference are not indicators of TMJ damage.


Osteoarthritis (OA) is a common condition that is often associated with chronic pain. Pain often leads patients to seek healthcare advice and treatment. In this retrospective cohort analysis of German longitudinal healthcare claims data, we aimed to explore the healthcare resource utilisation (HRU) and related healthcare costs for patients with OA who develop chronic pain.Patient-level data was extracted from the German Institut für Angewandte Gesundheitsforschung (InGef) database. Insured persons (≥18 years) were indexed between January 2015 and December 2017 with a recent (none in the last 2 years) diagnosis of OA. HRU and costs were compared between patients categorised as with (identified via diagnosis or opioid prescription) and without chronic pain. Unweighted HRU  and healthcare costs  were calculated per patient for the year following index. Due to potential demographic and comorbidity differences between the groups, inverse probability of treatment weighting (IPTW) was used to estimate weighted costs and rate ratio  of HRU by negative binomial regression modelling.Of 4,932,543 individuals sampled, 238,306 patients with OA were included in the analysis: 80,055 (34%) categorised as having chronic pain  and 158,251 (66%) categorised as not having chronic pain. The chronic pain cohort was slightly older, more likely to be female, and had more comorbidities. During the year following index, unweighted and IPTW-weighted HRU risk and healthcare costs were higher in patients with chronic pain vs those without for all categories. This led to a substantially higher total annual healthcare cost ─ observed mean; €6801  vs €3682 ; estimated RR = 1.51 .German patients with chronic pain and OA have higher healthcare costs and HRU than those with OA alone. Our findings suggest the need for better prevention and treatment of OA in order to reduce the incidence of chronic pain, and the resultant increase in disease burden experienced by patients.The online version contains supplementary material available at 10.1186/s12891-021-04180-1. Osteoarthritis (OA) is a common, chronic condition, primarily characterised by joint pain and impaired function that can lead to decreased quality of life for patients. The World Health Organization places OA among the top 10 most disabling diseases in developed countries, with 80% of patients experiencing limitations in movement and 25% left unable to perform their major daily activities . OA is oBesides non-pharmacological therapies and patient-centred care , most patients with OA receive pharmacological therapies. Recommendations for pharmacological therapies in international treatment guidelines for hip and knee OA have subtly evolved over time, generally moving away from paracetamol (acetaminophen) and more clearly defining the situations where opioids might be appropriate –12. ThisTo date, the incremental socioeconomic burden of chronic pain caused by OA in Germany has not been established. This study used German longitudinal healthcare claims data to quantify the healthcare resource utilisation (HRU) and associated healthcare costs of chronic pain due to OA. The overarching findings from this study are likely generalisable to other countries with similar healthcare systems and demonstrate the substantial costs involved in the attempt to treat patients with OA and chronic pain.This was a retrospective cohort study based on anonymised claims data from the Institut für Angewandte Gesundheitsforschung (InGef) database. This database contains treatment and diagnosis data for more than 4 million insured persons in Germany, stratified by age and gender  to ensure adequate representativeness of the German population.Patients ≥18 years of age were indexed on main or secondary hospital or assured ambulatory diagnosis of hip or knee OA  between 01 January 2015 and 31 December 2017 , an assured ambulatory diagnoses of chronic pain in at least 2 quarters, or ≥ 1 prescription for a weak or strong opioid  represents the proportion of patients with chronic pain (i.e. the intercept of a logistic regression model without any covariates).The following formulas were used to calculate the IPTW, where Patients categorised as with chronic pain:Patients categorised as being without chronic pain:The distribution of IPTW was truncated using the 99th percentile as a cut-off point. Based on the accordingly weighted population, logistic regression models were used to estimate the effect of chronic pain on the HRU and cost outcomes, respectively. Rate ratios (RR) with 95% confidence intervals (CIs) were estimated for HRU outcomes.This study is based on data from the anonymised InGef database and publication was approved by InGef. All analyses were conducted by Elsevier Health Analytics at the Institute for Applied Health Research, Berlin, Germany (InGef). The study was conducted in accordance with all legal and regulatory requirements, as well as with scientific purpose, value, and rigour.Of 4,932,543 individuals in the sample, 238,306 patients with OA met the inclusion criteria for the study Fig. . One-thiThe mean age of all included patients was 64.2 years (standard deviation 13.8 years). As shown in Table Patients categorised as having chronic pain appeared to show a generally higher prevalence of pre-specified comorbidities Table . Within The observed incidence of healthcare resource utilisation during follow-up for patients with and without chronic pain is shown in Table Total observed healthcare cost over the follow-up year in mean Euros  were 6801  for patients categorised as with chronic pain, compared with 3682  for patients without chronic pain; representing an 85% increase in total cost for patients categorised as having chronic pain. Patients with chronic pain had higher observed mean healthcare costs in all categories  of self-paid services, suggesting that a significant proportion of OA treatment might not be captured in claims data . How mucThe burden of disease in patients with OA is substantially higher in those who also experience chronic pain. This burden was visible as higher HRU across hospitalisations, outpatient physician contacts, incapacity to work, and prescriptions for physical therapy or psychotherapy, and also as higher associated healthcare costs. To reduce the burden of disease for the individual and for society, new ways to optimise the prevention and treatment of chronic pain in OA are required.Additional file 1: Supplementary Table 1. Definitions for health resource utilisation outcomes and healthcare costs. Definitions used for the assessment of health resource utilisation outcomes and healthcare costs.Additional file 2: Supplementary Table 2. Logistic regression coefficients for variables contributing to the propensity score. Factors incorporated into the logistic regression model to estimate the individual probability of a patient being classified as ‘with chronic pain’. Due to the operational definition of pain in this study, pain medications were excluded from the set of assessed factors. CI 95% confidence intervalAdditional file 3: Supplementary Table 3. Propensity score distribution by percentile. Patients in each percentile of the propensity score.Additional file 4: Supplementary Figure 1. Propensity score distribution. Percentage of patients with each propensity score.Additional file 5: Supplementary Table 4. Most frequently prescribed drugs . Top 10 most frequently prescribed drug classes  for the two years prior to index (baseline) and the last quarter of the follow-up year for patients with osteoarthritis, classified as with and without chronic pain. Defined by Anatomical Therapeutic Chemical Classification System. yr YearAdditional file 6: Supplementary Table 5. Estimated healthcare resource utilisation in 2016 based on negative binomial regression with inverse probability of treatment weighting. Conditional means and rate ratios  for healthcare resource utilisation for patients with osteoarthritis, classified as with and without chronic pain in the year following index, estimated using negative binomial regression with inverse probability of treatment weighting. All are per patient-year. *p < 0.001; †p < 0.05 by chi squared with Wald test. 95%CI 95% confidence interval


Standard opioid tapers tend to be associated with increased patient anxiety and higher pain ratings. Pre-authorized concealed opioid reductions may minimize expectations such as fear of increased pain due to the reduction of opioids and, prolong analgesic benefits in experimental settings. We recently observed that patients and clinicians are open to concealed opioid tapering. However, little is known about the “why” behind their attitudes. Based on this lack of data, we analyzed qualitative responses to survey questions on patients' and clinicians' acceptance of a concealed opioid reduction for chronic pain. Seventy-four patients with a history of high dose opioid therapy and 49 clinicians completed a web-based questionnaire with open-ended questions examining responses to two hypothetical clinical trials comparing a concealed opioid reduction pre-authorized by patients vs. standard tapering. We used content analysis based on qualitative descriptive methodology to analyze comments from the patients and clinicians. Five themes were identified: informed consent; anxiety; safety; support; and ignorance is bliss, or not. These themes highlight the overall positive attitudes toward concealed opioid tapers. Our findings reinforce the importance of patient-centered care and are expected to inform the design of clinical trials from both the patient and clinician perspective. This qualitative study presents patients' and clinicians' attitudes toward hypothetical scenarios for a trial of pre-authorized reduction of opioids. The findings indicate positive attitudes and the relevance of engaging patients with effective decision-making processes. In an effort to reduce the harms associated with long-term opioid use, the Department of Defense (DoD)/Veterans Affair (VA) and the Centers for Disease Control (CDC) have published guidelines that recommend limiting prescriptions of opioids for the management of chronic pain to no more than 90 morphine milligram equivalents (MME) a day –3. WhileAnalgesic benefits of opioids may be prolonged by minimizing negative expectations through the use of a concealed opioid reduction. Prior research has demonstrated that patient expectations directly influence pain outcomes. Higher pain ratings have been linked to fear of pain, increased stress, high anxiety, and pessimism, while lower pain ratings have been linked to reduced stress and anxiety . The simWhile the empirical literature on blind opioid tapering is limited, our research group has written about how this novel approach may benefit patients with chronic pain . One expTransparency is an important construct in ethical research and concerns arise whenever when patients are misled –21. HoweWhile hiding the interruption of opioids remains highly questionable in research and clinical practices , 23, patResearch on attitudes toward blinded tapers suggests that patients with chronic pain and clinicians who manage patients with chronic pain may be open to a trial with a concealed opioid taper. In addition, studies examining clinicians' perspectives highlight several factors, such as effective communication, that may further bolster opioid tapering efforts –31. In tThis is a qualitative descriptive study based on written data from a cross-sectional survey. Quantitative findings from this cross-sectional survey examining patient and clinician acceptance of a concealed opioid reduction for chronic pain have been previously reported . Both paEach patient respondent answered a 13-question survey including general questions related to demographic information and addressing their responses to two hypothetical patient scenarios of opioid-dose tapering. The first scenario depicted a standard tapering (overt administration) and the second scenario depicted a concealed dose tapering (covert administration). For details, see hypothetical scenarios below:Hypothetical scenario 1.A 46-year-old man had a back injury 10 years ago, for which he started taking 50 morphine equivalent daily dose (MEDD). Now, many years later, his dose has risen to 200 MEDD. His doctor wants to recruit him for a 6-week clinical study to help reduce his opioid use. The study consists of two groups: Group 1 (standard 6-week taper) receives a standard, gradual opioid taper (consistent with DoD/CDC recommendations) for 6 weeks. Throughout the study, the participant is monitored over the phone and provided supportive counseling and psychotherapy for chronic pain. Group 2  is also told they will receive a gradual opioid taper for 3 months. However, during the informed consent process, the participant is informed that they will not be aware of how much their opioids are being decreased from week to week as the number of pills will remain the same. Throughout the study, the participant is monitored over the phone and provided supportive counseling and psychotherapy for chronic pain.”  sees the doctor, she is fine. So, if she was in group 2, and getting lower doses and not knowing it but still seeing the doctor, I believe that she would be fine and it would work better for her.” Clinicians had varying views on the amount and types of support that would be beneficial for the hypothetical patient. For example, “Beyond being a placebo responder … she did not also have much response to opioids.” The standard “supportive counseling and psychotherapy for chronic pain” may not be adequate and “I think a supported wean with no ‘set goal’ is probably one of the few ways to do this right.”Many patients and clinicians highlighted the psychological factors that influence pain. Responses that were grouped in this theme expressed two opposing beliefs: that not knowing one's dosages would be a positive attribute of this study, or (the opposite) that not knowing the dosage would have a detrimental psychological effect on the patient's pain levels. Some wrote about the psychological benefits of not knowing if they were receiving a concealed reduction. Many patients viewed the hypothetical patient presented in the concealed dosing scenario as being the best fit for the concealed reduction trial. “Out of sight out of mind” and “Yes because she starts feeling pain if she knows her dose is reduced therefore group 2 is suitable for her where she will not know about amount of dose reduced with time” are two examples. However, other patients did not think either group would be helpful because the hypothetical patient's pain was directly related to her “knowing” if she is receiving the medication: “I don't think she would make a good participant because the clinician will not know if her pain is real or not.”On the other hand, some clinicians thought that the concealed reduction group would not help the hypothetical patient. One clinician wrote that “not knowing could push her to exaggerate her pain/ withdrawal symptoms at all times.” Another clinician wrote that “just knowing they're tapering, will cause opioid users' pain.”Some patients personally recognized the psychological aspects of tapering. One patient wrote “If not knowing my dose helps me out mentally in terms of the calmness level and [I] have less side effects physically. The mental always goes from the mental to the physical. It'd be weaning me off.” Another patient wrote “Most of it isn't mental but yes there is a mental part to pain, and there's a medical part to knowing you're being cared of by a physician. Basically you're trying to trick people into not knowing their dose is lower since their pain is the same. Which is why I would be a willing participant even though I wouldn't want to.”In this study, we explored patient and clinician openness toward a concealed reduction of opioids using qualitative data from a web-based survey. We analyzed 39 qualitative comments for common themes from patients and 64 comments from clinicians. Comparing patient and clinician perspectives toward a pre-authorized concealed reduction, five themes emerged: (1) informed consent, (2) anxiety, (3) safety, (4) support, and (5) ignorance is bliss, or not.Our findings expand upon the work done by James et al.  and our Themes of negative affect, safety, support, and tapering ambivalence have been identified in other qualitative studies of opioid tapering. Frank et al.  showed hStudies of clinicians' perspectives on opioid tapering have emphasized the importance of effective communication and patient-centered care , 31. OneOur study found that patients and clinicians were most open to a pre-authorized concealed reduction in the setting of informed consent. Patients emphasized their need to understand the benefits, while clinicians were comfortable referring patients for the hypothetical clinical trial when patients were fully informed about both groups . Both patients and clinicians recognized the challenge in providing informed consent when concealment is part of the study design. We recommend consenting patients at the beginning of the study using the patient-centered “authorized” concealed opioid taper or standard taper. Patients would need to consent to enrollment into either group in order to participate in the study. Those assigned to the patient-centered “authorized” concealed opioid taper should be willing to accept that they may not know the time or dose of the opioid they would receive. Preliminary research suggests that some patients with chronic pain are generally open to the use of authorized deception in research . As poinDespite the benefits of informed consent, we found that many patients reported anxiety about reducing their opioid dosage blindly. However, our study was unique in that it also found that clinicians, too, were concerned about patients experiencing anxiety with a concealed taper. Researchers need to consider how the patient will be feeling at each stage of the taper based on the speed and dosage reduction of the taper . CommuniBoth patients and clinicians in our study reported that some patients may not be candidates for the hypothetical clinical trial that we described. Researchers have an obligation to minimize patient harm by developing specific inclusion and exclusion criteria. Researchers may want to consider exclusion criteria for patients who think concealment will increase their pain, whereby only patients who believe their pain will stay the same or be reduced with the clinical trial should be permitted to enroll. Alternatively, given that prior therapeutic experience rather than expectations can trigger placebo effects , those wOur findings highlight the importance of integrating the diverse perspectives of patients and other relevant stakeholders  to successfully translate these results into applied experimental and clinical settings . The PatThe major strength of this study is the rich perspectives that both patients and clinicians shared in response to the two hypothetical scenarios. Content analysis is an unobtrusive method to directly analyze communication as text. These results, in addition to previously published quantitative data , provideLimitations in our study stemmed from the qualitative design and the study population. Content analysis, by its very nature, involves some level of subjective interpretation. Findings from this study were limited to the responses that respondents provided. Some respondents chose to answer more of the open-ended responses than others. We do not know why some respondents did not answer each open-ended question. We do not know if respondents may have answered the open-ended questions differently if the questions were asked in-person. The use of other qualitative methods/designs  may have provided greater context for these results. Finally, it is noted that this study represented responses to hypothetical vignettes. While patients and clinicians were asked to respond as if they were participating in or referring patients to the hypothetical clinical trials, it is possible that their actual responses may be different if they were participating in real clinical scenarios. Despite these limitations, the findings from this study are important and serve as a baseline for future research and study design in the area of concealed opioid reduction.Our study provides patient and clinician perspectives for a concealed opioid taper clinical trial. We identified five common themes among patients and clinicians to describe their attitudes toward concealment: (1) informed consent, (2) anxiety, (3) safety, (4) support, and (5) ignorance is bliss, or not. Our study emphasizes the need to consider patients' and clinicians' perspectives when designing clinical trials to support a patient-centered approach and improve both clinical applicability and patient outcomes. Our study supports the development of clinical trials with strong informed consent processes that improve patient anxiety and minimize harm, optimize patient support, and mitigate the psychological factors that exacerbate pain during opioid tapering.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Maryland Baltimore. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.TB conducted the study, data analyses, and drafted the manuscript. NK helped with drafting the manuscript. NH conducted the study, analyses, and commented on the final draft. CM, TW, and MC commented on the final draft. LH helped supervise the data analyses, interpreting the results, and writing the manuscript. LC designed the study, supervised the team, and wrote the manuscript approving the final version. All authors contributed to the article and approved the submitted version.This work was funded by the Agency for Healthcare Research and Quality , MPowering the State Initiatives: Strategic Partnership Grant (LC), and University of Maryland Center for Addiction Research, Education, and Service .The opinions expressed herein are those of the authors and are not necessarily representative of the official policy or position of the Uniformed Services University of the Health Sciences, Department of Defense, Department of Health Affairs, or United States Air Force. The views expressed here are the authors own and do not reflect the position or policy of the Agency for Healthcare Research and Quality, Maryland State and University of Maryland or any other part of the federal and state government.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD. Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the  Severe adverse reactions to fluoropyrimidines are some of the main problems related to chemotherapy treatment in solid cancers . These rDPYD gene, have been revealed as the most common cause of severe and life-threatening events induced by fluoropyrimidines [DPYD or phenotyping of DPD activity before starting treatment with fluoropyrimidines [Multiple factors, such as age and sex, are associated with severe adverse reactions to fluoropyrimidines and have been used for therapy individualization ,7. Howevimidines . Severalimidines .DPYD are also clearly associated with fluoropyrimidine-induced toxicity and many others are probably still unknown [DPYD genetic testing in clinical practice [DPYD can suffer severe adverse reactions to fluoropyrimidines [At least four variants are widely recommended for genotyping prior to the first administration of fluoropyrimidines, due to their well-established relationship with toxicity . These v unknown . In addipractice ,15. Furtimidines , which sDPYD which includes exon 4 was found with a high prevalence in Finnish cancer patients receiving capecitabine. This deletion causes a defect in the splicing and thus the loss of exon 4, leading to the generation of a truncated DPD (p.Cys79Thrfs*8).Variation in copy number of intragenic regions has also been described as affecting DPD functionality . RecentlDPYD genotyping. DPD participates in the conversion of uracil (U) to dihydrouracil (UH2). The European Medicine Agency (EMA) recommends DPD testing prior to treatment with fluoropyrimidines [DPD phenotyping is an alternative to imidines . Meanwhiimidines .DPYD. Epigenetic alterations may affect DPYD expression, as shown in the RKO colorectal cancer cell line [DPYD mRNA expression could affect the quantity of DPD generated in some tissues and potentially correlate with fluoropyrimidine-induced toxicity.Another mechanism of DPD activity variation and changes in risk induced by fluoropyrimidines is thorough transcriptional regulation of ell line . These cDPYD gene, DPD activity and DPYD mRNA expression in patients with toxicity grade ≥3 during the first three cycles versus a control cohort with toxicity <3 during at least eight cycles of fluoropyrimidine treatment.The approach of genotyping patients with an extreme phenotype has been shown to be useful in pharmacogenetics to identify new biomarkers ,21. In tThis was a retrospective, observational, longitudinal case–control study. It included patients aged ≥ 18 years, diagnosed with a solid tumor and newly treated with a chemotherapy regime based on fluoropyrimidines. An exhaustive review of 464 medical records from patients treated with fluoropyrimidines since January of 2018 was carried out to select two extreme phenotypes. First, 28 patients presenting severe adverse reactions (grade ≥ 3 following the CTCAE v5 classification) during the three first cycles of fluoropyrimidine-based treatment and, second, 14 patients who did not present any toxicity grade ≤ 1 during at least eight cycles of treatment. The previous periods were the minimum to classify the patients in one of the two groups. Patients were recruited from January 2020 to March 2021. In our hospital, all patients are usually genotyped for c.1905 + 1G > A (rs3918290), c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129–5923 (rs75017182) prior to the first administration of the fluoropyrimidine. Those participants who were not previously genotyped for these variants were screened and, if positive, excluded from the study.The following clinical and demographic variables were recorded: age, sex, fluoropyrimidine used and concomitant medication and type of cancer.Adverse events during every cycle were compiled from the hospital’s medical records. These included GI disorders such as diarrhea, nausea and/or vomiting; hand–foot syndrome, mucositis, hematologic toxicity and other biochemical parameters. Classification and severity rates were based on National Cancer Institute common terminology criteria for adverse events v5.This study was approved by the Institutional Ethics Committee of Hospital Gregorio Marañón . All patients signed a written informed consent.DPYD gene and flanking intron regions were amplified as described in García-González et al. [Genomic DNA was isolated from whole blood using a QIAamp DNA Blood Mini Kit following the manufacturer’s instructions . All of the 23 exons from the z et al. . PCR proz et al. ,23,24. Lz et al. .Blood samples were collected from patients in EDTA tubes between 8:00 a.m. and 11:00 a.m. Plasma was isolated by centrifugation at 3000 r.p.m. for 10 minutes. U concentration was measured in all patients as described previously . A patie® tubes using a PAXgene™ Blood RNA kit . Complementary DNA (cDNA) was synthetized from 300 ng of total RNA using a High-Capacity cDNA Reverse Transcription kit  in a final volume of 20 µL using random hexamers. A 1/10 dilution was used in real-time PCR. All of these procedures were performed as recommended by the manufacturers.Total RNA was isolated from whole blood and preserved in PAXgeneDPYD was relatively quantified by RT-PCR in a StepOne  using HPRT1 for normalization. RT-PCR was performed in triplicate using the following TaqMan probes: DPYD (Hs115750_m1) and HPRT1 (Hs02800695_m1)  in 20µL of final volume . Relative DPYD expression in toxicity versus control group was quantified using the 2−∆∆Ct method, taking as relative expression the sample D031, and in StepOnePlus v-2.3.2 (Applied Biosystems). Relative values of mRNA DPYD expression were represented in Prism version 8 .Blood was collected in Paxgene Blood RNA tubes  and RNA isolated using a PaxGene RNA blood RNA kit . cDNA was synthesized and diluted as described in The DPD sequence generated by 2197insA and wild type DPD were exported from SnapGene v5.2 in Fasta format. The 3D modeling of wild type DPD and DPD 2197insA was carried out using the RaptorX structure prediction server . ProteinThe cDNA region from exon E1-2 to E5 was amplified in all participants to identify the loss of exon 4. PCR amplifications were performed in 10 µL , 1 µM of primer E5-R (5’ AGA GGT TGG ACA TAC CAT TCC A) and 2µL of 1/20 cDNA dilution). PCR was performed with the following conditions: 94 °C 8 min, 40 cycles of 94 °C 30 s, 60 °C 30 s, 72 °C 1 min and a final step of 72 °C 5 min. Fragment length was analyzed using a DNA1000 kit in a 2100 Bioanalyzer . A fragment of 375 nucleotides in length was expected for wild type individuals and a fragment of 287 nucleotides for individuals who skip exon 4.p value < 0.05).After review of 464 clinical records, 41 patients met the inclusion criteria. They were separated into two groups: 14 patients were included in the control group (fluoropyrimidine-related adverse reactions ≤ 1) and 28 patients in the toxicity group (adverse reactions grade ≥3 during the first three cycles). Characteristics of participants are summarized in DPYD sequencing of the coding exon and flanking intron regions (20 bp on both sides) in the 41 patients revealed the presence of 14 SNPs: three synonymous, eight non-synonymous (seven missense and one nonsense), one in the 3′ untranslated region (UTR) and two in the intron region close to an exon. The variants found in every patient can be found in DPYD gene between controls and patients with early severe toxicity .The whole The SNPs were categorized into three groups: specific to the toxicity group, shared by toxicity and control groups and specific to the control group . The mos2 = 0.911). This analysis was also performed by tumor type and no statistically significant association was obtained . However, this increase was not statistically significant. Interestingly, the haplotype c.496G/c.1129-15C was more frequently observed in the toxicity group (25.9%) than in the control one (7.1%). Both SNPs are in disequilibrium linkage   .DPYD was measured in 13 controls and 21 patients of the early severe toxicity group  of DPYD mRNA between controls and patients with early severe toxicity . This anomaly of DPD breaks the flavin mononucleotide domain, where the pyrimidine binding site is located, and lacks the 4Fe-4S domain. Results of 3D modeling of mutated and wild type DPD were obtained using the RaptorX web server and colored and then visualized using Chimera .DPYD sequence followed by measurement of DPD activity is an efficient approach to identify new pathogenic genetic variants [DPYD mRNA expression in 41 cancer patients receiving fluoropyrimidine-based treatment. We have separated them in two groups: those that suffered early severe toxicity (cycles 1–3) and those that did not.The use of the whole coding variants ,16,28,29Our study has disclosed and characterized c.2197insA, a new and infrequent genetic variant most likely associated with DPD deficiency and early severe toxicity to fluoropyrimidine-based treatments. The predicted human DPD model showed that the sequence carrying variant c.2197insA generates a truncated protein (p.Thr733AsnfsTer14) affecting the flavin mononucleotide/pyrimidine binding domain and the C-terminal Fe-S clusters . DPD worDPYD mRNA in this patient was low in comparison with other samples. No 3′UTR DPYD variants have been associated with toxicity to fluoropyrimidines to date. Nevertheless, a study analyzing 33 germline polymorphisms in the 3′UTR of genes involved in drug absorption, distribution, metabolism and elimination (ADME) showed that DPYD rs291593 was associated with recurrence-free survival in breast cancer patients [DPYD expression have been reported, but the variant position suggests a putative posttranscriptional regulation, a role that would explain its relationship with treatment response. In a similar way, c*159A>G could alter DPYD mRNA stability and decrease DPD translation, leading to the early toxicity observed in this patient. The low frequency of this variant hampers the chance to prove this relationship in bigger cohort studies.A SNP in the position c*159A>G in the 3′UTR was identified in patient 9. Variants in the 3′UTR may affect mRNA stability, translation efficiency, nuclear export and cellular location . This vaDPYD mRNA expression levels that were within range. pVal691Leu was considered probably damaging by Polyphen-2 and tolerated by SIFT. In vitro DPD activity was measured for this SNP and considered normal [Another two non-synonymous genetic variants were only found in the group of patients with early severe toxicity to fluoropyrimidines, p.Met406Ile (patient 55) and p.Val691Leu (patients 48 and 54). p.Met406Ile was categorized as benign by SIFT and tolerated by PolyPhen, but ClinVar recognized a conflicting interpretation. No damaging effect of this SNP on DPD activity has been reported . Accordid normal . Both pa2/U ratio, another indirect way to measure DPD activity [Recently, a Dutch pharmacogenetics group has identified SNPs pMet166Val and c.1129-15 as fully functional with a weak level of evidence . The SNPactivity . The higUnfortunately, the approach followed in this work was not able to explain why most of the recruited patients suffered early severe toxicity as a consequence of their fluoropyrimidine-based treatment. Recently, in a similar study, the skipping of exon 4 was found to be common in patients from Finland with severe toxicity to fluoropyrimidines . This esDPYD mRNA expression correlates with poor disease-free survival [DPYD mRNA expression (data not shown) in descendants of a breast cancer patient suffering from severe toxicity to capecitabine and carrying a genetic variant in DPYD skipping of exon 19 [DPYD mRNA expression in control and toxicity groups of patients treated with fluoropyrimidines. DPYD mRNA expression was similar in control and toxicity groups and failed to identify patients at risk of severe fluoropyrimidine toxicity. On the one hand, previous studies found a strong correlation between DPYD mRNA expression with DPD activity in liver sections [DPYD mRNA might not be reflective of global DPD activity, because it does not distinguish mRNA coding for non-functional DPD [DPYD expression is regulated by STAT3 [TWIST1 [High survival . Our gro exon 19 . In thissections  and in tsections . On the onal DPD . DPYD exby STAT3 , interfeby STAT3 , TWIST1  [TWIST1  and seve [TWIST1 ,54. NoneDPYD gene had aberrant methylation of the DPYD promoter [2/U and DPYD mRNA expression, suggesting that DPD activity is not dependent on gene expression in whole blood.Only one of the newly discovered variants in the toxicity group, c.2197insA, seemed to be clearly associated with DPD deficiency and early toxicity, based on DPD modeling and the patient’s level of plasma U. Furthermore, the absence of inactivating mutations is not the only mechanism involved in DPD activity, for example, methylation has been recognized as a gene silencing mechanism . Ezzeldipromoter . MoreoveDPYD variant. Intriguingly, no DPYD variants were observed in the patient with the greatest activity deficit  and their DPYD mRNA expression was above the 25th percentile. Intriguingly, patient 42 in the control group showed partial DPD deficiency by plasma U and presented low DPYD mRNA expression.Interestingly, two patients with a DPD-deficient phenotype, as established by plasmatic U in the toxicity group (patients 3 and 52) and one in the control group (patient 20), did not carry any The measurement of plasma U is widely accepted for detecting DPD deficiency ,57. HoweAltogether, the present findings strongly suggest that several other variables may influence the tolerability of fluoropyrimidine-based treatments. Nevertheless, a larger comparative case–control study involving thousands of individuals is needed to draw statistically significant conclusions. In addition, these results support the use of approaches including multiple genes and other parameters in future studies in order to try to better predict fluoropyrimidine-induced toxicity.DPYD genetic variants, mRNA expression and indirect measuring of DPD activity to try to identify the cause of severe fluoropyrimidine-induced toxicity in a group of cancer patients. For most of the patients, our approach was unable to provide the cause of toxicity. Other authors have used multiparametric approaches for predicting patients at risk of toxicity due to fluoropyrimidine-based treatment [DPYD mRNA expression in whole blood and early severe toxicity has been observed in this work, in our opinion, the effort to find new biomarkers for toxicity should be focused in genotyping not only DPYD but also other genes, such as TYMS, CDA, ENOSF1 and others related to fluoropyrimidine’s pharmacodynamics and pharmacokinetics, such as CES1, CES2 or UMPS. Implementation of functional studies to prevent toxicity in those patients in whom DPD deficits were detected would be necessary as well.We used a multiple approach, studying reatment . This seDPYD gene sequencing, expression and measurement of DPD activity does not explain all the toxicity observed in fluoropyrimidine-treated patients. Thus, it is necessary to investigate other genes and factors. However, the whole DPYD sequencing helped us to identify a new deleterious variant, c.2197insA, that potentially codes for a non-functional DPD protein (p.Thr733AsnfsTer14) which could cause early severe toxicity.The proposed multiple approach including


There were no significant differences between the QLB and control groups regarding the occurrence of chronic postsurgical pain after 6 months following CS (p = 0.102). No statistical differences between the groups were recorded when we compared the results of the questionnaire after a period of 48 h from CS (the number of participants were limited in number). Conclusions: QLB type I is an analgetic option that increased the satisfaction of parturients with pain therapy after CS compared to patients who did not receive the block, and there is a tendency for a lower incidence of CPSP.Background: Quadratus lumborum block (QLB) provides a reduction in pain scores and opioid consumption after cesarean section (CS). Intrathecal morphine (ITM) is still considered as the gold standard of acute postoperative pain therapy, but it does have some significant side effects. The aim of this clinical study was to evaluate whether performing the quadratus lumborum block type I in patients undergoing CS would be associated with an increased satisfaction of pain therapy and a decreased incidence of chronic postsurgical pain (CPSP). Methods: Sixty patients scheduled for elective CS were enrolled. All patients received spinal anesthesia and were randomly allocated to either the QLB group  or the control group (received no block). The level of satisfaction was evaluated using a three-step scale and the answers provided in a questionnaire regarding the patients’ satisfaction with the method of postoperative pain treatment in the first 48 h. After a 6-month period, all patients were interviewed to evaluate the incidence and possible severity of CPSP. Results: Satisfaction scores were significantly lower in the QLB group than in the control group ( Over several decades, there was a steady increase in the percentage of completed births by cesarean section globally . Pain foWe hypothesized that QLB type I, as part of a multimodal analgesic treatment, would result in higher patient satisfaction and would decrease the incidence of chronic postsurgical pain, as assessed by the questionnaires taken after 48 h following a cesarean section and at 6 months from surgery in comparison to patients who did not receive a block. The aim of this study was to test these hypotheses and to observe any additional positive effects in postoperative pain treatment in patients undergoing elective cesarean section under spinal anesthesia.http://www.randomization.com, accessed on 19 August 2014) and a computer-generated table of unallocated numbers, thus determining who would receive a bilateral quadratus lumborum block type I  or would not receive a block . On arrival to the operating room, all parturients were started on standard noninvasive blood pressure monitoring, electrocardiography, and pulse oximetry. An intravenous cannula was placed in the hand or forearm. All patients received a standardized spinal anesthesia in the sitting position at the L3–L4 interspace with 12.5 mg of 0.5% hyperbaric bupivacaine  and 20 mcg of fentanyl . Following this, patients were placed in a supine position with a 15° left uterine displacement position and supplemental oxygen was provided through a facemask at 6 L/min. The cesarean section was allowed to proceed after a T6 sensory blockade to ensure the loss of cold and touch was confirmed. Intravenous crystalloids and ephedrine were administered as needed to treat hypotension. Patients received an intravenous infusion of 10 of IU oxytocin  after delivery. A dose of 10 mg of metoclopramide was given intraoperatively for prophylaxis of nausea and vomiting. At the end of the cesarean section, patients in both groups received intravenous paracetamol (1 g) .The study was approved by the Bioethics Committee at the University of Warmia and Mazury, Poland (reference number 21/2014), and was conducted between September 2014 and September 2015. Sixty patients, with the American Society of Anesthesiologists’ (ASA) physical status scores of I–II, were included. All patients were scheduled for elective cesarean section via a Pfannensteil incision under spinal anesthesia. Written informed consent for their inclusion in the trial was obtained from the patients. The exclusion criteria were: known drug allergies to those used in the trial, infection or erythema at the injection site, pregnancy-induced hypertension, anatomic anomalies affecting the fascial block, coagulation disorders, and a history of paracetamol or opioid abuse. Patients were randomized using a website application  and connected to routine monitoring. Nurses providing postoperative care were blinded to the study group allocation. According to the study protocol, all patients received intravenous paracetamol (1 g) at regular 6 h intervals and 5 mg of morphine was administered subcutaneously to patients with a pain intensity of more than 3 in the NRS scale or on demand at 4 h intervals for the next 48 h.The level of satisfaction with the analgesic treatment was evaluated by a blinded investigator at 6, 12, 18, 24, 36 and 48 h postoperatively using a 3-step scale; 1—highly satisfied, 2—satisfied, and 3—unsatisfied with the analgesia. After 48 h from the completion of surgery, all patients received a questionnaire regarding their satisfaction with the method of postoperative pain treatment. Additional comments from patients were allowed. Following a 6-month period, all patients included in the study were interviewed by phone to evaluate the incidence and possible severity of chronic postsurgical pain. Other relevant outcomes, such as 48 h morphine consumption, postoperative pain severity, time to the first morphine request, the incidence of postoperative nausea and vomiting, and the presence of pruritus, were reported by the authors in a previous study .Our primary outcome measure in this study was the level of patient satisfaction with the treatment of postoperative pain. Our secondary outcome measures included the assessment of chronic postsurgical pain (CPSP) occurrence.p = 0.05. The Shapiro–Wilk test was used to test for normality. A non-parametric Mann–Whitney U test was used when the obtained values did not follow a normal distribution. An assessment of whether elapsed time had a significant impact on the levels of satisfaction of the studied patients was made and whether similar changes occurred in both the control group and QLB I group. As the assumption of sphericity was not met, a multivariate analysis of variance was made with a Greenhouse–Geisser test. A Chi-square test was used to compare responses collected from the chronic postsurgical pain phone survey. It was not possible to define numerical statistical differences between the groups in the questionnaire given to patients after 48 h of care.A sample size was calculated based on data from a pilot study previously published and from similar clinical trials ,12,13. ASixty patients were recruited and randomly assigned to the QLB I group or control group. However, two patients from the QLB I group were excluded due to postoperative analgesic protocol violations, resulting in 58 patients in the final analysis . The basp < 0.05) However, no difference was seen after 48 h from surgery (p = 0.17) (p = 0.000) , showed a statistically meaningful difference between the groups in 6, 12, 18, 24 and 36 h after the cesarean section ( = 0.17) . Elapsed= 0.000) .p = 0.102)  .The effectiveness of pain therapy was significantly better, as assessed by the patients in the QLB I group when compared with the control group, given the results of the questionnaire after a period of 48 h from surgery . HoweverParturients undergoing cesarean section are a unique group of patients in terms of optimizing postoperative pain relief . On the For decades, both opioid and non-opioid analgetic drugs were the mainstay in the treatment of postoperative pain after cesarean section . HoweverIn our study, we investigated whether QLB type I was effective in improving satisfaction with postoperative pain treatment among parturients after cesarean section and its effect on the incidence of postsurgical chronic pain. In the year 2014, when the study was designed, QLB type I with a lateral approach technique was the first described point of injection by Blanco et al. and was, therefore, chosen by the authors . Since tSalama et al. assessed satisfaction with analgesia in a three-point scale between patients receiving QLB, patients receiving no block, and a third group of patients receiving intrathecal morphine . In the We would like to underline the answers provided in the questionnaire after 48 h of treatment by a subgroup of parturients in our trial. All the patients in the QLB group who had a cesarean section in the past without an ultrasound-guided regional anesthetic block stated that they would like to have QLB performed again for a future cesarean section or other abdominal surgery.Another rarely assessed, but important aspect of patient quality of life following surgery is the occurrence of chronic postsurgical pain (CPSP), which is considered one of the most common surgery-related complications ,27. The p = 0.102). This result correlates with those published by Borys et al., in which statistically significant differences between all groups were not seen after 3 and 6 months from the cesarean section, but such differences were noted only after 1 month [In our study, the incidence of CPSP in the surgical incision area after 6 months from the cesarean section was lower in the QLB I group when compared to the control group , but this was not statistically significant  methods due to the lack of equipment at the time of the trial and subcutaneous morphine administration might have affected patient satisfaction. Another limitation was the fact that only staff taking care of the parturient after cesarean section (nurses and obstetricians) were blinded, which could have led to bias. A more direct comparison could have been made between the QLB I group and the control group if a sham block was administered. Statistical analysis of the answers to the questionnaire after 48 h from surgery was not performed due to the low number of answers provided by the involved participants.The results of this study demonstrate that QLB type I is an analgetic option that increases the satisfaction of parturients with pain therapy following cesarean section when compared to patients that did not receive the block, and there is a tendency for the lower incidence of chronic postoperative pain, although no statistical difference was demonstrated. However, significant differences in opioid consumption or lower pain scores do not necessarily translate into the best quality of postoperative pain treatment, as seen by our patients. Additional tools for satisfaction assessment and appropriate follow up on the incidence and severity of chronic pain should be considered as part of pain therapy efficacy following cesarean sections. Further studies may be needed to focus on other aspects of pain treatment perception.


Multimodal therapies comprising spa applications are widely used as non-pharmaceutical treatment options for musculoskeletal diseases. The purpose of this randomized, controlled, open pilot study was to elucidate the involvement of the endocannabinoid system in a multimodal therapy approach. Twenty-five elderly patients with knee osteoarthritis (OA) received a 2-week spa therapy with or without combination of low-dose radon therapy in the Bad Gastein radon gallery. A 10-point numerical rating scale (pain in motion and at rest), WOMAC questionnaire, and the EuroQol-5D (EQ-5D) questionnaire were recorded at baseline, and during treatment period at weeks one and two, and at 3-month and 6-month follow-ups. Plasma levels of the endocannabinoid anandamide (AEA) were determined at baseline and at 2 weeks, and serum levels of several cartilage metabolism markers at all five time-points. A significant and sustained reduction of self-reported knee pain was observed in the study population, but no further significant effect of the additional radon therapy up and above base therapy. This pain reduction was accompanied by a significant reduction of AEA plasma levels during treatment in both groups. No significant differences were seen in serum marker concentrations between the groups treated with or without radon, but a small reduction of serum cartilage degradation markers was observed during treatment in both groups. This is the first study investigating AEA levels in the context of a non-pharmacological OA treatment. Since the endocannabinoid system represents a potential target for the development of new therapeutics, further studies will have to elucidate its involvement in OA pain. Osteoarthritis (OA) is a major public health problem among the increasing aged and obese population. OA involves the entire joint and is characterized not only by progressive cartilage breakdown but also by inflammation of the synovial compartment, changes in subchondral bone and osteophyte formation, bone marrow lesions, and changes in the joint capsule and ligaments (Lambova and Muller-Ladner There are no disease-modifying drugs (DMOADs) for the treatment of OA available at the moment. Therefore, treatment is restricted to symptoms management like pain reduction, improvement of joint mobility and functionality, and delay of disease progression. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for symptom relief but are also known to elicit potentially serious gastrointestinal and renal adverse effects during long-term oral application  system plays an important role in pain modulation and has been implicated in the manifestations of OA pain . Patients (planned 30) were recruited by a press release and advertisements in local newspapers and included for participation by a physician of the University Hospital for Orthopedics and Traumatology, Salzburg. Inclusion criteria were radiographically diagnosed OA of one or both knees, age 60–75 years, pain score before study onset ≥ 3 on a numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain), and suffering for a minimum of 1 year from OA-related pain. Excluded were patients with diseases representing a contraindication to radon therapy in the radon gallery. The recruiting orthopedist also performed the Kellgren-Lawrence classification on the basis of the radiographs.https://www.evidat.com/rita). All study participants stayed in a Bad Gastein health resort (1.000 m a.s.l.) for 2 weeks and received the same number of basic therapies: 4x under water therapies, 4x massage, 2x sensorimotor training, 2x mudpacks, 4x ergometer training, and 2x knee-specific training. The radon group undertook 8 additional 1-h treatments in the radon gallery (yearly average 44 kBq/m3). Blood (serum and plasma) and urine samples were collected at start (T0), after 1 week (T1), and at the end of the cure regimen (T2). Follow-ups took place at the Paracelsus Medical University 3 (T3) and 6 (T4) months after the therapy. At all time-points, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, the EuroQol-5D (EQ-5D) questionnaire, and a numeric rating scale (NRS) addressing pain in motion and at rest were handed out to the patients for the acquisition of patient-reported outcome. In addition, at the end of the cure regimen (T2), patients completed a short questionnaire addressing their estimation of the treatment success.Enrolled patients were randomized in two arms into a radon and a control group with an online randomization tool . Twelve milliliters of blood from each individual was collected in serum and plasma tubes  according to manufacturer’s guidelines, and plasma and serum aliquots were immediately frozen and stored at −80°C until further processing. Urine samples of each participant were equally frozen immediately. All samples were collected in a non-fasted state between 9 and 12 am.Serum levels of cartilage oligomeric matrix protein (COMP) and N-propeptide of collagen IIA (PIIANP) were quantified by enzyme-linked immunosorbent assays (ELISA) according to the manufacturer’s guidelines . Urinary C-terminal cross-linked telopeptide of type II collagen (uCTXII) was analyzed by ELISA , and the raw values normalized to urinary creatinine quantified by diagnostic test strips according to the manufacturer’s protocol 18 HyperSep–Retain SPE cartridges  were used to enrich unpolar analytes from plasma samples. After equilibration with 1 mL acetonitrile ) and washing with 1 mL H2O (0.1% FA) 500μL of plasma spiked with 1 μL of internal standard d4-AEA (c = 1 ng mL−1) were directly applied onto the column bed, sucked through, washed with 1 mL of 20% ACN (0.1% FA) and sucking through air for 30 s to dry the column bed. Elution of the enriched analytes was done by sucking through 400 μL of ACN (0.1% FA) and directly collecting the flow through in 0.5 mL Eppendorf vials. HPLC-MS measurements were done with a Thermo Ultimate 3000 System, equipped with two different Thermo Hypersil Gold C18 columns, a narrow bore 100 mm × 1 mm i.d. column, and a 100 mm × 2.1 mm i.d. column. The complete series was measured on the 2.1 mm i.d. column at a flow rate of 300 μL min−1. Injection volume was 5 μL. Mass spectrometric detection was done by selected reaction monitoring using the mass of the intact molecule and the 3 most intensive MS transitions . In order to compensate for system performance fluctuations, MS ion suppression effects and varying losses through sample preparation analyte peak areas were normalized to the internal standard peak area.Plasma samples were thawed just prior to sample preparation. Cannabinoid enrichment was performed by solid phase extraction. Thermo 1mL Cα ≤ 0.05 for all tests.Statistical analyses were performed using SPSS software , and graphs were created using GraphPad Prism 8.1.2 . All variables are expressed as mean ± standard deviation (SD) unless otherwise indicated. A linear mixed model approach with time, treatment, and time*treatment as fixed factors was used for statistical analysis. Statistical significance was set at the level of Figure p < 0.001; stiffness: p < 0.001; physical activity: p = 0.026; total score: p = 0.002). However, between-group pairwise comparisons did not disclose any significant impact of the radon treatment over time. The reduction of all scores is most prominent at T2 at the end of the patient’s sojourn in Bad Gastein, and then the scores rise until the last measurement but are still below starting values indicating a sustained improvement of OA symptoms even 6 months after the end of the cure regimen.The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is internationally used for the assessment of knee and hip OA. Figure p = 0.005; pain in motion: p = 0.001), showing up to 50% improvement of pain at the end of the treatment phase. However, additional radon therapy again did not cause any further statistically relevant improvement compared to the control group. Pain-reducing effects of the whole treatment are still evident after 3 and 6 months. In contrast, health-related quality of life assessed by the EQ-5D questionnaire is slightly but not statistically significant elevated until T2 in both groups and then drops below baseline values at T4.The reduction of WOMAC OA scores is also reflected by a mitigation of self-assessed pain in a numeric rating scale ranging from 0  to 10 (worst imaginable pain). Pain at rest Fig.  as well To interpret changes in OA scores at the individual level, we measured the portion of improved patients at the end of the treatment phase by a short questionnaire addressing the self-estimated success of the therapy on a 5-point Likert scale . 61.54% of patients in the radon group assessed a good effect of the treatment at T3, compared to 25% in the control group  is defined as the smallest change in measurement that signifies an important improvement. Among the patients, who considered the effect of the radon treatment as good, 75% experienced a decrease in pain > 2 points on a 10-point NRS for pain in motion.The question, whether the known pain reducing effects of the Gastein multimodal therapy affect the endocannabinoid system or are mediated by it, prompted us to quantify the endogenous cannabinoid anandamide (AEA) in the plasma samples. We were able to determine AEA concentrations in 22 samples, and in 3 samples, AEA levels were beyond the detection limit. Analysis revealed a significant reduction of AEA after the 2-week cure regimen in both treatment groups Fig. .Fig. 5Plp = 0.041) indicating a potential chondroprotective effect of the whole treatment, but no additional effect of the radon therapy. This is supported by a slight but not statistically relevant decline in uCTX levels in both groups during the cure regimen. Serum PIIANP levels, indicative of type II collagen synthesis, reveal individual variations, but in sum remain unaffected by the treatment.Levels of the putative cartilage degradation markers urinary CTXII and serum COMP and serum levels of PIIANP are shown in Table In the present explanatory, longitudinal pilot study with 25 OA patients, we investigated the effects of a multimodal treatment and additional radon therapy on pain and biomarkers of cartilage metabolism. In addition, we quantified levels of endogenous AEA to determine potential effects of the cure regimen on the endocannabinoid system.Statistical analysis revealed a significant sustained reduction of the WOMAC total score and the WOMAC subscores for pain, stiffness, and physical function. A significant reduction of pain was also evident in pain numeric rating scales addressing pain in motion and pain at rest. Although symptom reduction seemed slightly stronger and more sustained in the radon group , no statistically significant impact of the additional radon treatment could be shown in this pilot study. Health-related quality of life was improved as well in both groups until 3 months after the end of the cure regimen.Interestingly, we could also show a significant decline of AEA plasma levels during the cure regimen in both groups. The endocannabinoid AEA has been shown to modulate inflammation by suppressing the production of pro-inflammatory cytokines. It also inhibits NO synthesis and TNF-α-mediated activation of transcription nuclear factor B  measure.Many effects of radon therapy have been shown for systemic inflammatory diseases (Falkenbach et al. Balneotherapy or spa therapy is often prescribed as complementary therapy, but also for patients suffering from severe side effects by pharmacological treatments or from comorbidities contraindicating pharmacological treatment. However, scientific evidence for these treatments is low. Our study was aimed to provide a basis for further and larger studies about the impact of complementary therapies for OA.


Painful total knee replacement (TKR) without an obvious underlying identifiable pathology is not uncommon. Dissatisfaction after TKR can be up to 20%. Different treatment modalities, including non-operative and operative procedures, have been described in the literature. Radiofrequency ablation of genicular nerves (GNRFA) is emerging as a newer treatment modality for painful TKR without an obvious underlying identifiable pathology. Despite a modest number of publications demonstrating the usefulness of GNRFA in managing pain in knee osteoarthritis, the efficacy of GNRFA has not been completely established in the management of residual pain after TKR. This systematic review aimed to analyze all published studies (nine studies) on GNRFA as an option to manage residual pain after TKR. Based on this current systematic review, we noted that GNRFA is a modality to treat post residual pain and patients can anticipate improvement in pain up to three months with minimal complications. This article provides an overview of the currently available knowledge and techniques employed for this procedure, as well as the expected outcome and safety profile of GNRFA in painful TKR. Dissatisfaction after total knee replacement (TKR) can be up to 20% . The mosNevertheless, minimally invasive modalities can be appealing for managing residual post-TKR knee “residual pain” in patients where no identifiable cause is found. Radiofrequency ablation (RFA) of genicular nerves (GNRFA) is gaining popularity as one of the modalities in managing chronic pain in knee osteoarthritis (KOA) and painful TKR -10. DespMethodologytrials.gov through March 31, 2021. We reviewed the results obtained after this search about our inclusion criteria. We also screened all the references from fully retrieved articles not to miss any further relevant studies. Article titles were screened, relevant abstracts were reviewed, and relevant full-text articles were downloaded. We also considered posters presented in the literature. As described below, inclusion criteria and exclusion criteria were rigorously applied to these articles.Two independent reviewers  performed a search on PubMed using the following MeSH terms: “Total Knee replacement,” “Total Knee arthroplasty,” “Knee pain,” “Genicular nerve ablation,” “Radiofrequency ablation,” “Cryoneurolysis,” “genicular nerve.” We found 34 results. As the number of results was less than anticipated, we also used the keyword “Genicular nerve ablation” on PubMed, Google Scholar, Medline, Cochrane database, Web of Science, CINAHL, and clinical Inclusion CriteriaWe included all studies in which GNRFA was used to manage residual TKR pain (GNRFA) in this review. Moreover, we included all English-language articles or articles whose translations were available in English.Exclusion CriteriaWe excluded patients who had GNRFA in a knee without an artificial knee, including both total and partial uni knee replacement. We also excluded studies in which RFA was applied to patients with residual TKR pain in the non-genicular nerve distribution. Studies that applied RFA before TKR to manage perioperative pain caused by TKR were also excluded. No cadaveric studies and review articles were included in this review.ResultsWe were able to identify 25 relevant articles after a thorough initial review. After reading the full text of the articles, we excluded five articles that discussed using GNRFA for immediate postoperative pain relief -15. FourQuality AssessmentThe eligible papers were scored according to the National Heart Lung and Blood Institute criteria in quality assessment . One ranWe noted several inconsistencies in data presentation, outcomes, protocols, and follow-up. The studies were heterogeneous regarding the outcome measures, duration of follow-up, types of modality, and guidance for RFA used. Therefore, we could not perform a statistical comparison. However, descriptive statistics were reported. The data were normally distributed, as evidenced by the Shapiro Wilk test, and hence, data were analyzed using the parametric test. We obtained pooled data from the above-mentioned selected nine studies Table . The totDifferent functional scores, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score, Short Form 36 (SF-36), were used in these studies, making it difficult to compare the outcomes. Overall, 42/70 (60%) of patients reported WOMAC scores as patient-reported outcome measures (PROM) ,30. YoshThree types  of RFA can be applied for genicular nerve ablation. In this study, after applying exclusion criteria, there were no cases with pulsed GNRFA. Overall, 59/70(84%) patients underwent conventional GNRFA, and 11/70 (16%) patients underwent cooled RFA  patients underwent the RFA procedure using fluoroscopy, while 15 (22%) received ultrasound guidance for the placement of RFA needles. We attempted to compare the outcomes of these two groups, but sufficient data points and details were not available for a meaningful comparison.Some authors have recommended using preoperative blocks to predict successful outcomes following GNRFA. On a closer look, only 10 (14%) patients had information about the use of blocks. There is no information available from the rest of the articles. There is a good possibility that the rest of the authors might not have used pre-procedure blocks. However, as this information is not available, we did not draw any conclusions. Three patients received preoperative blocks while seven patients did not receive the blocks ,31,32,34The studies were further analyzed to determine how long after TKR the RFA procedure was performed. This information was available for only 30 (42%) patients. Two authors reported using RFA after six months, while one author reported that RFA was applied in one knee after three years and in another after five years ,33.Injection of intralesional corticosteroids after GNRFA is practiced by some specialists to reduce post-procedural pain and discomfort. This data was available only for 15 (21%) patients, while the rest of the studies did not mention if steroids were used. Only one patient received corticosteroid injections after the procedure, whereas 14 patients did not receive corticosteroids. All authors used RFA for superomedial, superolateral, and inferior medial genicular nerves. None of the authors reported ablating the other genicular nerve .None of the studies reported significant complications. Some of the minor complications included pruritus and erythema. One of the studies mentioned increased falls in four patients post-RFA. However, the article was not clear if the patients were from the TKR group. The decrease in proprioceptive input was the probable reason according to the author. We noted one case report of infection after GNRFA which was not included for analysis as it did not mention what kind of RFA and which nerves have been ablated . The patDiscussionTKR is one of the most performed orthopedic procedures for symptomatic KOA. After TKR, it might take three to six months for the post-surgical pain to resolve. Any pain that lasts longer can be classified as post-surgical persistent pain (PSPP) ,37. PSPPRFA was first introduced in 1970 to manage chronic pain. It was first successfully used to treat trigeminal neuralgia and later expanded to radiculopathic pain management. Currently, there are three kinds of radiofrequency ablation devices available: conventional (heated) RFA often referred to as RFA, cooled RFA, and pulsed RFA. In RFA, radiofrequency waves are delivered to the target tissue through percutaneously inserted special needles which are insulated in the shaft and have an active tip. The active tip can be 8 mm,10 mm, and 12 mm long, depending upon the lesion area to be targeted. As the radio waves exit through the needle tip, heat is generated through an area of tissue with relatively high resistance. Heat coagulates the local area, denatures local proteins, and results in Wallerian degeneration of the surrounding nerves.The extent of coagulation is determined by the length of the tip, conduction medium, the needle diameter, the temperature used, and the duration of RFA. It has been hypothesized that RFA preserves the basal lamina of Schwann cells, allowing the possibility of nerve regeneration. RFA also promotes neuromodulation by inhibition of the excitatory C fibers ,45. PulsAlthough pulsed RFA is similar to heated RFA, as soon as the temperature reaches 41°, the machine cuts off the electricity. It results in less tissue damage and more precise ablation of the nerves, with similar patient outcomes . It has GNRFA has become popular after Choi et al. conducted a randomized double-blinded study with conventional RFA and sham control for osteoarthritis chronic knee pain . Since iIn our review, we noted that there is a lack of high-quality studies on this topic. The available studies are not well structured and do not provide the best evidence . We wereThe articles we reviewed showed significant variations in how GNRFA is employed. There were dissimilarities regarding technical steps, the guidance used (ultrasound vs. fluoroscopy), post-procedural use of steroids, the number of nerves ablated, and the type of RFA used (cooled RFA vs. heated RFA vs. pulsed RFA). Due to these heterogeneous ways of applying GNRFA, the complications and outcomes cannot be generalized to GNRFA. We suspect these variations can theoretically lead to different outcomes and complications.Our systematic review noted a 50-55% reduction in pain. This pain relief can last for three months. Most studies did not report the duration of follow-up beyond three months. The systematic review conducted by Gupta et al. concluded that RFA in KOA (native knee) can cause significant pain relief that can last up to one year with minimal complications . HoweverOnly one randomized study compared genicular nerve blocks with triamcinolone injection . The stuSome complications such as septic arthritis, inferomedial skin burns, injury to pes anserine tendons, bleeding, and hematoma have been reported with GNRFA in KOA -55. HoweWe noted that three of the articles originated from the United States and two from Spain, and the rest from different parts of the world, including Italy, Turkey, and Japan. The first authors of most of the articles were pain and anesthesiology specialists. The first author of one article was from an orthopedic hospital and another from a physical medicine and rehabilitation specialist hospital. None of these articles were published in mainstream orthopedic journals in the United States. Based on this observation, it is possible that this technique is not popular among orthopedic surgeons. We believe that orthopedic surgeons should be well aware of the efficacy of GNRFA as well as the complications involved in this procedure before either performing or referring patients with residual pain after TKR. In our view, this information helps to appropriately counsel patients and set the right expectations before the procedure is performed.Although RFA is a well-established technique for pain management, its effectiveness in managing post-residual pain for TKA is not fully established. We highlight the fact that there are no properly conducted studies to recommend this technique for this subset of the population with painful TKA without an obvious cause. Based on published studies, RFA can cause temporary and partial pain relief (50%) that can last for at least three months. Pain reduction beyond three months has not been reported in a majority of articles. No significant complications were reported secondary to this procedure except a case report of infection. Minor complications such as local inflammation have been reported in one case. Because of the limited sample size and inconsistent presentation of the literature, meaningful conclusions could not be derived. Available data do not establish the superiority of one modality of RFA over the other. Further, available studies did not report any major complications even though there are isolated reports of complications. Further studies are needed to generate more robust evidence for the above-mentioned points. We recommend that surgeons use GNRFA with extreme caution in treating post-residual pain after TKA as there is not enough evidence to support the procedure to date.


Cancer pain, the most common skeleton-related event of bone metastases, significantly disturbs patients’ life. MRI-guided focused ultrasound (MRgFUS) is a therapeutic option to relieve pain; however, its efficacy and safety have not been fully explored. Therefore, we aim to conduct a meta-analysis on studies reporting MRgFUS for patients with bone metastases.Randomized controlled trials (RCT) and non-RCTs on MRgFUS treatment for patients with bone metastases were collected using PubMed, MEDLINE In-Process , National Institutes of Health , Embase (Elsevier), Web of Science, CINAHL, and the Cochrane Library between August 2007 and September 2019. Data on quantitative pain assessment before/after MRgFUS, response rate, and complication were extracted and analyzed.p < 0.01), at 1–5 weeks was 3.56 , and at 5–14 weeks was 4.22 . Change from baseline in OMEDD at 2 weeks after treatment was −15.11 , at 1 month after treatment was −10.87 , and at 3 months after treatment was −5.53 . The overall CR rate was 0.36 (95% CI: 0.24–0.48), PR rate was 0.47 (95% CI: 0.36–0.58), and NR rate was 0.23 (95% CI: 0.13–0.34). Among 14 studies including 352 patients, 93 (26.4%) patients with minor complications and 5 (1.42%) patients with major complications were recorded.Fifteen eligible studies with 362 patients were selected in this meta-analysis. The average pain score was 6.74 (95% CI: 6.30–7.18) at baseline, 4.15 (95% CI: 3.31–4.99) at 0–1 week, 3.09 (95% CI: 2.46–3.72) at 1–5 weeks, and 2.28 (95% CI: 1.37–3.19) at 5–14 weeks. Compared with baseline, the pain improvement at 0–1 week was 2.54 (95% CI: 1.92–3.16, This meta-analysis identifies MRgFUS as a reliable therapeutic option to relieve cancer pain for patients with metastatic bone tumors with controllable related complications. Bone is the third most common distant metastatic organ secondary to lung and liver , and aboGenerally, conventional radiotherapy (RT) is the main therapeutic option to relieve local pain and restore normal function in patients with symptomatic bone metastases. In terms of pain relief, RT provides a relief rate of 60% to 80% , 6. BesiFocused ultrasound is a non-invasive technology proposed by Lele et al. 40 years ago . It deliAlthough preliminary clinical studies of MRgFUS have shown excellent response rates and safety to relieve painful bone metastases, reliable data regarding long-term efficacy and complications are still scarce. In this regard, we aim to perform a meta-analysis to evaluate the pain relief efficacy and safety of MRgFUS in patients with bone metastases. Our results may provide a more reliable basis for the clinical applications of MRgFUS in painful bone metastases.The study was in accordance with the guidelines included in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement  and Cochin vitro, or animal studies, or patients who also underwent other therapies  , non-RCT between August 2007 and September 2019, and the research objects were patients with bone metastases. The intervention measures were that the trial group was given MRgFUS with cases more than 10; it was not limited whether there was a control group, and if a control group was set, the intervention measures were not limited. The exclusion criteria were as follows: studies reporting molecular, focused, oplasty) ; the evaoplasty) .The main evaluation indicators include pain grade scores, the change from baseline in oral morphine equivalent dose (OMEDD), and the response rate. All but one paper included in the study used 10-point scales to assess pain and the one paper used 100-point scales. The data of the one paper was transformed from a 100-point scale into a 10-point scale for comparison purposes . Change Two independent investigators (X.H. and R.H.) extracted the following data from each included study: the first author, year of publication, sample size, type of study, follow-up time, and evaluation indicators. Any discrepancy was resolved through discussion. All data obtained was carefully checked to ensure accuracy . The litI statistic was used to access statistical heterogeneity among studies. I values of 25%, 50%, and 75% defined mild, moderate, and severe heterogeneity, respectively  was used for meta-analysis of the pain grade scores in each follow-up period. The meta-analysis was performed using the generic inverse variance. ectively . The fixectively . The prenificant .n = 35) or other types of studies . Finally, a total of 15 studies were included in this study , the United States (n = 112), Israel (n = 38), Italy (n = 23), France (n = 17), Netherlands (n = 15), Canada (n = 21), Japan (n = 10), South Korea (n = 5), and the United Kingdom (n = 9) (The basic characteristics of the selected studies are presented in I2 = 98.1%). The average reported pain scores at baseline was 6.74 (95% CI: 6.30–7.18). Nine studies (268 patients) assessed pain grade scores at 0–1 week with a high heterogeneity (I2 = 98.7%). The mean reported pain scores at 0–1 week was 4.15 (95% CI: 3.31–4.99). In addition, 10 trials (291 patients) assessed pain grade scores at 1–5 weeks with a high heterogeneity (I2 = 98.2%). The average reported pain scores was 3.09 (95% CI: 2.46–3.72) at 1–5 weeks. Nine trials (289 patients) assessed pain grade scores at 5–14 weeks with a high heterogeneity (I2 = 99.7%). The mean reported pain scores was 2.28 (95% CI: 1.37–3.19) at 5–14 weeks.p < 0.01). Besides, compared with baseline, the pain was further improved at 1–5 weeks with a mean reduced pain score of 3.56 . Moreover, we also found significant pain improvement at 5–14 weeks, with a mean reduced pain score of 4.22 .Generally, the pain scores gradually decreased from baseline to the last follow-up (I2 = 86.4%). Change from baseline in OMEDD at 2 weeks after treatment was −15.11 . Additionally, four studies (175 patients) evaluated OMEDD at 1 month after treatment, with a high heterogeneity (I2 = 78.3%). Change from baseline in OMEDD at 1 month after treatment was −10.87 . Three trials (158 patients) assessed OMEDD at 3 months after treatment, with a high heterogeneity (I2 = 76.8%). Change from baseline in OMEDD at 3 months after treatment was −5.53 .OMEDD was also an important index and three trials (158 patients) assessed OMEDD at 2 weeks after treatment  assessed response rate. The results revealed that the overall CR rate was 0.36  patients had minor complications. The main reported minor complications of MRgFUS included sonication pain, position pain, early postprocedural pain, grade I skin burn, and limbs numbness , the Shanghai Jiaotong University Medical-Industrial Intersection Project (Key) (ZH2018ZDA18), the National Natural Science Foundation of China (No. 81772856), and the Youth Fund of Shanghai Municipal Health Planning Commission (20174Y0117).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.