To determine whether acetabular dysplasia is associated with hip pain at physical examination among adults with recent-onset inflammatory back pain (IBP) suggesting axial spondyloarthritis (axSpA).This cross-sectional ancillary study was conducted on the prospective DESIR cohort, which enrolled patients aged 18–50 years who had recent-onset IBP. Two readers used antero-posterior pelvic radiographs to assess the Tönnis angle, acetabular angle (AA), lateral centre-edge angle (LCEA), and femoral head extrusion index (FHEI). Abnormality of one or more of these four variables defined acetabular dysplasia. Hip pain upon physical examination was assessed based on Ritchie’s articular index.The overall prevalence of acetabular dysplasia was 22% (139/636). The proportion of females was higher in the group with acetabular dysplasia. Hip pain was found in 21% (29/139) of patients with versus 12% (59/497) without acetabular dysplasia ; the association was significant in males  but not females . Results were similar when acetabular dysplasia was defined on the basis of LCEA alone .Among patients with recent-onset IBP suggesting axSpA, acetabular dysplasia was significantly associated with hip pain in males. Hip pain related to acetabular dysplasia might result in overdiagnosis of hip involvement by axSpA. What is already known about this subject?Undiagnosed mild acetabular dysplasia is common in adults and may cause hip pain.Axial spondyloarthritis is challenging to diagnose and can involve the hips.What does this study add?In patients with recent-onset inflammatory back pain suggesting axial spondyloarthritis, the common disorder of acetabular dysplasia was significantly associated with hip pain upon physical examination in males but not in females.How might this impact on clinical practice or future developments?Acetabular dysplasia should be sought routinely in patients with suspected axial spondyloarthropathy and, if present, should be considered among the possible causes of hip pain.Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease that predominantly affects the axial skeleton, causing inflammatory back pain (IBP) . The diaInflammatory hip involvement is common in axSpA. In a retrospective single-centre observational study, radiological evidence of inflammatory hip disease was found in 18% of patients with axSpA, often within the first few years after the diagnosis and was mostly bilateral . In addiConditions that can cause unilateral or bilateral hip pain in adults include tendinitis, osteoarthritis, impingement syndrome, and acetabular dysplasia. Acetabular dysplasia is common in adults  and can cause pain even before the common complication of premature osteoarthritis –8. Pain Here, our objective was to determine whether radiological acetabular dysplasia was associated with hip pain upon physical examination in adults with recent-onset IBP suggesting axSpA and might, therefore, mistakenly suggest clinical hip disease related to axSpA.DEvenir des Spondylarthropathies Indifférenciées Récentes, outcomes of recent-onset undifferentiated spondyloarthritis) cohort included 708 patients aged 18–50 years who had IBP for at least 3 months with onset within the past 3 years and symptoms suggesting axSpA according to the local investigator  on  on 16] oValues of the parameters were calculated automatically from these data. For each parameter measured in DESIR-cohort patients, the mean of the two values obtained by each independent reader was taken as the reference. Cut-offs used to define acetabular dysplasia were Tönnis angle > 12°, AA> 45°, LCEA< 20°, and FHEI< 70%, in agreement with many previous studies . At the In the dataset of 50 radiographs, inter-observer and intra-observer reproducibility of radiographic parameter measurement was evaluated by computing the intraclass correlation coefficients (ICC), which were interpreted as follows: < 0.50, poor; 0.50 to < 0.75, moderate; 0.75 to < 0.90, good; and ≥ 0.90, excellent .2 test or Fisher’s exact test, as appropriate, for categorical variables. We performed logistic regression to ensure that significant associations found at individual level persisted after adjusting on main potential confounders for which data were available . Values of p smaller than 0.05 were taken to indicate statistically significant differences. The statistical analyses were performed using SPSS software version 23.0 .The variables from DESIR-cohort patients were described as mean ± SD if continuous and n (%) if categorical. We reported the prevalence of acetabular dysplasia and of each abnormal acetabular-dysplasia parameter at the patient level and hip level, overall and separately for females and males. Prevalence of hip pain upon physical examination and radiological hip osteoarthritis were also reported. The groups with acetabular dysplasia  and without acetabular dysplasia were compared regarding general characteristics and features relevant to the diagnosis of axSpA. Association between acetabular dysplasia and hip pain upon physical examination was then assessed, at the patient level and hip level, considering assessment at the patient level as the main objective of the study. Given that LCEA is the most consensual indicator of acetabular dysplasia, we then conducted similar analyses with acetabular dysplasia defined as LCEA< 20°. Finally, we performed sub-groups analyses in groups defined by sex and age . Differences were assessed using the Mann-Whitney test for continuous variables and the χ2.Among the 708 patients in the DESIR cohort, 636 had baseline antero-posterior pelvic radiographs that allowed valid measurement of acetabular-dysplasia parameters, 341 (53.6%) females and 296 (46.4%) males. Mean age at inclusion was 33.7 ± 8.5 years and mean BMI was 23.9 ± 4.7 kg/mThe ICC values indicated excellent intra-observer and inter-observer reproducibility of radiographic measurements at both hips (≥ 0.93), except for AA at the left hip, for which reproducibility was good . Of the 636 patients, 139 21.9%) had acetabular dysplasia at one or both hips. The prevalence was 26.4% (90/341) in females and 16.6% (49/295) in males. Table 1.9% had Overall, the RAI indicated unilateral or bilateral hip pain at the baseline physical examination in 88 (13.8%) patients. Right hip pain was found in 64 patients and left hip pain in 52 patients. The analysis by sex showed hip pain in 53 (15.5%) females and 35 (11.9%) males.Hip osteoarthritis was present in 8 (1.3%) patients at baseline; all 8 had osteoarthritis of the right hip and 3 also had osteoarthritis of the left hip. Of these 8 patients, 3 (37.5%) had at least one abnormal acetabular-dysplasia parameter. Of the 8 patients with radiological hip osteoarthritis, only 1 had hip pain.p = 0.007). Logistic regression analysis showed that this association persisted after adjusting for age, sex and BMI . When we separately assessed the patients with RAI values of 1, 2, and 3, we found that the prevalence of acetabular dysplasia was 26.3% (15/57), 44.0% (11/25), and 50.0% (3/6), respectively. The analysis by sex showed that acetabular dysplasia was significantly associated with hip pain in males  but not in females  (Table p = 0.004). At the hip level, the presence of acetabular dysplasia was significantly associated with pain. The findings were similar when LCEA< 20° was required to define acetabular dysplasia in the whole population, for both unadjusted  and adjusted analysis . In contrast, the association between acetabular dysplasia and hip pain was similar in all age groups.In the groups with vs. without acetabular dysplasia of the right and/or left hip, the prevalence of hip pain at the baseline physical examination was 20.9% 29/139) and 11.9% (59/497), respectively .The association between acetabular dysplasia and hip pain was significant in males but not in females. We suggest two hypotheses to explain this finding. First, conditions other than acetabular dysplasia and likely to be responsible for hip pain, such as fibromyalgia, may be more common in females . HoweverAnalyses at hip level showed some counter-intuitive results regarding the association between acetabular dysplasia at hip level and contralateral pain upon physical examination. For example, the results highlighted a strong association between right hip acetabular dysplasia and left hip pain among men, more marked than with the ipsilateral hip. Beyond type I error, there is no unequivocal explanation to these intriguing findings. This potentially illustrates the limits of the current definition of acetabular dysplasia, based on several parameters which are assessed binary, not accounting for global hip morphology and not accounting for subtle morphological differences that exist between right and left hip, at population level . It may This study has several limitations. First, data on the characteristics of hip pain are limited, because the DESIR cohort was designed to assess axSpA. We assessed only hip pain elicited during a physical examination by a senior rheumatologist. No data were available on self-reported hip pain or on features suggesting inflammatory vs. mechanical hip pain. As a result, the possibility of an underlying coxitis in some participants cannot be formally ruled out. Regarding this last point, however, a study has shown that acetabular dysplasia can be responsible for pain at night . Second,In conclusion, among males with recent-onset IBP suggesting axSpA, acetabular dysplasia was associated with hip pain upon physical examination. Thus, the common disorder of acetabular dysplasia may mistakenly suggest hip involvement by axSpA in patients with recent-onset IBP. Acetabular dysplasia should be sought routinely on radiographs in patients with suspected axSpA. Studies are needed to further characterise the association between acetabular dysplasia and hip pain and its potential effects on the diagnosis of axSpA.


Topical NSAID use in the first two postoperative days to control pain and inflammation after PRK/TransPRK or epithelium-off CXL, when used in combination with topical steroid therapy, does not appear to be associated with corneal melting or delayed epithelial healing. This approach may represent an improvement over current methods of handling post-surgical pain in procedures that require corneal epithelial debridement.Corneal epithelium removal during photorefractive keratotomy (PRK), TransPRK, or corneal cross-linking (CXL) means that patients experience pain and inflammation after the procedure, which need to be carefully managed with topical drug regimens. One highly effective class of topical analgesics is non-steroidal anti-inflammatory drugs (NSAIDs), but these must be used carefully, as their use has been associated with delayed re-epithelialization and, in rare cases, corneal melting. However, our clinical experience has been that the concomitant use of topical corticosteroids obviates this risk. Here, we present a mechanistic explanation for our observations, our TransPRK and epithelium-off CXL protocols, and the postoperative medication regimens where topical NSAIDs are used in combination with topical steroid therapy during the first two postoperative days (where pain and inflammation levels are the highest). We detail the results of a single-center retrospective case analysis that examined eyes that underwent TransPRK ( Transepithelial photorefractive keratotomy (TransPRK) and epithelium-off corneal cross-linking (CXL) are commonly performed corneal procedures, where the first step of the surgery is to remove corneal epithelial cells, either mechanically or by using an excimer laser ,2,3. ThiNon-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat inflammation and pain, and at first glance, would appear to be suitable to manage the peak levels of pain and inflammation that occur during the first 1–2 postoperative days. However, this approach is only taken with caution in clinical practice. Several reports have been published describing NSAID-induced corneal melting —a rare bWe developed a method that combines both NSAIDs and steroids in the first two days after these procedures, when pain and inflammation are at peak levels. Our empirical clinical experience has been that this gives patients the desired analgesic effect of NSAIDs, but without the drawbacks of delayed re-epithelization or even corneal melting. To validate this approach, we performed a single-center retrospective case analysis to determine the occurrence of corneal melting in eyes that underwent a procedure that involved an initial step of corneal epithelium removal (TransPRK or epithelium-off CXL), which received topical NSAID use in the first two postoperative days to control pain and inflammation after PRK/TransPRK or epithelium-off CXL.For all procedures, preoperative topical anesthesia was administered in the waiting room, with one drop of oxybruprocaine hydrochloride , followed by one drop of tetracaine 1% , applied three times each over a 10-minute period. For the various epi-off CXL procedures, the application of anesthesia was adapted according to the protocol of choice.All procedures were performed by a single surgeon (F.H.) using the SCHWIND Amaris 750S excimer laser platform . After the patient reclined on the excimer laser bed, the eye and periorbital region were thoroughly disinfected with sterile cotton wool buds soaked in octenidine hydrochloride . After the placement of a lid speculum, a moistened Merocel sponge  was applied to the corneal surface, with slow, painting movements to avoid uneven surface humidification. Immediately afterward, laser ablation was performed, and the cornea was then cooled with a 20 mL chilled balanced salt solution. When the stromal ablation was more than 90 μm, mitomycin-C  was immediately applied for 30 s using a damp Merocel sponge, then copiously irrigated, and dried. Topical ketorolac (0.5%) and moxifloxacin (0.3%) were subsequently instilled, and a bandage contact lens  was inserted.The patient was brought to the slit lamp , where the height of the chair and slit lamp were adjusted to ensure the patient’s maximal comfort. This step is important, because once comfortably seated, the patient is able to keep a steady position more easily during irradiation. For that purpose, we also used a chair with two armrests, rather than a simple stool. While the patient was in the sitting position, the eye and periorbital region were thoroughly disinfected with sterile cotton wool buds soaked in octenidine hydrochloride. A lightweight open-wire speculum  was inserted, and sterile surgical gauze was taped laterally to the temporal canthus to collect any riboflavin solution run-off.For epi-off CXL, several different approaches can be used to remove the epithelium, such as by means of a hockey knife or an Amoils brush. However, these surgical tools may be challenging to maneuver in the upright position. Additionally, special attention should be taken not to injure the Bowman’s membrane during the epithelial removal process. Therefore, we used an alternative approach to remove the epithelium. This approach was a modified laser-assisted subepithelial keratectomy (LASEK) approach  using a Our post-TransPRK/CXL medication scheme is depicted in A subset of patients was asked to complete a pain questionnaire within the first two postoperative days, in which the patients were asked to rate their ocular pain from a scale of 0  to 10 (worst pain imaginable), according to the visual analogue scale .At 4 weeks after surgery, corneal haze was determined both clinically at the slit lamp and by using corneal densitometry. Depending on the grade of haze, we either continued with fluorometholone 0.1% eyedrops or switched to loteprednol etabonate 0.5% or preservative-free dexamethasone 0.1% eye drops for another 8 weeks.In the period between 11 January 2016 and 29 April 2022, a single surgeon (F.H.) at the ELZA Institute, Zurich, performed TransPRK on 301 eyes and epithelium-off CXL on 576 eyes , all of which received the postoperative medication regimen detailed in Epithelial closure usually occurred within 4 to 5 days. Not a single patient experienced a corneal melt, nor were any instances of delayed corneal re-epithelialization (≥8 days) noted. Two cases of a suspected beginning sterile infiltrate were noted, but all resolved within 10 days, and no cases of infectious keratitis were observed. Pain questionnaire scores were available for 77 eyes, with the mean pain score (standard deviation) being 0.85 (1.77).2 [Inflammation can be caused by two main pathways: the cyclooxygenase (COX) pathway and the lipoxygenase pathway  12]. Mo. Mo12]. 2 , locatedA twice-daily administration of topical NSAID therapy during the first two postoperative days after PRK, TransPRK, or epithelium-off CXL surgery provides patients with effective pain and inflammation prophylaxis. This, combined with topical steroid therapy, appears to obviate the risk of corneal melt formation and delayed re-epithelialization that has been associated with the increased lipoxygenase and matrix metalloproteinase activity that can occur when NSAIDs are used in the absence of steroid therapy. This approach may not be suitable for all patients, such as those with autoimmune diseases, such as rheumatoid arthritis or Sjögren’s syndrome, who may already be receiving high-dose oral NSAID therapy. In these patients, the conventional post-surgical drug regimen may be more appropriate, or in the case of eyes requiring cross-linking, epithelium-on CXL protocols should be considered.This study has limitations. The study was a large, retrospective case series, and because the protocol described above was routine clinical practice at the study site, there was no “traditional” pain relief population to act as a control group, nor were pain assessment questionnaires issued routinely to patients. While we did not experience any NSAID-related adverse events, and the risks related to this combined approach appear to be minimal, a formal clinical trial comparing patient outcomes using standard-of-care and this novel approach, including comprehensive pain assessments, would be worthwhile, as would continued outcome surveillance.Topical NSAID use in the first two postoperative days to control pain and inflammation after PRK/TransPRK or epithelium-off CXL, when used in combination with topical steroid therapy, appears not to be associated with corneal melting or delayed epithelial healing. Given that this approach provides patients with effective pain relief during the period of peak postoperative pain, this regimen could represent an improvement over current methods of handling post-surgical pain in procedures that require corneal epithelial debridement, such as PRK and CXL.


AB frequency was obtained by ecological momentary assessment with a dedicated smartphone application that sent sound alerts at random intervals during the day for one week. Upon receiving the alert, the volunteer reported the current muscular condition and/or the teeth position, i.e., relaxed jaw muscle, jaw bracing, teeth contact, teeth clenching, or teeth grinding. Data were evaluated by independent t-test (α = 0.05). During the seven days, AB frequency was 62.1% ± 26.8% for TMD patients and 36.2% ± 27.3% for pain-free subjects (p < 0.001). Mandible bracing was most common in the TMD group (p < 0.001), while teeth contact, clenching, and grinding did not differ between groups. Moreover, no differences were found in AB frequency between myofascial pain and TMJ pain patients. Therefore, TMD patients have higher AB frequency characterized by jaw bracing, irrespective of pain location.Self-reported awake bruxism (AB) has been associated with temporomandibular disorders (TMD). However, the daily amount of AB behavior has not been quantified in pain patients. Therefore, this study aimed to assess AB frequency in patients with myofascial pain and temporomandibular joint (TMJ) pain and compare it to a group of pain-free individuals. Eighty-four individuals belonging to either a TMD group ( Awake bruxism (AB) has been defined as masticatory muscle activity during wakefulness that is characterized by repetitive or sustained tooth contact and/or by bracing or thrusting of the mandible . AccordiAn association between repetitive low-level long-lasting non-functional muscle activity has been reported to cause muscle fatigue and pain , and theDespite that electromyography-based evaluation has been suggested to achieve a definitive diagnosis of AB , a contiUntil now, EMA has been used to investigate the frequency of AB in healthy young adults—specifically university students ,15,16,17Therefore, information about the AB characteristics in TMD patients is limited, especially considering a comparison with healthy individuals, which may improve knowledge on AB as a risk factor for TMD and further clarify some possible pathophysiological mechanisms that are implicated in symptom onset . Thus, tThis cross-sectional study investigated AB frequency in TMD patients and pain-free volunteers. Participants in the TMD group were selected from consecutive patients attending the Orofacial Pain Clinic at the University of Siena, Italy. Participants in the control group were selected from consecutive patients attending the School of Dentistry at the University of Siena, Italy, for conservative dental care. Volunteer selection occurred without gender or ethical restrictions.To be included in the study, volunteers needed to have good general health, received at least one painful diagnosis according to the diagnostic criteria for temporomandibular disorders (DC/TMD) , and ownAll volunteers invited to participate had to sign a consent form, which was approved by the local IRB (#344-CES-AULSS9) and followed the Helsinki Declaration. Participants were assured that they could withdraw from the study at any time without any nuisance.® smartphone application (WMA srl) to assess five oral conditions. The application is programmed to send 20 sound alerts at random intervals during the day, with the aim of reducing expectation bias. The subject can choose the type of sound alert to distinguish it from other notifications. Recording time was set from 8:00 to 12:30 and from 14:30 to 22:00 to allow a break during lunchtime [AB frequency was obtained using the EMA approach by use of the BruxAppunchtime .Relaxed jaw muscles: condition of perceived jaw muscles relaxation, with mandibles kept apart;®; Bausch KG, Koln, Germany) is put between the dental arches and he/she is asked to slightly keep the teeth in contact to retain it on site. In short, this condition is defined as a light touching of teeth when the mouth is closed;Teeth contact: condition of slight teeth contact similar to the teeth contact that the subject perceives when a 40 μ articulating paper : condition of jaw muscle stiffness or tension similar to teeth clenching but with teeth kept apart ;Teeth grinding: a condition in which the opposite teeth are gnashed or ground independent of intensity and direction of antagonist teeth contact.Before starting the evaluation period, the investigator provided detailed information on how to use the smartphone application and how to identify each condition, since it has been proved that training participants on such manifestations provides better understanding and compliance . The conhttps://www.youtube.com/watch?v=xL79AcnpBCY&t=15s).For a better understanding of how to recognize the five behaviors, an educational video recorded by the project coordinator (DM) could be accessed by the participants . Additionally, alerts received during functional activities, such as eating or talking, were to be discarded. Data recording was followed for 7 days, and a minimum of 60% replies was necessary to consider the day as valid . In case of failure to reach the minimum percentage of valid answers, the app automatically generated one additional day to complete the 7 valid day protocol. When completing the observation period, an anonymous file was generated (.csv format), and the participant was instructed to send it to the researchers via dedicated email.t-test. Moreover, TMD patients were also compared according to the presence of joint or myofascial pain symptoms. All statistical analyses were performed using the SPSS 21.0  considering a significance level of 5%.The collected data were evaluated by means and frequencies of each AB condition. Data showed normal distribution as verified by the Shapiro–Wilk test. Then, between-group and between-gender comparisons were performed using independent One hundred five individuals were invited to participate in this study. However, 21 of them were excluded due to lack of compliance in replying to the alerts. Thus, 84 participants comprised the final sample: 54 of them belonging to the TMD group  and 30 non-TMD volunteers as the control group .The smartphone app should have been used for one week; however, several participants did not reply to at least 60% of the alerts over seven consecutive days. The mean compliance recorded with the smartphone application was 70.4 ± 8.1% (range 61.4–92.9%) of the total alerts. On average, 9.3 ± 2.9 days (range 7–16) were necessary to achieve the targeted goal of 7 days with a minimum of 60% alerts/day. No gender differences were detected in any compliance data.p > 0.05). Considering bracing behavior, females had a frequency almost twice as high as males .Potential gender-related differences in AB values were investigated. All AB manifestations, except for bracing, did not show statistically significant differences between males and females (p < 0.001). Detailed values for each of the AB manifestations according to each group can be found in During the 7 valid days, AB frequency was 62.1% ± 26.8% for TMD patients and 36.2% ± 27.3% for pain-free subjects  were different between groups. Although previous reports had not examined the jaw bracing condition, some authors  found thConsidering former studies using the same app to collect data on AB behaviors, the healthy subjects included in this research had a similar AB frequency over the seven evaluation days. Although sample characteristics are different among the investigations on young adults ,16,17,18Interestingly, within the TMD patients, no differences in AB frequency were found between patients with muscle vs. joint pain. This finding suggests that the onset and location of symptoms are likely host-mediated and that a common physiopathology of muscle-induced overload may exist for muscle and joint symptoms. This hypothesis is also in line with previous studies reporting that AB is a risk factor for the presence of articular pain in patients with TMJ clicking as well as for intermittent locking ,29.Some limitations should be remarked. Regarding participants’ compliance, the present study lost approximately 25% of the respondents during the week-long interval, highlighting slightly lower compliance compared to the reference study, and pointing out the need to address this issue as part of any future study protocol . NonetheTMD patients have higher AB frequency than healthy individuals, and such manifestations are mainly characterized by jaw bracing. Thus, managing AB could be an important step to reduce pain symptoms, and instructing patients regarding physiological muscle positioning could prevent TMD onset.


Approximately 20% of patients experience chronic pain after total knee replacement (TKR). The impact of chronic pain after TKR on primary care services in the UK is currently unknown. The aim of this study was to compare primary care consultations and pain medicine prescriptions between patients with and without chronic pain after TKR.Data from 5,055 patients who received TKR between 2009 and 2016 with anonymised linked data from the Clinical Practice Research Datalink Gold (CPRD) and English Hospital Episode Statistics (HES) Patient Reported Outcome Measures (PROMs) programme were analysed. The exposure time was from 10 years pre-operative to eight years post-operative. Patients with a score ≤ 14 on the Oxford Knee Score pain component scale at 6 months post-operative were classified as having chronic pain after TKR. Primary care consultations and prescribed pain medicines were quantified, and costs calculated based on national cost data.721 patients (14%) had chronic pain after TKR. The prevalence and costs of primary care consultations and pain medicine prescriptions per year were consistently higher for patients with chronic pain after TKR compared with those without chronic pain after TKR; these differences were observed both before and after surgery. There was a substantial and sustained increase in the cost of opioid prescriptions after surgery for patients with chronic pain after TKR, peaking at seven years post-operative.Increased primary care consultations and pain medicine prescriptions associated with chronic pain after TKR represent a considerable financial cost to primary care services. Evaluation of interventions to reduce the risk of developing this pain condition and improve the early management of pain after TKR are needed to improve outcomes for patients and reduce costs to healthcare services.The online version contains supplementary material available at 10.1186/s12891-022-05492-6. Osteoarthritis is the most common musculoskeletal condition worldwide and is the leading cause of disability in the UK, with one third of people aged ≥ 45 year old having sought treatment for their osteoarthritis . It is aTKR is one of the most common elective operations; it has been estimated that nearly five million people were living with a TKR in the USA in 2010 . In the In the UK, management of chronic pain after TKR is provided within primary and secondary care services. Primary care services provide the first point of contact in the healthcare system and are free at the point of delivery and receipt. Research indicates that 32% of healthcare costs in the second year after TKR are primary care costs . HoweverThis was a retrospective observational study using anonymised linked data from the Clinical Practice Research Datalink Gold (CPRD), English Hospital Episode Statistics (HES) Patient Reported Outcome Measures programme (PROMs), HES Admitted Patient Care, HES outpatient, Office for National Statistics (ONS) mortality data and Index of Multiple Deprivation 2015. All methods were performed in accordance with the relevant guidelines and regulations and reporting of the findings adhere to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.The CPRD dataset contained anonymised information on > 14 million patients registered at 714 UK general practices. Data include computerised records of all consultation and prescription events in primary care and comprehensive demographic information. CPRD provides access to HES-PROMs data held under the CPRD Data Linkage Scheme. HES holds information on patients admitted to NHS hospitals in England, including diagnostic International Classification of Diseases (ICD) codes providing information about a patient’s condition and OPCS Classification of Interventions and Procedures version 4 procedural codes for surgery. Since April 2009, HES provides PROMs data on patients undergoing knee replacement in English NHS hospitals, including a preoperative and 6 month post-operative quality of life questionnaire (EQ-5D) and joint-specific PROM .Our linked CPRD-HES-PROMs dataset included all NHS patients with a CPRD record for a primary TKR between 2009 (when PROMs data collection began) and 2016 (when the data were extracted). Analysis was limited to patients with linked HES records who completed a 6-month post-operative OKS. A data science tool was used to perform automated data engineering, data mining and advanced curation on CPRD and HES data cuts. The tool received raw data as input and provided as output selected and structured information ready for analysis.The OKS is a validated 12-item joint-specific questionnaire that assesses knee pain and function in patients undergoing TKR . A 7-iteA primary care consultation was defined as any direct health-related encounter with a primary care healthcare professional. Given the large number of staff roles , these whttps://bnf.nice.org.uk/medicinal-forms/paracetamol.html) and extracted unit cost based on strength and number of units. Based on the unit cost and quantity prescribed as reported in CPRD records, the total cost of each pain medicine prescription was calculated.Included medicines were those identified using a list developed with expert clinicians based on their views about which medications would be prescribed to patients with pain related to their knee. Pain medicines were grouped into paracetamol (acetaminophen), antidepressants, non-steroidal anti-inflammatories (NSAIDs), and opioids . To calcExposure time was defined as the period valid CPRD data were collected for patients before and after TKR; this varied from patient to patient because of different start and end dates linked to surgery data collection; quality of data; and patient registration, change, or death. Death was calculated using CPRD GOLD and ONS linked data using a published algorithm . ReportiDescriptive analyses were undertaken to report patients’ demographic and clinical characteristics. Primary care consultations and pain medicine prescriptions were calculated for patients with and without chronic pain after TKR. Resource use was calculated as the mean number of primary care consultations per patient per year for any cause and associated costs were calculated as the mean cost per patient per year. Pain medicine prescription costs were calculated as mean cost per patient per year. Some specific medicinal forms were excluded because formulation was not costed or because the quantity was not available. In all such cases, the number of prescriptions excluded as a percentage of the total is reported. To assess whether costs between chronic pain groups were different, bootstrap confidence intervals were calculated for over 1,000 samples with replacement for yearly consultation and prescription costs. Bootstrapped methods were used because cost data are right-skewed and standard parametric methods are hence not appropriate. Differences in outcomes between men and women were assessed via generalised estimating equations (GEE) models using the Gamma distribution and log link function. Analyses were conducted using R.A total of 5,055 patients were included in the analyses. Of these, 721 (14.3%) had a score of ≤ 14 on their 6-month post-operative OKS-PS and were classified as having chronic pain after TKR. Patient demographics and clinical characteristics are displayed in Table The mean number of primary care consultations for patients with and without chronic pain after TKR from the 10 years before surgery to eight years after surgery is displayed in Fig. p < 0.001) than that of women. The difference persisted after controlling for chronic pain group (p < 0.001) and drinking and smoking (p < 0.001). A figure showing sex-stratified mean yearly consultation costs with bootstrap confidence intervals by chronic pain group is shown in the The mean primary care consultation costs per year for patients with and without chronic pain after TKR, overall and by healthcare professional category, are provided in Table p = 0.018) than that of women. This was also the case after controlling for chronic pain group (p = 0.011) but the difference was not evident after adding drinking and smoking (p = 0.062). A figure showing the mean yearly prescription costs for men and women, with bootstrap confidence intervals by chronic pain group, is shown in the Yearly costs for paracetamol, antidepressants, NSAIDs and opioids for patients with and without chronic pain are summarised in Fig. Of particular note, whilst the cost of opioid prescriptions decreased only slightly after TKR and remained relatively stable after that for patients without chronic pain, for those with chronic pain it increased, peaking at seven years post-operative. The proportion of patients receiving a prescription for opioids increased for both groups as they approached surgery , peaking the year after (52% and 32%). After that, the proportion of patients receiving a prescription for opioids averaged values similar to those observed the year before surgery.Our analysis of English routine NHS healthcare data indicated that primary care consultations and prescribed pain medicines were consistently higher for patients with chronic pain after TKR compared to patients without chronic pain. These differences were evident during the entire observational period of our analyses, persisting from 10 years pre-operative until eight years post-operative. There was a considerable difference in the prescription of opioids in the period after surgery, with a steep increase in costs for patients with chronic pain after TKR which peaked at seven years post-operative.It is well known that chronic pain is associated with high societal and healthcare costs, with the national cost of pain found to exceed the costs of heart disease, cancer and diabetes in the United States . People The cost of opioid prescriptions increased substantially after surgery for patients with chronic pain after TKR and remained high over the eight-year post-operative observational period. This suggests that opioids were prescribed with primary care for long-term management of chronic pain after TKR. However, the data analysed was from 2009 to 2016, and medical practice and prescribing is likely to have changed over time, reflecting the consensus amongst healthcare professionals that opioids are not indicated for chronic pain , with clOur analyses used CPRD data, which contains detailed patient-level and prescription-level data on a large sample of patients from across England. However, limitations of our analyses should be acknowledged when interpreting the results. The data in CPRD are based on a subset of GP practices, and our analysis was restricted to those patients with linked HES records that completed a 6-month post-operative OKS, which may have introduced selection bias into our findings and limited generalisability. The data only contain GP prescriptions and not pharmacy dispensations, and therefore it was not possible to confirm the quantity of medications that were bought. We also did not capture the costs to patients of purchasing their own pain medication, and this is an area which may warrant further research. We defined chronic pain status at six months post-operative, a time point at which pain outcomes generally plateau after TKR . HoweverIn conclusion, our study demonstrated that increased primary care consultations and pain medicine prescriptions associated with chronic pain after TKR represent a considerable financial cost to primary care services in England and that patients with chronic pain after TKR are prescribed more opioid medications than those without chronic pain. Evaluation of interventions to reduce the risk of developing this pain condition and improve the early management of pain after TKR are needed to improve outcomes for patients and reduce costs to healthcare services.Additional file 1.


DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients.Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1–172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1,  DPYD gene and constitutes the keystone of fluoropyrimidine elimination. It is responsible for nearly 85% of their catabolism -Uracil , the stable isotope for uracil, was used as an internal standard. The total chromatographic run time was 7 min. The validated concentration range for U and UH2 was from 3.13 to 200 µg/L. Inter-assay bias and precision for uracil ranged from −2.21 to 1.08% and from 2.18 to 7.20%, respectively. For UH2, inter-assay bias and precision ranged from −7.69 to −0.47% and from 5.65 to 8.43%, respectively. All assays were within the recommended limits (±15%)  for non-normal distributions. For qualitative parameters, data are presented as the number of cases n (percentage (%) of patients) Statistical analyses were performed with R 3.4.1.  group and DPD NPG for the dihydropyrimidine dehydrogenase non phenotyped (non-screened) group.To control for confounding factors in the case of an unknown relationship between the DPD PG and DPD NPG groups and covariates, we used inverse probability weighting (IPTW). IPTW weights were estimated as the inverse of patients’ estimated probability of belonging to the DPD PG group. The ability to use all the individuals in the groups for the outcomes analysis is advantageous for propensity score weighting. All the individuals were included in the analysis, and the statistical power to detect the group effect was maintained. Propensity scores were calculated based on the probability of being in the two groups using generalised boosted models, a multivariate nonparametric regression technique ,29,30. Tp-values for the KS statistics were derived from Monte Carlo simulations. All p-values were two-tailed, with statistical significance indicated by a value of p < 0.05.The covariate imbalance was assessed using standardised effect size (std.eff.sz) or standardised bias, defined as the treatment group mean minus the control group mean divided by the treatment group standard deviation, and by Kolmogorov-Smirnov (KS) statistics for each covariate as well as interactions. The study was conducted in accordance with the Helsinki Declaration. As the study was based on medical data systematically recorded for standard care at the Reims University Hospital and authorised by the French national commission for data privacy , the study did not require approval by an Ethics Committee according to French legislation on human research. Data were processed after anonymisation, and the database was created in accordance with the CNIL MR004 method .Among 349 patients screened by plasmatic U quantification, a total of 198 5-FU-treated patients were included during the study period. The mean age in this group was 66.4 ± 11.8 years. As a reference population, 100 patients were randomly drawn from patients treated by 5-FU in 2017, of which 6 were excluded. The mean age in the final reference group was 61 ± 12 years. For our analysis, we thus compared 198 patients who underwent DPD deficiency screening (DPD PG group) to 94 reference patients (DPD NPG group). The study flow chart is presented in Clinical and treatment characteristics of the 292 included patients are described in p < 0.001), the second treatment cycle , the third treatment cycle , and the fourth treatment cycle  (p = 0.028)   as was t= 0.028) .There was no significant difference between the two groups regarding the prevalence of at least one severe toxicity, which was estimated at 5.6% at treatment cycle 1, 4.2% at treatment cycle 2, 4.3% at treatment cycle 3, and 3.4% at treatment cycle 4 in the DPD PG group and at 8.5% at treatment cycle 1, 9.8% at treatment cycle 2, 9.8% at treatment cycle 3, and 4.4% at treatment cycle 4 in the DPD NPG group. Details about encountered acute severe toxicities are presented in p = 0.313 and 0.606, respectively). Still, treatment postponement was significantly more frequent in the DPD PG group for the third course of treatment (p = 0.012)  .p = 0.723, 0.280, and 0.067 after the 1st, the 2nd, and the 3rd treatment cycle, respectively)  .n = 31), median uracil concentration was 19 ng/mL (range: 16.1–52.2).In the DPD PG group, 31 out of 198 (15.7%) patients were identified as DPD deficient. Among the DPD deficient patients (5-FU dose (bolus and infusion) was reduced for DPD deficient patients by 0 to 100% from the beginning of the treatment: the bolus dose was reduced in 81%, 62%, 48%, and 44% of patients  and the 2  vs. 2800 mg/m2 , p = 0.060 for the first course, 2800 mg/m2  vs. 2800 mg/m2 , p = 0.257 for the second course, 2800 mg/m2  vs. 2800 mg/m2 , p = 0.352 at the third course, and 2800 mg/m2  vs. 2800 mg/m2 , p = 0.146 at the fourth course (There was no significant difference for the median 5-FU dose between the DPD PG and the DPD NPG groups: 2800 mg/mh course .2/week) than in non-deficient patients (1233 ± 251 mg/m2/week) (p < 0.001).In the DPD phenotyped group, median dose-intensity was significantly lower in deficient patients  than what is usually described in the literature. Toxicity occurrences may have been underestimated by focusing on grade ≥ 3 side effects, which are more biologically or clinically relevant. As reported by several studies, the toxicities avoidable by phenotyping are those of the first and second cycles ,32,34. ITreatment postponements and dropouts were significant, potentially leading to an increased risk of treatment failure. In our opinion, the main strength of this study is the large number of patients studied with homogeneous baseline characteristics such as gender, anthropometric indicators , estimated glomerular filtration rate , performance status, and tumour location. As previously reported for genotyping , phenotyDPYD variant carriers [Interestingly, this study is at odds with recent research. For example, the Ontario Health study concluded an uncertain benefit in preventing severe toxicity by dose reduction in DPD deficient patients. This Canadian work was made with genotype-guided fluoropyrimidine dose reduction in heterozygous carriers , which cA recent study compared the prevalence of toxicities between patients with and without DPD deficiency, screened by uracil plasmatic determination . It demoA partial DPD deficiency was found in about 15.7% of the included patients. This observation is higher than the proportion usually described in the general population. As described in the literature, using genotyping, the prevalence of partial deficiency in Caucasians is estimated between 3 and 8%, and that of complete deficiency is between 0.01 and 0.5% ,12,13,14In a Dutch prospective study, significant between-centre differences were observed in uracil levels, and no association could be found between pre-treatment uracilemia and DPD activity in peripheral blood mononuclear cells or fluoropyrimidine-related toxicity . To imprContrarily to the mandatory pre-therapeutic determination of the DPD status, there are no strict guidelines in France for the management of fluoropyrimidines dose reduction in partially deficient patients. That is why this study showed a heterogenicity of medical practices. At the initiation of fluoropyrimidines treatment, no 5-FU dose adjustment was observed for 19% of deficient patients for the first-course bolus and 29% for the infusion. Moreover, for some patients, treatment was not adjusted through the four first courses of treatment. In the second cycle, usually time for upwards dose adjustments when the initial diminished dose was well tolerated, the study described an important abstention. This absence of adjustment could be the result of 5-FU toxicity, but considering our results on acute severe side effects, non-optimal tailoring could be imagined. In deduction, the heterogeneity of the adjustment protocol may subsequently increase the risk of treatment failure.A recent study  suggesteTo improve the initiation of fluoropyrimidines treatment in DPD deficient patients, pharmacokinetics Bayesian tools could be used ,42,43. ITherefore, as proposed by Dolat et al., therapeutic drug monitoring of 5-FU in DPD deficient patients could be conducted to improve practices  to avoidThis study had several limitations. It was a retrospective, multicentric study but focused on a single French region and the same multidisciplinary board meeting. DPYD genetic background is missing from our study as it is not recommended in France. The lack of genetic data constrains the evaluation of the correspondence between the two predictive markers.Information about the patients’ Our study did not evaluate the clinical utility, effectiveness, and cost-effectiveness ratio as it was not designed for this. DPD-phenotyping was only based on the measurement of uracilemia, but a recent study  describeAt least, it is difficult to compare our work with the numerous international studies based only on genetic analysis as a marker of DPD phenotype.The outcome of our investigation may be adversely affected by non-homogeneous heterogeneity variables relating to the patients’ characteristics and the administration of their medication . A prospective randomised controlled study would be needed to confirm our results.We could not find any difference between the two groups regarding some clinical parameters. For example, the frequency of postponing treatment is only different after three cycles. Toxicity may be cumulative, which requires several cycles in our population to detect it. Regarding treatment discontinuation, we found a tendency for a difference only after the third course of treatment. Dose adjustments between each course are left to the discretion of the individual physician and the lack of power to show a difference partly explains why only toxicities of grades greater than three combined with their frequency are significantly reduced by phenotyping. The retrospective nature of the study also limits the sensitivity to detect toxicities below grade 3.clinicaltrials.gov identifier NCT04194957).As expected with the management of fluoropyrimidines in DPD deficient patients, this study showed that the dose intensity of 5U is inferior in deficient than non-deficient patients. However, our study does not allow us to correlate this decrease in dose to a diminution in survival. A large prospective study is ongoing, investigating the effect of phenotype-guided dosing based on pre-treatment uracil level (This study showed, based on real data, that the new French guidelines limit severe toxicities due to 5-FU during the four first cycles of chemotherapy. For the management of fluoropyrimidines in deficient patients, we observed heterogeneity of medical practices and a significant presence of severe side effects, both of which could increase the risk of therapeutic failure. In this sense, we propose the use of fluoropyrimidines therapeutic drug monitoring in deficient patients.


Pain relief is one of the main objectives of radiotherapy for cancer patients with bone metastases. Stereotactic body radiotherapy (SBRT) enables precise delivery of a higher dosage to the target area. Several trials have reported comparisons between SBRT and conventional radiotherapy (cRT) in patients with painful bone metastasis. However, the results of those investigations were inconsistent, and no systematic review or meta-analysis has been done till now.We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov up to May 1, 2022 for relevant studies. Patients with painful bone metastasis who received SBRT or cRT were included. The primary outcome was the patients’ pain response rate at three months. The secondary outcomes included the rate of pain responders at one month and six months, oral morphine equivalent dose (OMED) use, and any adverse events. STATA software 12.0 was used for the statistical analysis.2I = 0.0%, P = 0.003). However, no significant difference was found in pain response rate at 1 month  and 6 months . OMED consumption was not significantly different in patients treated with SBRT compared with control group . For safety outcome, no statistical difference was found between SBRT and cRT .We collected 533 patients’ data from 4 randomized controlled trials (RCTs), there was a significant difference of pain response rate at 3 months between two groups (RR = 1.41, 95% CI: 1.12-1.77, This study shows that for painful bone metastases, patients with SBRT experienced better pain relief 3 months after radiation than patients with cRT, and SBRT did not increase the incidence of adverse events.https://inplasy.com/inplasy-2022-6-0099/, identifier INPLASY202260099. Bones are a common site of metastasis for some advanced cancers, such as breast and prostate cancer or lung and kidney cancer, and they can often cause several complications such as pain, pathological fractures, hypercalcemia, hemorrhage, and spinal cord compression, with sensory disturbance and dyskinesia . The maiSome percutaneous techniques like radiofrequency ablation, cryoablation, and vertebral augmentation have been reported to be effective in alleviating pain . But forPreviously, several trials and meta-analyses focused on determining the optimal radiation dose and fractionation for painful bone metastases. While the study by Rich et al. indicated that patients who received single-fraction treatments and those who received multiple-fraction treatments had similar overall response rates . SeveralThe study was registered on the INPLASY website (INPLASY202260099) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement .MEDLINE, EMBASE, the Clinical Trials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) has been systematically searched by two separate investigations to identify relevant studies published until May 1, 2022. The following keywords (in the title/abstract) were used: (Stereotactic body radiotherapy OR SBRT) AND  AND painThe following are the criteria we set: (1) patient: adult patients diagnosed with painful bone metastases ; (2) intervention: patients who received SBRT in Intent-to-Treat Population. (3) comparison: patients who received cRT in the Intent-to-Treat Population; (4) outcomes: The primary outcome was the rate of patients with pain response at 3 months. The secondary outcomes included the rate of pain responders at 1 month and 6 months, and oral morphine equivalent dose (OMED) use. Safety outcome is adverse events. (5) study type: RCT. Included studies were not required to provide all of the aforementioned outcomes.The following are the exclusion criteria we set: (1) study type: comment, letter, review, case report or case series, non-randomized; (2) language: non-English article; (3) no extractable data.All entries queried from the database, RCTs, and relevant systematic reviews or meta-analyses were examined separately by the two authors (ZLW and LYL), removing duplicates and abstract-only research papers. When differences between the two authors arose, a third author (ZQC), who was not involved in the data collection procedure, made the final choices about disputed data.The Review Manager 5.3 software was used to examine the risk of bias plot for individual research. The Cochrane Collaboration’s consistent criteria for assessing the risk of bias in RCTs were used, including selection bias, performance bias, detection bias, attrition bias, reporting bias, and other potential biases. The bias criteria were categorized as “low,” “high,” or “unclear.”International Consensus on Palliative Radiotherapy Endpoints (ICPRE) defines a complete response (CR) as BPI = 0 with no associated increase in daily oral morphine equivalent (OME) consumption. And the partial response (PR) is defined as a reduction in the worst pain score of 2 or more points above baseline with no increase in OME, or no increase in the worst pain score and a reduction in daily OME consumption of at least 25%. Pain progression (PP) is defined as an increase from baseline in the worst pain score of 2 or more points without reduced daily OME consumption, or as no change in the worst pain score and an increase in daily OME consumption of at least 25%. Besides, any response not included in the above definition will be considered as intermediate pain (IP). CR and PR can be regarded as responders, and the others (PP and IP) are non-responders.2I statistic was used to measure heterogeneity; a value of less than 30% suggests “low heterogeneity,” a value between 30% and 50% indicates “moderate heterogeneity,” and a value of more than 50% indicates “severe heterogeneity.” The stability of the consolidated data was investigated using sensitivity analysis. Two-tailed tests were used for all of the analyses, and a P value of less than 0.05 was regarded as statistically significant.The data were evaluated using STATA software 12.0  by the two authors (XYY and HYT). Disputed data was solved by a third author (XXW). A random-effects model was used to assess and generate the risk ratio (RR) with the 95% confidence interval (CI) for the dichotomous outcomes. The 516 titles and abstracts were obtained for review from EMBASE, MEDLINE, CENTRAL, and ClinicalTrials.gov. We eliminated 106 duplicate articles and 251 irrelevant articles, leaving 159 articles, including 50 non-randomized clinical trials, 84 reviews, two letters, and 19 others. Finally, four RCTs Figure 12I = 0.0%, P = 0.003, 2I = 31.5%, P = 0.201, 2I = 0.0%, P = 0.140, 2I = 0.0%, P = 0.894, In this meta-analysis, we assessed rates of pain response at one month, three months, and six months after radiation, as well as OMED consumption. Three studies –18 repor2I = 20.1%, P = 0.162, As for the safety outcome, three out of the four studies –19 reporThe risk of bias for included studies were shown in We collected four RCTs to analyze, which mainly discussed the comparison of pain relief rates between SBRT and cRT. Our meta-analysis showed that at 3 months, SBRT is significantly superior to cRT for treating painful bone metastases pain. However, no significant difference has been found between SBRT and cRT group in the pain response at one month and six months. In addition, compared to the control group, SBRT group failed to reduce the use of OMED significantly.Overall, according to our analysis, only pain response at 3 month was significantly improved in SBRT group. Several factors may attribute to the negative results at 1 month and 6 months between SBRT group and cRT group. Firstly, for pain response at 1 month, both Pelkenrood’s trial and Sahgal’s trial concluded that SBRT did not significantly improve pain response, while Nguyen’s trial drew the opposite conclusion. For pain response at 6 months, only Sahgal’s trial and Nguyen’s trial were included. As Nguyen’s trial mainly included patients with nonespinal metastases, it may interfere with the results’ extrapolation to the general population with spinal metastases. When evaluating which patients should be treated with SBRT, those RCTs also offered conflicting opinions. Sahgal et al. and Sparve et al. proposed that SBRT provides faster and better pain relief and should be recommended for patients with shorter expected survival , 19. NguRadiation therapy has been considered as the main treatment for cancer with bone metastases. Radiation therapy uses externally generated electromagnetic and ion beams fired into the body to induce interactions between chemical free radicals and DNA, or other intracellular targets, leading to apoptosis . For conIn the past ten years, there has been a revolution in radiation therapy, SBRT is a novel treatment for cancer with spinal and bone metastases, as it can deliver higher doses precisely to the cancer cells in the target area . In 2012Studies with a higher level of evidence are urgently required to verify the efficacy and safety of SBRT for pain relief. In 2019, a prospective study compared SBRT with cRT plan, they put forward that SBRT can improve patients’ quality of life . Sakr etIn addition, in terms of the safety of the two regimens, three of the four RCTs we included reported adverse events, including dysphagia, oesophagitis, nausea, pain, fatigue, radiodermatitis, and vertebral compression fracture. No statistical difference was found according to our meta-analysis, indicating the safety of SBRT as compared to cRT. However, the probability of spinal compression fractures after SBRT should not be ignored, a systematic review by Sahgal et al. analyzed risk factors for pathologic fracture after SBRT, and they put forward that the patients with SBRT have a higher risk of pathological fracture . To noteThere are some limitations in this meta-analysis. Firstly, our analysis was based on limited data from four published RCTs to test the efficacy and safety of SBRT. And only three out of the four RCTs were included for the analysis of our primary outcome as Sprave et al.’s study did not reported data of the Intent-to-Treat analysis. Secondly, different extracorporeal radiotherapy segmentation schemes were adopted in the included RCTs. Thirdly, the study by Pelkenrood et al. only reported follow-up data within 3 months. Lastly, the response to SBRT and subsequent pain response may be impacted by the variations in tumor histology and molecular subtype. These are all possible reasons for heterogeneity.In the future, defining the most effective and safe SBRT dose and segmentation schemes are new directions for SBRT development. Further larger randomized controlled trials are still required to determine the optimum treatment for patients with painful bone metastases.In conclusion, this study shows that for painful bone metastases, patients with SBRT experienced better pain relief three months after radiation than patients with cRT, and did not increase the incidence of adverse events. For patients who expect better quality of life after palliative radiotherapy, SBRT seems to have a promising application prospect.The original contributions presented in the study are included in the article/ZLW and LL was the principal investigator. ZLW, LL and ZC designed the study and developed the analysis plan. XY, HT and XW analyzed the data and performed meta-analysis. ZLW and LL contributed in writing of the article. XY and HT revised the manuscript and polish the language. ZC, ZW and GC supervised the project. All authors contributed to the article and approved the submitted version.This work was supported by the Natural Science Foundation of Jiangsu Province (Grants No. BK20200203) and the National Natural Science Foundation of China (Grant No. 81873741).We appreciate the valuable and constructive suggestions and assistance from our Team of Neurosurgical study.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.


CYP2D6*10 has the most clinical relevance in tramadol treatment. Other SNPs such as rs7439366 (UGT2B7), rs1641025 (ABAT) and rs1718125 (P2RX7) though significant have limited pharmacogenetic implications due to insufficient evidence. OPRM1 rs1799971, COMT rs4680 and ABCB1  need to be further explored in future for relevance in Asian populations.In advanced cancer, pain is a poor prognostic factor, significantly impacting patients’ quality of life. It has been shown that up to 30% of cancer patients in Southeast Asian countries may receive inadequate analgesia from opioid therapy. This significant under-management of cancer pain is largely due to the inter-individual variability in opioid dosage and relative efficacy of available opioids, leading to unpredictable clinical responses to opioid treatment. Single nucleotide polymorphisms (SNPs) cause the variability in opioid treatment outcomes, yet their association in Asian populations remains unclear. Therefore, this review aimed to evaluate the association of SNPs with variability in opioid treatment responses in Asian populations. A literature search was conducted in Medline and Embase databases and included primary studies investigating the association of SNPs in opioid treatment outcomes, namely pharmacokinetics, opioid dose requirements, and pain control among Asian cancer patients. The results show that  Pain is the most prevalent symptom experienced by patients with advanced cancer. Affecting up to 96% of patients , cancer Since the introduction of the three-step analgesic ladder by the World Health Organization (WHO) , strong Clinical evidence shows that patients need variable opioid doses, and that the relative efficacy of available opioids varies between patients ,12. SeveCYP2D6, CYP3A4, CYP3A5), membrane drug transport proteins (ABCB1), opioid receptors (OPRM1), and pain receptors (COMT) associated with the efficacy, dose, and toxicity of opioids . Th. ThCYP2DFentanylCYP2D6*10 polymorphism on 207 Chinese gastric cancer patients, particularly those treated with fentanyl after undergoing radical gastrectomy ..CYP2D6*1CYP3A4, CYP3A5, CYP3A7 and CYP3A43, is one of the most versatile biotransformation systems that facilitate the elimination of drugs. CYP3A4 and CYP3A5 together account for approximately 30% of hepatic cytochrome P450, and approximately half of medications that are oxidatively metabolized by P450 are CYP3A substrates. Both CYP3A4 and CYP3A5 are expressed in the liver and intestine, with CYP3A5 being the predominant form expressed in extrahepatic tissues [The human CYP3A subfamily, consisting of  tissues .CYP3A5 on fentanyl pharmacokinetics among 60 Japanese cancer patients undergoing conversion to a transdermal fentanyl from a previous treatment of either oral morphine or oxycodone [CYP3A5*3*3 genotype than in those with the *1*1 and *1*3 genotypes [Takashina et al. investigated the impact of xycodone . In thisenotypes .UGT2B7 encodes for UDP-Glucuronosyltransferase-2B7 phase II metabolism isoenzyme. Morphine is primarily metabolized by the hepatic enzyme UGT2B7 to two active metabolites morphine-3-glucuronide (M3G) and morphine-6 glucuronide (M6G) [de (M6G) .MorphineUGT2B7 and the efficacy of morphine treatment in cancer pain was investigated in 120 Chinese cancer patients [UGT2B7, the plasma concentration of morphine for patients with the CC genotype was significantly lower than that in patients carrying the CT or TT genotypes (p < 0.05). The VAS score of patients with either CT or TT genotypes was significantly higher than those with CC genotype (p < 0.05) [UGT2B7 was also analyzed in this study. Carriers of the G allele (patients with GG and GT genotypes) had no significant difference in pain scores [The relationship between SNPs in patients . Morphin < 0.05) . G221T, n scores .OxycodoneUGT2B7 C802T (rs7439366) on pain relief in 47 Han Chinese patients with malignant tumors receiving prolonged-release oxycodone [p = 0.047). The authors also found that there were more patients with TT genotype in the refractory group (23.5%) compared to the remission group (2.5%)(60%) (p < 0.05) [Li et al. investigated the impact of xycodone . Patient < 0.05) .OPRM1 encodes for the mu (μ) opioid receptor. OPRM1 is the primary target of both endogenous and exogenous opiates including morphine and tramadol and has been shown to mediate both baseline nociception and response to OPRM1 agonists [agonists .MorphineOPRM1 SNP as a genetic factor in the optimization of cancer pain treatment was evaluated by Hajj et al. [p = 0.043) but increased with the duration of morphine treatment (p = 0.029). Patients carrying the AG genotype for OPRM1 c.118A > G (rs1799971) required significantly higher morphine doses than patients with the AA genotype (p < 0.001) [The added value of determining j et al. . A total< 0.001) .Tramadol/Paracetamol combinationOPRM1 A118G (rs1799971) polymorphism [p <0.001) [In 2011, Liu et al. explored the efficacy of tramadol/paracetamol combination in 96 Chinese patients with adenocarcinoma of the colon, rectum, or stomach and the morphism . Compare <0.001) .SufentanilOPRM1 SNPs on the analgesic effect and consumption of sufentanil after thoracoscopic-assisted radical resection of lung cancer were evaluated in 225 Han Chinese cancer patients [OPRM1 at three different time points (both p> 0.05) [The effects of patients . The autpatients . Howeverp> 0.05) .COMT encodes for the catechol-O-methyltransferase (COMT) enzyme which is responsible for catalyzing the transfer of a methyl group from S-adenosylmethionine to catecholamines, including neurotransmitters dopamine, epinephrine, and norepinephrine. In addition, COMT is known to be involved in pain modulation, through dopamine-mediated change in enkephalins neuronal content [ content , followe content ,43.MorphineCOMT on plasma concentration and dose requirements of morphine were evaluated in a prospective study conducted in 48 Japanese patients with cancer [p = 0.008 and 0.03, respectively). However, this significance was lost on day 8 of the treatment [The effects of the G472A (rs4680) SNP in h cancer . The autreatment .p = 0.013) [The significant difference was later replicated by the same group in a later study . This ti= 0.013) . However= 0.013) . Interes= 0.013) .ABAT codes for the γ-Aminobutyric acid (GABA)-transaminase enzyme, which is responsible for the metabolism of inhibitory neurotransmitter GABA. In addition, GABA neurons and receptors are found in supraspinal sites known to coordinate the perception and response to painful stimuli and this system has been shown to regulate sensory information processing in the spinal cord [nal cord ,45.Multiple opioidsABAT was significantly associated with opioid responsiveness in cancer pain [p < 0.001). Additionally, the CT genotype was found to have the lowest mean pain severity after the increment in the opioid dose (p < 0.001) [The rs1641025 SNP in cer pain . The aut< 0.001) .The protein encoded by this gene, P-glycoprotein (P-gp), is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs .FentanylABCB1 1236TT (rs1128503) on fentanyl pharmacokinetics among 60 Japanese cancer patients undergoing conversion to transdermal fentanyl from previous treatment of either oral morphine or oxycodone [p = 0.036) [Takashina et al. investigated the impact of xycodone . They sh= 0.036) .SufentanilABCB1 SNPs, rs2032582 and rs1128503 with the analgesic effect and dose of sufentanil taken for pain relief [ABCB1 did not show any significance (p > 0.05). There were no significant differences in the VAS scores at the three time points nor association with adverse effects [A study conducted among 225 Han Chinese patients with lung cancer reported the association of n relief . The dosn relief . However effects .Multiple opioidsABCB1 C3435T (rs1045642) polymorphism on opioid requirements among 112 Chinese patients [p = 0.057 and 0.028, respectively) [Gong et al. evaluated the influence of P2RX7, encodes the purinergic receptor P2X7 which is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. P2X7 is expressed in peripheral and central nervous systems and the immune system, mediating and modulating pain. P2X7 function has been previously linked to chronic inflammatory and neuropathic pain [The purinergic receptor P2X, ligand-gated ion channel 7, hic pain .FentanylP2RX7 with postoperative fentanyl analgesia was investigated in an observational study among Han Chinese patients with lung cancer [p < 0.05). Patients carrying the GA and AA genotypes required more fentanyl doses for pain control within 48 h postoperatively (p < 0.05). The postoperative VAS score was also significantly higher in carriers of the GA genotype when compared to the GG genotype group in the period of analepsis after general anesthesia and 6 h post-surgery . Meanwhile, the postoperative VAS score was significantly higher in the A homozygotes than in the period of analepsis after general anesthesia (p < 0.001), at 6 (p = 0.006) and 24 h (p = 0.016) post-surgery [The correlation of rs1718125 in g cancer . This SN-surgery .CYP2D6, CYP3A5, UGT2B7), neurotransmitter-metabolizing enzymes , transporters (ABCB1) and drug receptor (OPRM1) and ion channels (P2RX7) in contributing to inter-individual variability in opioid treatment responses in Asian patients with cancer pain.The findings of this review have highlighted the role of genetic variants in drug-metabolizing enzymes  to serine leading to a decreased enzymatic activity [CYP2D6*10 polymorphism produces an intermediate metabolizer phenotype and is predominant and well-documented among Asian populations [Genetic polymorphisms in capacity . The CYPdol dose  and lowedol dose  due to adol dose . The CYPactivity . The redactivity ,51, leadulations ,53,54.CYP2D6*1/*5 and *2/*5 genotypes have been re-classified from NM to IM phenotype based on their activity scores [CYP2D6*5/*14 and *14/*14 have been re-classified from PM to IM phenotype. Based on this update, the carriers of the CYP2D6*1/*5 and *2/*5 genotypes would have to be re-classified from the NM to the IM + PM group [CYP2D6*5 variant has been reported to be relatively low at 6.3% in Japanese populations [CYP2D6 activity [CYP2B6 and CYP3A enzymes [CYP2D6*10 variant  has been associated with higher fentanyl dose and pain scores compared to the wild type CYP2D6*1  [CYP2D6*9 and *29 alleles were associated with impaired clearance of fentanyl in burn patients [In the study by Tanaka et al. , patienty scores . SimilarPM group ,53. As tulations , it is hactivity . The hig enzymes . Althoug allele) . Grimsrupatients . The metpatients ,57. It ipatients ,57.UGT2B7 are known to affect morphine glucuronidation to form M3G and M6G metabolites [UGT2B7*1) to histidine (UGT2B7*2). UGT2B7*2 homozygotes are lower in the Chinese population (9.2%) when compared to the Caucasian population (25.3%) (p < 0.001) [UGT2B7 was studied in patients receiving morphine and prolonged-release oxycodone [Polymorphisms in abolites ,58.rs743< 0.001) . In thisxycodone ,27. Carrxycodone . ConversUGT2B7 rs7439366 allele had a higher affinity for M3G and M6G compared to their wild type UGT2B7 counterparts [UGT1A9 polymorphisms, the homozygous mutant UGT2B7 allele carriers tend to produce M6G, which is known to be more potent than M3G [UGT2B7 rs7439366*T allele has been listed as insufficient (levels 3 to 4) to be used as a biomarker for treatment response in the PharmGKB database [These results are consistent with previous studies suggesting that the rs7439366*C allele may enhance analgesic efficacy ,59. M3G terparts . Paired than M3G ,60, and database .OPRM1 is the G472A (rs1799971) SNP, which brings about the substitution of asparagine at position 40  to aspartic acid  [Exogenous opioids including morphine bind to the μ-opioid receptor to bring about opioid-induced analgesia ,63. The  allele) . This SN allele) . The res allele) . Carrier allele) . These f allele) ,67.OPRM1 [Sufentanil, being a fentanyl analog, also binds to the μ-opioid receptor. Among sufentanil-treated patients, both sufentanil dose and analgesic effect were associated with the rs1799971 and rs1323040 in OPRM1 . The dosOPRM1  suggestiOPRM1 ,67.COMT SNP G472A (rs4680) has been widely associated with various neuropsychological phenotypes from the dopaminergic pathway, including pain modulation, hyperalgesia, anxiety disorders, opioid-related disorders, and substance addiction [COMT is responsible for degrading the majority of the dopamine in the prefrontal cortical regions of the brain . The COMddiction . This SNddiction . In thisddiction  comparedddiction . Two studdiction .COMT rs4680′s genotypes [However, these results are contradictory to other studies that have reported the A allele being associated with reduced analgesic efficacy ,72. The enotypes ,32.COMT rs4680 homozygous wild type G allele and mutant A allele in the first 24 h of treatment [Pooled data from a meta-analysis did not find any statistical difference in opioid consumption in patients carrying reatment . Howeverreatment .ABAT rs1641025 SNP represents a substitution of wild type T allele to the mutant C allele in the gene encoding for GABA transaminase. In this review, the opioid dose requirement was found to be lowest in patients with homozygous for the ABAT rs1621025*C allele, while pain scores were lowest in patients who were heterozygous for this SNP [ABAT rs1641025 may not influence the opioid dose requirement directly, the pain perception modulated by this SNP may be associated with a higher pain threshold and thus a lower opioid dose requirement. Further studies are needed to explore the potential pharmacogenetic role this SNP may play in pain control and opioid analgesic responsiveness and possibly its usefulness as a biomarker.The this SNP . These fthis SNP . To datethis SNP . Hence, ABCB1 that will remove drugs [ABCB1 is in exon 26, C3435T (rs1045642), while the others are present in exon 21, G2677T (rs2032582) and exon 12, C1236T (rs1128503). Of the three, only rs2032582 SNP results in the change in amino acid . Previous studies have demonstrated that patients homozygous for the mutant rs1045642*T allele display two to three folds lower expression of P-gp relative to the wild type CC genotype [The bioavailability of administered opioids is affected by P-gp, an ATP-binding cassette (ABC) family of efflux transporters encoded by ve drugs . One of genotype ,75. Althgenotype .ABCB1 and activity of P-gp [In the current review, rs1128503, rs2032582 and rs1045642 were studied in patients receiving fentanyl , and mul of P-gp ,75,76. I of P-gp , which m of P-gp ,75,76. H of P-gp . Pain sc of P-gp .P2X7, encoded by P2RX7, has been linked to chronic inflammatory and neuropathic pain. The expression of P2X7 receptors is upregulated in both dorsal root ganglia and injured nerves, and monocytes and lymphocytes in patients with neuropathic pain. In animal models of inflammatory and neuropathic pain, P2RX7 disruption reduces hypersensitivity [P2RX7 rs1718125 SNP was significantly associated with postoperative pain and fentanyl dose in patients with lung cancer [P2RX7 polymorphisms and opioid dose requirements, pharmacokinetics, or pain control. The potential pharmacogenetic relevance of this SNP needs to be further investigated as pre-clinical studies have shown that P2X7 may contribute to pain modulation both by its effect on peripheral tissue and through alterations in central nervous system processing [The function of purinergic receptor sitivity . In thisg cancer . Among pg cancer . The fing cancer . To dateocessing .A vast majority of the studies included in this review had patients of East Asian ancestry . As a result, the pharmacogenetic studies from the mentioned Asian populations may not be representative of other types of Asian populations such as those from Central, Southern, and Southeast Asia. In addition, outcome measures such as opioid dose requirements, duration of treatment, and assessment of pain control implemented in the included studies were different, limiting the ability to compare findings between studies. Compared to pharmacogenomic studies in Caucasian and European populations, pharmacogenetic studies in Asian patients with cancer pain treated with opioids tend to have smaller sample sizes lacking adequate statistical power. Additionally, genetic association studies have focused on a limited number of genes and a few SNPs within each gene, which does not take into account other facets of pain manifestation such as a combination of SNPs (haplotypes), epigenetic factors, and drug-drug interactions, as well as other possible confounding factors. This review only included articles published in English, which may have resulted in publication bias, where some relevant non-English studies could have been missed.CYP2D6*10 SNP is relevant to tramadol pharmacokinetics and opioid dose requirement, while SNPs within UGT2B7 (rs7439366), ABAT (rs1641025), and P2RX7 (rs1718125) have demonstrated some level of potential clinical relevance to cancer pain pharmacogenomics in Asian patients. SNPs within OPRM1, COMT, and ABCB1 were found to have low clinical significance due to several studies failing to replicate associations reported by others. Among these are the OPRM1 rs1799971 implicated in morphine pharmacokinetics and pain control and COMT rs4680 implicated in morphine pharmacokinetics, opioid dose requirement, and pain control. These SNPs do not have consistent findings between Caucasian and Asian populations. Multiple ABCB1 SNPs have been reported to have significance to opioid treatment. These include ABCB1 rs1045642 associated with a dose of multiple opioids, rs1128503 associated with a dose of fentanyl and sufentanil, and rs2032582 associated with a dose of sufentanil. Further investigations are required to unravel the role of these SNPs in opioid treatment outcomes.This review provides insights into the association of genetic variants and treatment responses in Asian patients treated with opioids for cancer pain. The CYP2D6, UGT2B7), neurotransmitter-metabolizing enzymes , transporters (ABCB1) and drug targets, including receptors (OPRM1) and ion channels (P2RX7). The clinical significance of pharmacogenetic biomarkers OPRM1 rs1799971, COMT rs4680 and ABCB1  should be further explored in future studies to improve precision pain management amongst Asian patients with cancer pain.Inter-individual variability in opioid responses has been associated with polymorphisms in genes encoding drug-metabolizing enzymes (


This study aimed to explore the clinical values of the percutaneous spinal endoscopy “isolation zone” technique for discogenic low back pain (DLBP).This retrospective case series study enrolled patients with intervertebral DLBP treated with the percutaneous spinal endoscopy “isolation zone” technique in the department of Orthopedics, Cangzhou central Hospital affiliated to TianJin Medical University between September 2017 and September 2020.Forty-five patients with DLBP were enrolled. The mean operation time was 94.7 ± 17.7 min. The visual analogue scale (VAS) score of lumbosacral pain was 6.95 ± 1.02 before operation, 2.64 ± 0.71, 1.80 ± 0.54, 1.42 ± 0.50, and 1.27 ± 0.45 at 1, 3, 6, and 12 months after operation, respectively. The Oswestry disability index (ODI) score of low back pain was 72.84 ± 5.95 before operation, 35.1 ± 5.30, 25.22 ± 4.85, 16.78 ± 4.63, and 10.91 ± 2.36 at 1, 3, 6, and 12 months after operation, respectively. At final follow-up, the treatment effect based on modified MacNab criteria was excellent in 24 cases, good in 13 cases, and fair in 8 cases. The excellent/good rate was 82.2%.The percutaneous spinal endoscopic “isolation zone” technique seems to be a promising surgical alternative for DLBP. Discogenic low back pain (DLBP) is a common type of spinal degenerative disease. DLBP results from multifactorial changes due to intervertebral disc degeneration that interact with the nervous system to induce pain . The paiThe traditional treatment of DLBP is mainly conservative such as rest, drug treatment, or physiotherapy, but this often cannot fundamentally solve the problem. For example, in cases of an intervertebral disc annulus fibrosus tear . For patMinimally invasive methods have been developed to improve the surgical outcomes of lumber disc surgery, such as the Yeung endoscopic spine system (YESS) technique , 9, intrTherefore, this study aimed to evaluate the clinical values of the percutaneous spinal endoscopy “isolation zone” technique for DLBP.This case series study enrolled patients with DLBP treated by spinal surgery in the department of Orthopedics, Cangzhou central Hospital affiliated to TianJin medical University between September 2017 and September 2020. The Ethics Committee of the Cangzhou central Hospital affiliated to TianJin medical University approved this study (No. 20210205). All patients provided written informed consent.The inclusion criteria were as follows: 1) patients with low back and lumbosacral pain symptoms, without typical sciatic nerve pain. Prolonged sitting, standing, bending, and physical labor could cause pain and discomfort in the lumbar back, hip, greater trochanter, and groin, and it was generally a dull pain; (2) preoperative X-ray, computed tomography (CT), magnetic resonance imaging (MRI) and/or other imaging data showed single segment disc lesions, mostly mild herniation of the intervertebral disc, no stenosis of bilateral lateral recess, and no obvious collapse of intervertebral space; (3) there was a high signal area of annulus fibrosus tear behind the responsible segment disc, and the MRI image showed a hiz (high intensity zone)  score of low back pain and pain around the buttocks were measured before operation and 1, 3, 6, and 12 months after operation. The treatment effect was evaluated by modified MacNab criteria at the last follow-up, alongside lumbar MRI imaging, and reporting of any complications.The modified MacNab criteria  evaluateAll patients were operated by a single senior physician skilled in spinal endoscopy in our research center. Regular oral nonsteroidal anti-inflammatory analgesics (such as diclofenac sodium) and central skeletal muscle relaxants (such as tizanidine hydrochloride) were administered 48 h before operation. All patients underwent the operation in the lateral position under the guidance of a G arm X-ray machine.Local anesthesia  was used in all patients. The anesthesia levels were skin and subcutaneous, lumbar dorsal fascia, articular process joint, and disc surface.All enrolled patients were treated with the “isolation zone” technique under percutaneous spinal endoscopy. The specific method involved puncture of the tip of the articular process on the target intervertebral space with an 18G puncture needle. The tip of the needle was located on the posterior edge of the intervertebral joint, and the anterior edge of the intervertebral joint. The guide wire was placed, the skin was cut about 7 mm, to place 2, 3.5, 4.5, and 5.5 mm catheters step by step to expand the soft tissue. The Tom Shidi needle was then placed along the guide wire, and the tip of the Tom Shidi needle was fixed at the tip of the facet joint under fluoroscopy, and pointed to the protruding target of the intervertebral disc. This was then used to gently hammer the bone penetrating the facet joint, while appropriately adjusting the depth of the Tom Shidi needle into the spinal canal according to the protruding position of the intervertebral disc. The guide wire was replaced after the positioning was confirmed by frontal and lateral fluoroscopy. Bone drills with diameters of 4.5, 6, 7, 8, and 9 mm were successively inserted along the guide wire for intervertebral foramen plasty. The guide wire was replaced again and the expansion guide rod was inserted and the 7.5-mm working channel was inserted along the guide rod. It was confirmed that the working channel reached the target through frontal and lateral fluoroscopy  exercise, and a lumbar spine health care program daily.t‐test or one‐way analysis of variance (ANOVA). Two-tailed P-values < 0.05 were considered significant.The data were analyzed by SPSS 22.0 statistical software . Continuous variables with a normal distribution were expressed by mean ± standard deviation (SD), and categorical variables were expressed as numbers (percentages). Comparisons for continuous data were performed using Student’s P < 0.05). At the last follow-up, the treatment effect according to the modified MacNab criteria was excellent in 24 cases, good in 13 cases, and fair in 8 cases. The excellent and good rate was 82.2%  years old were included. 29 cases were L4/5, 16 cases were L5/S1. Among the 45 patients, there was no forced interruption due to intolerable pain of local anesthesia. The mean operation time was 94.7 ± 17.7 (range: 65–125) min. The VAS score of lumbosacral pain was 6.95 ± 1.02 before operation, 2.64 ± 0.71, 1.80 ± 0.54, 1.42 ± 0.50, and 1.27 ± 0.45 at 1, 3, 6, and 12 months after operation, respectively. The ODI score of low back pain was 72.84 ± 5.95 before operation, 35.1 ± 5.30, 25.22 ± 4.85, 16.78 ± 4.63, and 10.91 ± 2.36 at 1, 3, 6, and 12 months after operation, respectively. There was significant improvement compared with that before operation  in 52 patients . In thatThe endoscopic methods above also improved spinal function as indicated by ODI. In this study, the ODI decreased from 72.84 ± 5.95 preoperatively to 10.91 ± 2.36 at 12 months postoperatively. The studies described above also showed the ODI score dropped from the preoperative level of 22.3 to 8.8 at 12 months , 35.8 ± DLBP is one of the common spinal degenerative diseases in clinic. It mainly manifests as atypical low back pain and lower limb pain. The pain is located mostly in the lower waist, hip and groin areas, posterolateral thigh, and knee joints. The positioning is inaccurate. The symptoms worsen when standing, sitting, or bending for long periods , 18. TheFor DLBP, it is very necessary to determine the responsible segment. In addition to the lumbar MRI showing signal changes of the intervertebral disc with hiz and modic signs and Schmorl nodules on the posterolateral side, discography, induction test, and transforaminal nerve block are important diagnostic techniques . The angAlthough there are many treatment schemes for DLBP, such as lumbar fusion surgery, intradiscal intervention technologies such as intradiscal electrotherapy, intradiscal injection of platelet rich plasma or hepatocytes, or intradiscal ozone technology the above technologies are controversial at present, and the treatment results are often uncertain , 29. ComOur experience suggests that the “isolation zone” spinal endoscopy technology used in this study has the following advantages in the treatment of DLBP: (1) nerve block through the intervertebral foramen can accurately determine the responsible segment of DLBP, and avoid the damage to the intervertebral disc caused by the traditional intradiscal injection of contrast agent and the false-positive test; (2) endoscopic treatment of the responsible segment through the intervertebral foramen not only has less damage to the stable structure of the lumbar spine, but also preserves the spinal motor unit. It has advantages over the traditional fusion surgery in preventing the adjacent segment lesions after lumbar surgery; (3) under local anesthesia, the patients can autonomously reflect the nerve function of the lower limbs during the operation. The risk of nerve injury is small, and the postoperative recovery is fast. Patients can exercise early; (4) the pathogenic factors of the responsible segments are comprehensively treated to achieve the purpose of treating DLBP.There were several limitations. Firstly, this was a single center study, and the sample size is limited. As a retrospective analysis there may have been some bias in the patients selection. There was no comparison group, so no clear conclusions can be made on the effectiveness of the treatment compared to standard treatment.The percutaneous spinal endoscopic “isolation zone” technique provided satisfactory clinical results for DLBP. The percutaneous spinal endoscopic “isolation zone” technique seems to be a promising surgical alternative for DLBP.