The recommended first-line treatment for unspecific and degenerative back pain consists of movement exercises and patient education.Using a pragmatic, randomized controlled trial, we evaluated the effectiveness of a digital home exercise program on self-reported pain intensity compared with the standard of care for physiotherapy.Participant recruitment was based on newspaper advertisements and a consecutive on-site assessment for eligibility and enrollment. Participants with unspecific and degenerative back pain aged ≥18 years were randomly assigned in a 1:1 ratio to receive a 12-week stand-alone digital home exercise program or physiotherapy. The digital home exercise program included 4 exercises daily, while physiotherapy included 6 to 12 sessions, depending on the severity of symptoms. The primary outcome was pain, which was assessed using a verbal numerical rating scale. The clinical relevance of pain reduction was assessed using the following thresholds: improvement of at least 1.4 points on the verbal numerical rating scale and a pain reduction of at least 30%.P<.01) in favor of the intervention group. The group receiving the digital therapeutic achieved a clinically relevant reduction in pain over the course of the study (baseline vs 12 weeks), with a mean change of −3.35 (SD 2.05) score points or −53.1% (SD 29.5). By contrast, this change did not reach clinical relevance in the control group . Retention rates of 89.9% in the intervention group and 97.3% in the control group were maintained throughout the study.During the study period, 108 participants were assigned to the intervention group and 105 participants to the control group. The mean difference in pain scores between the 2 groups at 12 weeks was −2.44 (95% CI −2.92 to −1.95; The use of the app-based home exercise program led to a significant and clinically relevant reduction in pain intensity throughout the 12-week duration of the program. The intervention studied showed superior improvement in self-reported pain intensity when compared with the standard of care. Given the great demand for standard physiotherapy for unspecific and degenerative back pain, digital therapeutics are evolving into a suitable therapeutic option that can overcome the limitations of access and availability of conventional modes of health care delivery into this spectrum of indications. However, further independent evaluations are required to support the growing body of evidence on the effectiveness of digital therapeutics in real-world care settings.German Clinical Trials Register DRKS00022781; https://tinyurl.com/hpdraa89 Musculoskeletal conditions are among the top drivers of the burden of disease worldwide. In the most recent Global Burden of Disease Study, lower unspecific back pain accounted for 2.5% of all disability-adjusted life years . AlthougIn this context, new and innovative approaches are required to develop and sustain a responsive and accessible health care delivery infrastructure. While numerous attempts have been made to digitize components of health care related to musculoskeletal conditions, most have failed to be integrated into existing health care systems and established care delivery pathways . HoweverIn view of this, ViViRA  is the first self-guided home exercise program for the treatment of degenerative and unspecific back pain that has been approved by the BfArM for use in the collectively funded statutory health insurance system. Thus, ViViRA can be integrated into routine medical care in Germany. For approval as a DiGA by the regulatory bodies, a randomized controlled trial demonstrating effectiveness was conducted. Hence, this publication presents data from a pragmatic, open-label randomized controlled trial that aimed to assess the comparative effectiveness of BfArM-approved DiGA ViViRA against the established standard of care for physiotherapy.We conducted a pragmatic randomized controlled trial with 1 intervention group and 1 control group. As the mode of administration of the experimental therapy  differed significantly from that of the control therapy , an open-label design was chosen. The intervention group used the digital therapeutic ViViRA, while the control group received the standard treatment of physiotherapy. Intervention and control therapies were administered in parallel. All study-related data  were collected between August 2020 and April 2021. No modifications were made to the trial design after its commencement.Inclusion criteria and requirements for participation in the study were defined as follows: (1) age >18 years; (2) diagnosis of a unspecific or degenerative pain of the lower back ; (3) a pain score of ≥4 out of 10 based on the verbal numerical rating scale (VNRS) at the time of enrollment, which corresponds to at least moderate pain and is a plausible indicator of therapeutic need in a real-world setting; (4) possession of a mobile device  and the ability to use such a device; and (5) ability to provide informed consent. The exclusion criteria are outlined in GeneralNo pain, pain score ≤3Previous movement therapy with a digital therapeutic for musculoskeletal painUse of analgesics before inclusionPregnancyLimited legal or insufficient language capacityPatients who are not able to follow the exercise protocol; for example, significantly impaired vision or blindnessInternalSevere organ failureCondition after heart attackNeed for dialysisCardiovascular decompensationPulmonary insufficiencyInflammationPast or present rheumatological diseaseAcute inflammatory diseasesFeverish conditionCoagulopathyThrombosisBlood coagulation disorders including anticoagulant therapyMusculoskeletalAny bone diseaseInjuries or surgeryFresh bone or joint fracturesInjury to spinal column, knee, or hip jointCondition afterSpine, hip, or joint surgeryOsteotomy (an operation to correct the axis of the leg)Arthrodesis (joint stiffening) in 1 of the 2 knee or hip jointsInflammatory diseaseSpinal column or joint inflammatory diseaseSituation after spinal column or joint inflammatory diseaseSpinal tumorOsteochondrosis dissecansBone necrosisHip dysplasiaAcute instability of the knee or hip jointFree joint bodiesDisc pathologySlipped discAcute herniated disc or other disorder with radiation to the legs (radiculopathy or sensorimotor failure)Herniated disc in the pastClinically relevant bone marrow edemaOsteoporosisNeuropsychiatricSerious neurological disordersStrokeParalysisMultiple sclerosisConvulsionsPosture insecurityNeurological motor disordersSensomotoric disordersVertigoSkin sensitivity disorderPsychosesDementiaDrug or alcohol abuseOncologicalMetastases of malignant tumorsAcute malignant diseaseRecruitment was initiated through newspaper advertisements in 2 regions of the state of Baden-Wuerttemberg, Germany. Patients interested in participation underwent prescreening by telephone before undergoing an interview and a physical examination. Physical examinations and baseline assessments were conducted by an investigator (HW and KW) and study nurses at an outpatient study center affiliated with the University Hospital Tübingen. All follow-up assessments were conducted remotely via phone calls and questionnaires. Study nurses coordinated follow-up appointments and monitored the completion of follow-up assessments. The trial ended after 12 weeks. No reason for the early termination of the trial was reported throughout the duration of the study. Participants were not paid for trial participation; however, costs resulting directly from trial participation were reimbursed .The interventional group was provided access to the digital therapeutic on their mobile device free of charge. Patients in this group were asked to exercise at least three days per week throughout the trial period of 12 weeks, and patients were advised to use the default notification setting with a daily reminder displayed as a push notification. The digital therapeutic assessed in this trial was the ViViRA app , an approved DiGA addressing the indication spectrum outlined earlier. It is a medical device used in mobile devices with iOS and Android operating systems, providing a self-directed home exercise program using the principles of movement therapy and functional regional interdependence, as outlined elsewhere ,14-16. TAdherence to self-directed exercise therapy was assumed if at least one training was finished per week, and the patient confirmed within the app that they had done the exercises by providing feedback on the feasibility of each exercise and any pain experienced during the exercises. Information on adherence to the standard of care was obtained during follow-up interviews.Self-reported pain intensity was assessed as the primary outcome measure using a VNRS that was linguistically adapted for German-speaking study participants. A nonequidistant scaling of pain score categories across an 11-point rating scale from 0 to 10  was used . An adapAn active surveillance of adverse events (AEs) and unintended effects in both the intervention and control groups was conducted during structured interviews at weeks 2, 6, and 12 after the baseline examination. A differentiation of AE and adverse reactions (ARs) to either the administration of the intervention or control exercise therapy was conducted accordingly.To determine the required sample size, a trial with a 2-sided question  was planned. We used retrospective pilot data from patients who had been applying the digital home exercise program between 2018 and 2019. According to the pilot data, the VNRS limit was 1 score point and the approximate SD was 2.5 score points. This produced a standardized delta of Δ=1/2.5=0.4. Calculations with a significance level of Cronbach α=5% and a power of 1-β=80% resulted in 2×99 patients (N=198). To account for a potential dropout to study surveys of approximately 10%, we included 213 patients in this study, with 108 (50.7%) and 105 (49.3%) randomized to the investigation and control groups, respectively. This study was designed to assess the superiority of the intervention against the standard of care treatment.Proc Plan The allocation ratio at the time of randomization was 1:1. The randomization list was generated by the data manager of the Contract Research Organization CRM Biometrics GmbH (DS). On entry into the study, each patient was assigned a patient identification number. Using the patient identification number, each included patient was assigned to either the intervention or control group in the sequence specified by the randomization blocks. No deviation from the randomization sequence was reported.Participants who met the inclusion criteria outlined earlier were randomly assigned to either the investigation or control group. Randomization was based on block randomization with a block size of 6, generated with the SAS module t test. Score differences and Cohen delta were calculated for confirmatory treatment group comparisons (intervention vs control group), as well as for intragroup score changes from baseline to follow-ups. Cohen d was used for a quantitative and metric-free estimation of the effect size, with values >0.20 defined as small effect sizes, >0.50 as medium effect sizes, and >0.80 as large effect sizes [P≤.05 was considered significant. Statistical analyses were performed with SAS, version 94M7 (SAS), and GraphPad Prism, version 9.1.0 (GraphPad).Data analysis was performed by a biostatistician who was not involved in the collection of the analyzed data. Analyses were performed according to the intention-to-treat (ITT) approach. Data from participants with pain scores based on the VNRS at baseline were used in this analysis. It included all participants who were randomized and showed values for the primary variable at baseline. Furthermore, we conducted the same analyses in the prespecified per-protocol (PP) set. This included patients who were not lost to follow-up. In addition, patients who stated at the follow-up assessments that they had received concomitant physiotherapy or taken pain medication during the intervention period were excluded from the PP analysis of the intervention group. Similarly, in the control group, patients who reported concomitant use of pain medications or of a home exercise program during the study period were excluded. Metric data are expressed as means with SDs or 95% CIs. Nominal (sex) and ordinal (shift of pain score) data are reported as the cell frequencies and percentages of patients in each category. Between-group and intragroup differences were calculated using Welch 2-tailed The study concept was reviewed and approved by the Institutional Ethics Commission of the Chamber of Physicians and Surgeons of the State of Baden-Wuerttemberg, Germany, under the registration number F-2020-122 and in agreement with current data protection regulations. The trial is registered at Deutsches Register Klinische Studien  with the identifier DRKS00022781. Before enrollment in the study, patients received oral information from a trial physician and written patient information that included a description and purpose of the study, possible AEs, the name and address of the insurer, and information on data protection. Thereafter, the patients signed a written informed consent form to participate in the study and consented to the use of their data. This manuscript was prepared in accordance with the 2010 CONSORT  guidelines. The intervention studied is outlined in detail in the attached TiDier (template for intervention description and replication) checklist .A total of 215 patients were enrolled and randomly allocated to the intervention (n=108) and control (n=107) groups. In total, 2 patients in the control group did not respond to the baseline follow-up call and did not provide any outcome data after randomization. Therefore, these patients were considered screening failures and were not included in the subsequent analysis. This reduced the total number of patients in the control group to 105. No violations of the protocol were reported, which would have led to an exclusion from the study. All patients enrolled and randomly allocated were included in the ITT analysis. For the PP analysis, 68 patients of the intervention group and 71 patients of the control group were considered. The recruitment period, as outlined in the Methods section, started in August 2020. The final follow-up was completed by the end of April 2021. The baseline assessment was conducted onsite, whereas follow-up assessments after 2, 6, and 12 weeks were conducted remotely via phone calls and questionnaires. The trial ended after 12 weeks. No reason for an early termination of the trial was reported during the 12-week study period. P<.001; Cohen d>0.8). Comparing the mean pain scores at baseline and after 12 weeks, the perceived pain decreased by a mean of −3.35 (SD 2.05) score points and −53.1% .Pain responses were assessed with a German VNRS validated for nonmalignant pain . All patP=.123; Cohen d=0.22) could be observed after 2 weeks. After 6 and 12 weeks, significant pain score reductions to 5.47  and 5.13 , respectively, were observed (P<.001).The control group of 105 participants reported a reduction in pain to a lesser extent as compared with the intervention group. From a reported mean baseline of 6.05 (SD 1.64), a marginal reduction to 5.71 , week 6 , and week 12  of the patients reported an increase in perceived pain after 6 weeks of treatment but fully recovered after the full duration of the 12-week exercise training program. However, most patients of this group  reported a reduction in perceived pain.By contrast, in the control group, 22.9% (24/105) of the patients experienced an increase in pain intensity after 2 weeks and 24.8% (26/105) of the patients after 6 weeks. The number of patients of the control group who reported an increase in pain decreased marginally to 17.1% (18/105) after 12 weeks. However, 60% of the patients of this group reported an improvement in perceived pain .Patients in the intervention group of the ITT cohort were using the exercise therapy on an average of 5.77 days out of 7 possible days per week. This corresponds to an adherence rate of 89.9%. The patients of the control group received a mean of 6.94 (SD 2.94) physiotherapy sessions during the 12-week study period. Adherence in the control group was defined as the percentage of 695 physiotherapy sessions completed versus the planned number of 714 sessions, resulting in an adherence rate of 97.3%.ARs were reported by 34.3% (37/108) of the patients in the intervention group and 29.5% (31/105) of the patients in the control group and are outlined in This study aimed to assess the comparative effectiveness of a digital home exercise program and the standard of care treatment for unspecific and degenerative back pain. The results of the present study show that the use of a digital home exercise program can lead to a significant and clinically relevant reduction in patient-reported unspecific and degenerative back pain. Moreover, the results of the present study indicate that the reduction of self-reported pain intensity achievable with the digital therapeutic under investigation is superior to the reduction of self-reported pain intensity achieved with the standard of care .The data presented in this paper contribute to the growing body of knowledge in the field of digital therapeutic interventions. Through a pragmatic randomized controlled design, this trial aimed to substantiate the evidence for the effectiveness of the digital home exercise program ViViRA. Nonetheless, we see factors that limit the external validity of our study and thus the generalizability of our findings.First, the decentralized nature of digital therapeutics is a key factor leading to better access to and availability of therapeutic resources compared with physiotherapy treatments in a physiotherapist’s practice. This comes at the expense of a close interpersonal relationship between patients and health care professionals, which naturally contributes to the effectiveness of therapeutic interventions ,22. HoweSecond, the enrollment for the trial presented was primarily based on newspaper advertisements in 2 regions in the German federal state of Baden-Wuerttemberg. As this differs from the enrollment in clinical practice, a selection bias is plausibly present in this study, as a DiGA typically requires a prescription from a health care professional  and is only very limited accessible through self-selection . As discussed earlier, more research on the relevance of these differential patient motivations is required.Third, the availability of physiotherapists is limited and varies by region. Therefore, system-related waiting times are likely to reduce the therapeutic density , which affects the expected effectiveness in the control group. This difference in effectiveness between the intervention and the standard of care is likely to be emphasized by the decentralized and on-demand availability of digital therapeutics. This could explain the small effect of physiotherapy on pain intensity in comparison with the intervention examined. However, given that improved access to and availability of digital therapeutics are key characteristics of digital therapeutics, we considered the comparison appropriate in the context of real-world use.Further limitations of this study include the nonblinded design, which was required as the mode of administration of the intervention and the control differed significantly and could not be feasibly blinded, and the lack of an objective measure for perceived pain intensity, which is challenging because of its highly individual nature. Generally, self-reported pain intensity is considered to be validly measured by different pain scales. This study relied on a German VNRS that has been validated for nonmalignant pain . In addiThis study focused on assessing the effectiveness of digital therapy compared with physiotherapy, the standard of care. During the 12-week exercise program with digital therapeutic, 91.7% (99/108) of the patients described pain relief. On the basis of the VNRS, which has been used to quantify pain, this corresponds to a mean pain relief of −52.3%. These results complement the existing literature, as comparable positive effects on pain intensity between −33.3% and −81% have been described in several studies assessing the effectiveness of digital therapeutics for musculoskeletal conditions -29. As eFinally, and especially in the case of patient-oriented outcomes, it is important to assess the clinical relevance of the results obtained. Several thresholds for assessing the clinical relevance of improvements in pain intensity have been defined in the literature. Exemplarily, and according to Ostelo et al , this thIn the face of an increasing burden of disease from unspecific and degenerative musculoskeletal conditions, novel and innovative therapeutic approaches are required to ensure access to and availability of effective care for this spectrum of conditions. With the introduction of the DiGA into the collectively funded German health care system, a regulatory framework for the system-wide implementation of digital therapeutics was created. This study presents effectiveness data for one of the first fully approved DiGAs and shows significant and clinically relevant improvements in self-reported pain intensity. These improvements were superior to those of the control group, representing the current standard of care in the German health care system. By expanding the available therapeutic capacities for unspecific and degenerative back pain through a decentralized and on-demand digital therapeutic, a significant added value in pain management can be achieved.Given the high burden of disease caused by back pain and the limited availability of and access to adequate health care, digital apps are an efficient treatment option for unspecific and degenerative back pain. In view of this, replication of the present trial in further independent studies considering additional outcome parameters, such as function, with longer follow-up periods, for example, 6 and 12 months, and its applicability in other countries and health care systems is of great interest. In addition, particularly in the field of digital therapeutics, further research on available real-world use data will complement the formalized and trial-based assessments of such therapeutics. By generating an increasing body of evidence as well as integrating digital apps into health care systems, digital therapeutics can contribute significantly to health care in the indication area.


Low back pain (LBP) is a common musculoskeletal condition and a major cause of disability worldwide. Previous studies have found associations of biomarkers with pain and pain-related disability in LBP patients. This study aimed to explore the association between serum biomarkers and pain and disability in patients with acute or subacute axial LBP.This study was ancillary to a parent randomized controlled trial. Enrolled participants were randomized into three intervention groups: one of two types of spinal manipulation or medical care. In the parent study, 107 adults who experienced a new episode of LBP within 3 months prior to enrollment were recruited. For this study, 90 of these 107 participants consented to have blood samples obtained, which were drawn immediately before the beginning of treatment. Seven biomarkers were chosen based on previous literature and analyzed. Clinical outcomes were pain and Oswestry Disability Index (ODI) evaluated at baseline and 4 weeks. Spearman’s |r| was used to study the association of initial levels of each biomarker with pain and ODI scores at baseline and with changes in outcome scores from baseline to 4 weeks (end of treatment) within each intervention group.r = 0.23, p = .028), E-Selectin , vitamin D , and c-reactive protein (CRP) . No baseline biomarker had an association with disability that was |r| ≥ 0.20. For the correlations of baseline biomarkers with 4-week change in outcomes, vitamin D showed a correlation with change in disability and/or pain  in manipulation-related groups, while CRP, NPY, and E-selectin along with TNFα, Substance P and RANTES showed at least one correlation with change in pain or disability  in at least one of the treatment groups.At baseline, 4 of 7 biomarkers had an association with pain that was |r| ≥ .20: neuropeptide Y (NPY) (In 90 LBP patients, the analyzed biomarkers, especially vitamin D, represent a small set of potential candidates for further research aimed at individualizing patient care. Overall, the associations investigated in the current study are an initial step in identifying the direct mechanisms of LBP and predicting outcomes of manipulation-related treatments or medical care.ClinicalTrials.gov Identifier: NCT01211613, Date of Registration: September 29, 2010, https://clinicaltrials.gov/ct2/show/NCT01211613?term=schneider&cond=Low+Back+Pain&cntry=US&state=US%3APA&draw=2&rank=1 Low back pain (LBP) is one of the most common musculoskeletal conditions requiring medical care and contributing to patient impairment and disability. Over 25% of the general population reports LBP at any given time , with a Despite these high costs, treatment outcomes and rates of disability have not improved , which mDiagnostic tools are necessary to identify patients with LBP who are likely to respond to different treatments, including manual therapy. Currently, a reliable method for selecting the most appropriate care for LBP patients is unavailable; identifying specific subgroups of patients would most likely improve outcomes and make interventions more cost-effective . Biomarkn = 173) investigating the effect of spinal manipulation on inflammatory biomarkers, moderate-quality evidence was found that spinal manipulation is more impactful than the control in influencing the short-term concentrations of tumor necrosis factor-alpha (TNFα) and interleukin 1 and 2 . These studies are characterized by a short-term assessment period of biomarkers’ levels after spinal manipulation, and they did not assess associations with clinical outcomes.Some biomarkers have already shown an association with pain and pain-related disability in LBP patients, superior to any contribution by imaging studies . BiomarkA more recent systematic review that focused on the effect of spinal manipulation and markers of immune function  found thA non-randomized clinical trial  showed tTwo systematic reviews were recently published on the relationship between inflammatory biomarkers and LBP. In one , the autOverall, as pointed out in the most recent systematic reviews , 16, theThis biomarkers study was ancillary to a parent RCT that investigated patient outcomes in response to two types of spinal manipulation and medical care . In the manual-thrust manipulation, using high-velocity, low-amplitude thrust manipulation using standard chiropractic methods by a licensed chiropractor (group 1); mechanically-assisted manipulation using an Activator IV Instrument  (group 2); or standard medical care provided by a board-certified physician in physical medicine and rehabilitation (group 3) ). Baseline correlations were computed using all 90 subjects because the data from the parent RCT were collected prior to randomization and interventions.The correlations of improvement of pain and disability outcomes with baseline biomarkers were evaluated by treatment type. This approach was chosen because of the effects of the interventions on the outcomes . Scatterp = .358): group 1 = 33/35 (85%), group 2 = 27/37 (89%), and group 3 = 30/35 (77%).The majority of participants from the randomized trial agreed to join the biomarker study (90/107 = 84%) Table . A chi-sr = 0.23, p = .028) and E-Selectin . Additionally, an association of |r| ≥ 0.30 was found for pain with vitamin D  and CRP . At baseline, there were no correlations of the 7 biomarkers with disability at the level of |r| ≥ 0.20.In the baseline analysis of all 90 subjects as a whole Table , an assop > .05). Of these, 4 biomarkers had correlations with disability improvement that reached |r| ≥ 0.30 (p > .05).The associations between baseline biomarkers levels and changes in pain from baseline to 4 weeks by treatment group are presented in Table This study was the first to examine molecular biomarkers and clinical metrics in patients with axial LBP randomized to manipulation versus standard medical care. As a secondary analysis of an RCT dataset, the goal was to examine and identify potential biomarkers of interest related to pain and functional disability for future validation.r| = 0.20 and |r| = 0.31 across the 3 treatment groups associated with changes in pain and in the manual manipulation and mechanical manipulation groups associated with changes in ODI. Previous literature has shown an association between CRP and LBP [The initial CRP levels were correlated with baseline pain values, with a |r| value of 0.37.; however, the correlation between CRP and baseline function showed a much smaller correlation. CRP also showed correlation coefficients of magnitude between | and LBP , 16, 26. and LBP . Our fin and LBP .The current lack of understanding of the mechanisms by which these markers affect pain and treatment trajectory underscores the need for studying this potential marker in future studies. This could potentially provide further insight into the interaction between CRP levels and LBP and potential mechanisms of action of manipulation. Nonetheless, this result highlights the need to consider this biomarker for future research on its mechanistic role in spinal manipulation.r = − 0.32). This baseline correlation is in line with growing evidence on the contributing role of vitamin D on musculoskeletal pain and, more specifically, on LBP [r| = 0.24 and |r| = 0.31.The second important finding was that baseline Vitamin D concentrations were inversely correlated with baseline pain  , 34. It Furthermore, we found associations between baseline levels of NPY and E-Selectin, both of which had a correlation coefficient above 0.20. NPY levels have been found in previous literature to be correlated with chronic pain , though This study allowed us to explore the potential association between biomarkers and treatment outcomes. This topic has been gaining increasing attention in the literature, having been explored across this population and by treatment groups. The examined biomarkers represent only a sampling of potential biomarkers that may show important associations. We chose to study well-known inflammatory and pain biomarkers in this initial effort to identify candidate predictive biomarkers. While clearly, additional validation and an examination of a broader array of biomarkers are needed, these findings support future research on the potential utility of circulating biomarkers in this population.Considering the small numbers of patients in each treatment group, though no significant correlations were found, even a 0.20 correlation may contribute to making impactful decisions when choosing manipulation-related treatments over usual medical care for LBP. Interestingly, vitamin D showed a change in disability and/or change in pain (|r| ≥ 0.20) in manipulation-related treatment groups only. This pattern warrants further study with a larger study population. The correlation coefficient of the other analyzed biomarkers was at least 0.20 associated with pain and/or ODI changes at 4 weeks in one of three treatment groups. These results are difficult to interpret since they present across different treatment groups.The small sample sizes for each group are clear limitations to these results. These limitations are even more relevant because we used this exploratory analysis for multiple comparisons. However, this limitation is tempered by the need for novel targets and the risk of missed findings. This study had some other limitations, including its small sample size and exploratory nature. The data distribution could not be considered normal, which was addressed using non-parametric statistical analysis. Furthermore, the average BMI value for the included population was elevated (29 ± 5.9), which has potential implications for the inflammatory markers. Nonetheless, numerous studies have presented similar average BMI values –41, whicAnother limitation of this study was the absence of a control group that received no treatment, which would have allowed for observation of changes in biomarker levels over time via natural history. This improvement could have been possible by having participants assigned to a wait-list control group and would have added a layer of information in comparing the various interventions. Additional work should be pursued in this area to gain further insight into the role of biomarkers and changes in clinical outcomes. Another limitation was the lack of a blood draw immediately after the first intervention session; this would have made the study more comparable to previous research in this article’s literature review section and could help form future research questions. However, on the contrary, the inclusion of later time points for clinical outcomes is a strength of this study since they support the association between baseline biomarkers and clinical outcomes. Last, confounders could have impacted the analysis results, such as medications, supplements, and other conditions which could contribute to the biomarker pool, even though the RCT design is generally accepted to address this potential issue.In identifying relevant serum biomarkers, previous work suggests that panels of biomarkers may provide greater predictive power than any single biomarker alone . Also, cWe found small correlations of vitamin D, CRP, NPY, and E-selectin with pain and disability at baseline and weak correlations of baseline vitamin D with improvement in outcomes following a four-week course of treatment with manipulative-related therapies. For acute and subacute LBP. We believe these data make an important contribution to the field of research on biomarkers and pain, suggesting that these serum biomarkers could have a potential role in further study of the mechanisms of prevalent LBP and prediction in related treatment outcomes and therefore warrant further evaluation. Future biomarkers research may help inform a personalized medicine approach to LBP management.


Background and Objectives: Intradiscal injection of Condoliase (chondroitin sulfate ABC endolyase), a glycosaminoglycan-degrading enzyme, is employed as a minimally invasive treatment for lumbar disc herniation (LDH) and represents a promising option between conservative treatment and surgical intervention. Since its 2018 approval in Japan, multiple single-site trails have highlighted its effectiveness, however, the effect of LDH types, and influences of patient age, sex, etc., on treatment success remains unclear. Moreover, data on teenagers and elderly patients has not been reported. In this retrospective multi-center study, we sought to classify prognostic factors for successful condoliase treatment for LDH and assess its effect on patients < 20 and ≥70 years old. Materials and Methods: We reviewed the records of 137 LDH patients treated through condoliase at four Japanese institutions and assessed its effectiveness among different age categories on alleviation of visual analog scale (VAS) of leg pain, low back pain and numbness, as well as ODI and JOA scores. Moreover, we divided them into either a “group-A” category if a ≥50% improvement in baseline leg pain VAS was observed or “group-N” if VAS leg pain improved <50%. Next, we assessed the differences in clinical and demographic distribution between group-A and group-N. Results: Fifty-five patients were classified as group-A (77.5%) and 16 patients were allocated to group-N (22.5%). A significant difference in Pfirrmann classification was found between both cohorts, with grade IV suggested to be most receptive. A posterior disc angle > 5° was also found to approach statical significance. In all age groups, average VAS scores showed improvement. However, 75% of adolescent patients showed deterioration in Pfirrmann classification following treatment. Conclusions: Intradiscal condoliase injection is an effective treatment for LDH, even in patients with large vertebral translation and posterior disc angles, regardless of age. However, since condoliase imposes a risk of progressing disc degeneration, its indication for younger patients remains controversial.  Lumbar disc herniation (LDH) is a progressive pathology caused by genetics, excessive loading, and aging, and involves deterioration of intervertebral disc (IVD) matrix organization. This deterioration may weaken the annulus fibrosus (AF) thereby potentially resulting in AF bulging or AF rupture and extrusion of nucleus pulposus (NP) material from the IVD ,2. The hProteus vulgaris bacteria [Chondroitin sulfate ABC endolyase (Condoliase) is an mucopolysaccharide-degrading lyase that specifically cleaves glycosaminoglycans with high specificity to chondroitin sulfate and hyaluronic acid ,18. Unlibacteria . As suchbacteria . Its appbacteria ,11,12,21bacteria  Regardlebacteria  have thuThis study was a retrospective multicenter case-series approved by the institutional review boards of the participating organizations. Data was collected by spine surgeons certified by the Board of the Japanese Society for Spine Surgery and Related Research, and were members of the Kanagawa Spine Research Society. Short-term outcomes were assessed via the VAS pain scores, Oswestry Disability Index (ODI) , as wellFour Japanese institutions  provided data from 137 patients who received intradiscal condoliase injection for the treatment of LDH. Specifically, patients with symptomatic LDH who wanted to avoid surgery and did not experience effective pain relief with medications or fluoroscopic nerve root block. All 137 patients were analyzed for the assessment of age on condoliase effectiveness, and categorized on age as: <20-years old (teens), 20–29 years old (20’s), 30–39 (30’s), 40–49 (40’s), 50–59 (50’s), 60–69 (60’s) and all aged 70 years or older (70 and above). For the group-A and group-N analysis, records with recorded data on initial leg pain VAS scores and at a 3-month course follow-up were included. Next, patients with ≥50% improvement in baseline leg pain VAS scores at the 3 months follow-up were defined as group-A and those who didn’t were categorized as group-N , and hert-test. If not parametric, a two-tailed Mann-Whitney test was employed. Finally, temporal data was assessed through Two-Way ANOVA with Geisser-Greenhouse correction, followed by post-hoc Tukey’s test (>2 categories) for multiple comparison or Sisak’s multiple comparison test (2 categories). Data is presented as means ± standard deviation. The significance level was set at p < 0.05. Graph plots were created by Prism 9 for MacOS  and illustrated using Adobe Illustrator .Statistical analysis was performed using Prism 9 for MacOS . Categorical demographic and clinical features distributions were analyzed through two-tailed Chi-square test. Continuous outcomes were confirmed normally distributed through Shapiro-Wilk test and analyzed using two-tailed unpaired Records of 137 LDH patients treated with condoliase were obtained from the four participating institutions. Records with initial VAS scores for leg pain were found for 89 patients of which 71 patients also had recorded postoperative scores at 3 months follow-up.  The 71 pp = 0.606), resulting in a ≥50% improvement for the group-A with a decrease in VAS score of 56.8 ± 19.9 mm at 3 months, compared to only 12.1 ± 18.7 mm in group-N. . Combining both cohorts, however, did suggest patients with transligamentous extrusion LDH to present higher low back pain reduction at 1 month follow-up, resulting in a significant difference between subligamentous extrusions and transligamentous extrusions (p = 0.015). However, overall pain reductions were similar for all types at 3 months follow-up. (p = 0.047) in this Pfirrmann grade distribution, with group-A presenting higher rates (50.9%) of grade IV, while group-N primarily presented with grade III (68.8%). Combining the results of both cohorts, did show a trend of reduced improvement in pain scores, for patients presenting a Pfirrmann classification grade III, unable to report a significant improvement at 3 months in VAS low back pain. Moreover, grade IV patients reported a significantly higher VAS low back pain improvement compared to grade III (p = 0.048) and grade V (p = 0.048) patients . Collective data, however, did suggest a trend of enhanced improvement rates for patients with a >3 mm vertebral translation (p = 0.066). Only group-A presented this clinical feature with 10 of the 55 (18.2%) patients (High intensity zones (HIZ) were recorded in 7 (12.7%) of group-A patients and 4 (25.0%) in group-N. The presence of HIZ did not show a relation with effectiveness of the treatment , VAS leg pain (p = 0.073), and VAS numbness (p = 0.051) approached statistically significant improvements at the 3-month follow-up. The lack of significance, however, is likely in part ascribed to the relatively small sample size of the cohort. On an individual level, all teen patients reported improvement in leg pain VAS scores at the 3 months follow-up, in which 2 reported full pain alleviation. (Focusing on the teen-category (<20 years old); eight patients were younger than 20 years of which 1 had a protrusion-type hernia, 6 had subligamentous extrusion-type hernia, and 1 had a transligamentous extrusion-type hernia . The herviation. A Similarviation. B,C. Noneviation. .Concentrating on the elderly population (70 years old and above), a total of 13 patients were recognized. Here, two patients reported HIZ. Eight patients were classified as Pfirrmann grade IV, 2 as grade V, and 3 as grade II. One patient presented with protrusion LDH, 2 with transligamentous extrusion and the remaining 10 patients with subligamentous extrusion. A reduction in VAS and ODI scores and improvement in JOA scores was observed, all but VAS numbness resulting in a significant improvement at 3 months . ExpecteA 42-year-old female patient presented with L5/S1-disc herniation, classified as Pfirrmann grade IV. Three months after condoliase injection, the hernia was reduced in size, however, also a clear reduction in signal intensity was observed . The JOAAccording to Andersson , back paIn our work we aimed to examine specific clinical- and demographic features associated with successful condoliase treatment derived pain relieve. Previous work by Okada et al. aimed at identifying prognostic factors for effective condoliase treatment found that a vertebral translation > 3 mm and a posterior disc angle > 5° may reduce efficacy of the treatment . HoweverOur study is the first report to examine the effect of condoliase specifically in teenagers and elderly patients. In teenagers, all 8 cases reported improvement in leg pain, but 5 cases had worsening in Pfirrmann grades, suggesting that further consideration for the indications for younger cases is required. Moreover, condoliase appears more effective for severely degenerated discs (Pfirrmann grade IV), and since condoliase can cause degeneration of the disc , researcLimitations of this study include the studies retrospective and single-arm (no data of comparison with placebo or other injection therapy) nature. Moreover, lack of information of other treatments  and condoliase treatment specifications could have affected outcome results and was not corrected for. Moreover, our and previous report have an overall limited follow-up and, despite the multicenter design sample, the included number of patients remains relatively small and heterogenous. Specifically, patient numbers in the young and elder categories were small, the made observations for these cohorts thus require examination in larger cohorts to confirm their validity. Here a follow-up period of three months was employed, as such long-term effects still remain unknown. Also, side effects and treatment complications were not analyzed in this study and remain a critical aspect to review in future work. Despite our reported improvement in pain outcomes, our study did not measure changes in the volume of herniated tissues. Further study is required to fully elucidate indications for condoliase therapy; however, initial outcomes appear very favorably is short term pain relief for LDH patients. Finally, future trials should aim to compare the safety and cost-efficacy profiles of condoliase intervention to standard microdiscectomy surgery to discern condoliase’s full potential in LDH treatment.Intradiscal condoliase injection proved effective in the majority of patients with LDH, as indicated by a strong clinically-significant improvements in leg pain, low back pain, and disability outcomes. The current study suggests that patients with large vertebral translation and posterior intervertebral angles may respond to treatment, even in patients older than 70 years with advanced degenerated IVD. Considering the possibility that degeneration of the IVD may progress due to the matrix degradation effects of condoliase, the indication for younger patients remains controversial.


Chronic pain (CP), a complex biopsychosocial disorder with a global prevalence of up to 33%, can be treated by following multidisciplinary approaches that may include cannabis-based medicine (CBM). However, because CBM continues to be a new treatment, questions remain regarding the ideal duration for CBM and its psychosocial determinants, including mental comorbidities.In a retrospective cross-sectional study involving 46 patients with CP (ICD-10 code F45.4-), three validated instruments—the German Pain Questionnaire, the Depression Anxiety Stress Scale (DASS), and the Marburg Questionnaire of Habitual WellBeing—were used to identify pain-specific psychosocial determinants and mental disorders. Descriptive analyses, a group differences analysis, and a logistic regression analysis were performed using SPSS.M = 5.13 years, SD = 1.41) and, as a consequence, faced significant restrictions in their everyday life and exhibited low subjective wellbeing . Comorbidities among the patients included depression, , anxiety , and stress . Between the two cannabis-based treatments with a course lasting either less or more than a year, the duration of treatment showed no between-group differences in terms of sociodemographic factors, pain-specific factors, conceptualizations of the illness, or mental disorders. Psychosocial determinants such as subjective wellbeing and mental comorbidities were not significant predictors of the duration of cannabis-based treatment.The patients most frequently reported low back pain as the primary location of their CP, and in attributing the condition to tissue damage, most had largely adopted a somatic orientation in conceptualizing their illness. Most had experienced CP for more than 5 years (We found no evidence indicating that the benefits of short-term vs. long-term cannabis-based treatment can be predicted by mental comorbidities or psychosocial factors. However, because CBM may be included in approaches to treat CP, questions about the ideal duration of such treatment remain to be answered. Chronic pain (CP) is a complex but common biopsychosocial disorder that causes severe personal and socioeconomic sequelae for each individual . As a copain as “an unpleasant sensory and emotional experience associated with, or resampling that associated with, actual or potential tissue damage” .CP as a condition of pain lasting more than 6 months  , the Depnot at all) to 3 (exactly) by asking patients to rate the kind of pain, its location, intensity, their conceptualization of the illness and causal attribution(s), the duration of the pain, and its effects. The kind of pain is assessed by having patients rate 12 adjectives  with their pain. Pain-associated factors are also assessed, including factors that improve or aggravate the pain. As for the pain’s location, patients are asked to draw the pain on a figure of the body. Meanwhile, pain’s intensity is assessed according to restrictions in everyday life using Von Korff et al.’s Chronic Pain Grade  to 3 (extremely or most of the time), for a maximum total score of 21. A cutoff of 6 is suggested for anxiety and 10 for depression and stress , is designed to assess positive aspects of mental health. The maximum total score on the MFHW is 35. The instrument’s psychometric quality has been assessed and found to be good , which served as the dependent variable.Sociodemographic data were analyzed using SPSS version 28.0.0 , which yThe mean age of the patients in the sample was 52.91 years , and 22 patients (46.8%) were male. Regarding socioeconomic characteristics, 27 patients (57.1%) were not employed, four patients (8.5%) reported being unable to work, and 22 patients (46.8%) reported a pension due to work-related disability. Further information is shown in M = 456.95 days; SD = 227.91); 22 patients (56.4%) received the treatment for less than a year and 17 patients (43.6%) for more than a year. We found no significant differences in the duration of cannabis-based treatment and the sociodemographic variables of gender , level of education , and pension .The average duration of cannabis-based treatment was more than a year  reported suffering from CP for more than 5 years , as shown in Descriptive analyses revealed that most patients in the sample , and some also had complaints of joint pain , pain in the extremities , head or face pain , and abdominal pain . Data from the DSF were analyzed with the duration of the cannabis-based treatment, the results of which are shown in The sample reported suffering predominantly from low back pain  = 0.019, p = 0.891, Cramér’s V = 0.023]; joint pain ; head or face pain ; and abdominal pain .We found no significant difference in cannabis-based treatment for less or more than a year with the location of pain: low back pain [χOf all patients, 34 (87.2%) had undergone an operation, whether an arthroscopy of the shoulder, knee, herniated disk, or endoprosthesis. Most often, treatment for the patient’s CP involved taking medication, including non-steroidal antirheumatics , opioids , and/or anticonvulsants . Patients had been treated in the past with a median of 4.00, different medications each .n = 37, Q1: 25.50; Q3: 90.00, range: 0–92), with a median of 8  on a visual analog scale ranging from 0 (no restrictions) to 10 (extremely high restrictions). The patients also reported being restricted in their work functioning, with a median of 8.00 . However, we again found no between-group difference for the duration of the cannabis-based treatment in relation to daily restrictions . The distribution for disability using Von Korff’s index is shown in Due to CP, patients reported having been restricted in their daily activities in the past 3 months for approximately 80.00 days  could identify a reason for their pain, the details of which are illustrated in Most of the patients . Patients with CP and cannabis-based treatment lasting less than a year had a median of 6.00 , whereas those who had received the treatment for more than a year had a median of 4.00 . There was no significant between-group difference between the duration of cannabis-based treatment and MFHW score .The analysis of the MFHW revealed a median of 4.00 , on the anxiety subscale of 4.50 , and the stress subscale of 11.00 . The distribution for patients who were above the cutoff to be diagnosed with the mental disorder is shown in U = 104.00, z = −0.83, p = 0.427; anxiety: U = 114.50, z = −0.215, p = 0.883; stress: U = 136.00, z = −0.02, p = 0.986).Analyses of the DASS data revealed a median score on the depression subscale of 11.50 , we used a binary logistic regression model. Both the MFHW and the DASS, including all three of its subscales , remained non-significant predictors, as shown in This article offers valuable insights into CBM as a commonly used treatment for patients suffering from CP. In particular, it answers essential questions regarding the impact of the duration of cannabis-based treatment lasting either more or less than a year, as well as questions regarding associations between the duration of such treatment and both mental illnesses and psychosocial determinants. In our study, we aimed to identify for the first time the effectiveness of short-term and long-term  cannabis-based treatment and compared those durations with mental disorders and determinants of the psychosocial environment to ultimately generate theoretical and practical implications for the treatment of CP.Assessments of mental disorders and determinants as psychosomatic and psychosocial variables that may influence cannabis-based treatment remain rare , despiteOur analyses also revealed that the majority of patients with CP had suffered from low back pain with high intensity for more than 5 years. Large systematic reviews report back pain as being the most frequent complaint of patients with CP , one witFor an in-depth understanding of the perception and processing of pain, conceptualizations of illness may offer insights into patients’ experiences. Thus, our analysis of conceptualizations of illness  is imporIn general, beliefs about pain, next to depressive mood, seem to be highly predictive of disability . In addiRegarding the duration of cannabis-based treatment, patients receiving CBM for more than a year did not differ significantly from patients with short-term cannabis-based treatment. To the best of our knowledge, no literature answers the question of which duration of treatment with CBM may improve mental comorbidities. From a clinical perspective, our findings underscore the importance of taking a multidisciplinary approach to managing CP . In pharFinally, our results should be viewed in the overall context of the position paper of European Pain, an expert group that empowers and informs specialists. The group has advocated cannabis-based treatment as an adjunctive medication as part of multidisciplinary treatment, particularly when guideline-recommended therapies are not successful . BecauseFirst, our study design is a retrospective analysis. However, by using that design, we were able to investigate a sample of patients with CP with a cannabis-based treatment that can be regarded as long-term, research on which remains sorely limited. At the same time, our sample size was rather small, we could not analyze causality with our study design, and we used self-report measurements, even though they are considered to be validated and are implemented regularly as assessment instruments. In light of those limitations, a longitudinal investigation would be clinically interesting for consolidating the outcomes of CBM and analyzing psychosomatic development. An analysis with another sample in Tübingen, also with treatment as usual , would be especially valuable.Cannabis-based medicine is a treatment option in the framework of multimodal treatment approaches for CP. Pain-specific, psychosocial factors, and mental comorbidities are indisputable factors in the success of CBM therapy. At the same time, our results do not implicate any benefit of those factors in the case of cannabis-based treatment lasting less than a year compared with treatment lasting more than a year. Neither mental comorbidities nor the patients’ subjective wellbeing predictors were able to differentiate treatment duration. Research into possible relationships between those determinants and cannabis-based treatment duration, therefore, remains necessary.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by University of Tübingen (number: 578/2021BO2). The patients/participants provided their written informed consent to participate in this study.AH-W, and TF-W designed the study with support of BS and AS. CR analyzed the data and wrote the manuscript with support of TF-W, SO, A-MJ, and AH-W. SZ, AS, and BS supported with scientific suggestions on the manuscript. All authors contributed to the article and approved the submitted version.


To determine the effect of aqua astricta flushing on ocular pain after Trans-PRK.  Three hundred and seventy eyes from 185 myopic patients were prospectively recruited for the study. Patients underwent Trans-PRK in both eyes. Postsurgically, one eye from each patient was randomly assigned to the trial group, and refrigerated normal saline was used to rinse the eye. The contralateral eye was assigned to the control group, and room temperature normal saline was used to rinse the eye. The primary target was postoperative pain experienced at the end of surgery and on the first, second, and third days after surgery. Secondary targets were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refractive spherical equivalent (MRSE), and haze. P < 0.05). Postoperative pain was not affected by patient cooperation, education level, refractive SE, optical zone, corneal bed, or cutting depth (P > 0.05). The level of pain at the end of surgery was affected by intraoperative rinsing. The pain level of the aqua astricta group was lower than the normal temperature saline group, and the difference was statistically significant (P < 0.01). Pain scores on the first, second, and third days after surgery were not affected by intraoperative rinse (P > 0.05).  Patient pain scores gradually decreased over time, and the difference between time points of all patients was statistically significant ( Trans-PRK is an important means of corneal refractive surgery, but postoperative pain remains unavoidable. These findings suggest that the use of cooled fluid during surgery reduces postoperative pain at the end of surgery. Corneal refractive surgery is currently one of the main approaches to correct refractive error . An incrThis prospective comparative study included 370 eyes from 185 patients with myopia who underwent Trans-PRK in the West China Hospital of Sichuan University. Patients with connective tissue diseases, correlative systemic diseases, serious medical conditions, dry eye, active ocular disease, suspected corneal ectasia and keratoconus, corneal dystrophy or degeneration, retinal disease, previous ocular surgery, and glaucoma were not considered candidates for surgery. Pregnant and lactating women were also excluded.Preoperatively, each patient underwent a full ophthalmic examination, including UDVA, CDVA, slit lamp examination, tonometry, dominant eye examination, subjective and objective refraction, retinal examination, corneal thickness as evaluated by ultrasound, and corneal topography. Antibiotic eye drops and diclofenac sodium eye drops were given four times per day 3 days before the operation. Preoperative medication included Benoxil eye drops  twice, 5 minutes apart.The surgery was performed under surface anesthesia by the same surgeon. The eyelid was opened with an eye speculum. According to the cutting procedure, the epithelial and stromal layers were cut in one step with an AMARS excimer laser system  using the Trans-PRK cutting mode of the customized ablation manager. Subsequently, one eye in each patient was randomly allocated to the trial group, and the contralateral eye was allocated to the control group automatically. In the trial group, refrigerated normal saline (approximately 4°C) was used to rinse the eye. In the control group, the eye was rinsed with room temperature (18°C) normal saline. The operating room requires a constant temperature, so room temperature was maintained at 18°C. The rinsing time of each eye was 15 seconds. At the end of the procedure, a bandage contact lens was applied to the surface, and a drop of cravit  was administered to the eye.All patients were instructed to apply levofloxacin hydrochloride eye drops (four times daily), diclofenac sodium eye drops (four times daily), and hyaluronate eye drops (four times daily). The contact lens was removed and the diclofenac sodium eye drops were stopped 5 days after the operation. Tobradex  eye drops were administered four times daily in the first week, three times daily in the second week, twice daily in the third week, and once a day in the fourth week.Postoperative pain questionnaires were completed at the end of the surgery and on the first, second, and third days after surgery. A physician blinded to the eye-specific treatment methods implemented the questionnaires. Assessment of pain was performed using numerical rating scales (NRS). All patients were presented the 11-point numeric scale of pain and were asked to state their pain intensity in each eye on a scale of 0–10, where 0 is no pain at all and 10 is the worst pain imaginable. UCVA, BCVA, manifest refractive spherical equivalent (MRSE), and haze were also recorded.t-test was used to compare UDVA, CDVA, mean refractive SE, optic zone, corneal bed, cutting time, cutting depth, and epithelial healing time. Generalized estimation equations (GEE) were used to analyze and plot repeated data . A Mann–Whitney test was used to compare postoperative pain and corneal haze scores. A p value less than 0.05 was considered statistically significant.Separate investigators who were not surgeons or pain recorders conducted data analysis and statistics. Data from all patients were entered into an SPSS 22.0  to create a database and perform statistical analysis of the two groups. The variables were first statistically described and then statistically inferred. A paired samples After the trial, the third investigator was unblinded.Of patients that recovered fully, 134/185 (72.4%) were male and 51/185 (27.6%) were female. Patient education level was mainly high school/secondary school/vocational high school, accounting for 75/185 (40.5%), followed by universities 53/185 (28.6%) and tertiary institutions 41/185 (22.2%). The average age was 20.98 years , among which 149/185 (80.5%) were teenagers aged 16–24 years, and 36/185 (19.5%) were young adults aged 25–34. In 285/370 eyes (76.5%), patients had good cooperation during surgery.Refractive SE, optic zone, corneal bed, cutting time, and cutting depth were −3.8 ± 1.23, 6.52 ± 0.27, 405.28 ± 33.55, 33.95 ± 5.73, and 121.55 ± 20.13, respectively. There was no statistically significant difference in the basic surgical information between treatment groups, as shown in P < 0.05).At the end of surgery, and on the first, second, and third days after surgery, the pain scores of all patients were 2.52 ± 2.08, 1.91 ± 1.95, 0.71 ± 1.17, and 0.16 ± 0.61, respectively. Pain scores gradually decreased with time, and the difference between time points was statistically significant (P > 0.05).Patient cooperation, education level, refractive SE, optical zone, corneal bed, and cutting depth did not affect pain levels (P < 0.01). Pain scores on the first, second, and third days after surgery were not affected by intraoperative rinse (P > 0.05), as shown in Pain level at the end of surgery was affected by intraoperative rinsing. The pain scores of the aqua astricta group and room temperature saline control group were 2.20 ± 2.04 and 2.83 ± 2.08, respectively. The aqua astricta group was lower than the room temperature saline group, and the difference was statistically significant (P < 0.05), as shown in The pain scores in the adolescent group  were lower than those in the young adult group (age older than 25 years old), with statistically significant differences in pain scores at the end of surgery and on the first postoperative day , as shown in On the second and third postoperative days, the pain score in eyes with a long cutting time (34–56 seconds) was higher than that of eyes with a short cutting time (10–33 seconds) (There was no haze in either group.Excimer laser keratectomy (PRK) removes corneal epithelial tissue using an excimer laser to cut the central region of the cornea to flatten the surface and reduce the refractive power, correcting myopia –5. PRK iμm [Transepithelial photorefractive keratectomy (Trans-PRK) is a modified and alternative method to conventional PRK. This approach uses an excimer laser to complete corneal epithelium cutting instead of a corneal scraper, alcohol, and blunt spatula and then continues to use the excimer laser for underlying stroma cutting. The whole process with the laser is completed in one step, so the operation is simpler. Trans-PRK is especially desirable for patients with a predisposition for contact injury or thin corneas in which the residual stromal bed would be less than 250–300 μm –13. HoweP < 0.05). However, 1–3 days after surgery, there was no significant difference in pain level between the two groups. Aqua astricta rinse during surgery can lower the local temperature, which leads to local vasoconstriction, decreased metabolic rate, decreased vascular inflammatory factors, and reduction of nerve fiber sensitivity and transmission of nerve impulses, thereby reducing pain immediately following surgery. However, over time, when the temperature of the local tissue increases, nerve stimulation caused by the injury recovers, and inflammatory chemokines released by injured tissue, such as prostaglandins, bradykinin, and serotonin, further stimulate nerve endings. Together, these factors restore the pain level. The effect of aqua astricta diminished after surgery, such that an aqua astricta rinse only controlled pain immediately following surgery and failed to reduce pain several days postoperatively.Some studies suggested using cooling of the corneal surface to reduce postoperative ocular discomfort and pain, as well as the incidence of haze –18, whilTaking patient age and gender into account, younger patients had less pain than older patients at the time of surgery and on the first day after surgery, but there was no significant difference after 2 days postoperatively. Women were more sensitive to pain than men at all time points. Because patients assessed pain, this relationship may be related to the mental status of different ages and genders. Pain is a complex psychological and physiological process. The degree of postoperative pain is not only related to the surgical site and incision but is also related to the patient's personality, age, education, and anxiety. However, previous studies , 22 idenIn regards to surgical cutting time, this study found that the length of cutting time had little effect on pain at the time of surgery and 1 day after surgery. However, in the later period (second and third days), patients with longer cutting times had higher pain than patients with shorter cutting times, which was statistically significant. As the cutting time increases, the cornea is injured by the laser for a longer time, producing more inflammatory stimulating factors and long-lasting pain. This may also result in more extensive corneal edema and slower recovery. A longer corneal recovery time may lead to increased pain levels at later stages. Previous studies did not examine the relationship between cutting time and pain.No significant haze occurred in either group. This result is very satisfactory. Most recent studies comparing Trans-PRK to alcohol-assisted PRK reported less haze , 25. SinTrans-PRK is an important method of corneal refractive surgery, but postoperative pain is currently unavoidable. However, the postoperative pain is not severe and in most cases completely resolves within 5 days postoperatively. This study, in combination with other clinical trials, suggests that the intraoperative use of cooled fluid reduces the local corneal temperature, which alleviates postoperative pain at the time of surgery, but does not affect postoperative pain in the following days. The patient's age, gender, cutting time, and other attributes impact postoperative pain. Further investigations into shortening the cutting time and otherwise decreasing postoperative pain are needed.


We investigated the neural correlates for chronic cancer pain conditions by retrospectively analyzing whole brain regions on 18F-fluoro-2-deoxyglucose-positron emission tomography images acquired from 80 patients with head and neck squamous cell carcinoma and esophageal cancer. The patients were divided into three groups according to perceived pain severity and type of analgesic treatment, namely patients not under analgesic treatment because of no or minor pain, patients with good pain control under analgesic treatment, and patients with poor pain control despite analgesic treatment. Uncontrollable cancer pain enhanced the activity of the hippocampus, amygdala, inferior temporal gyrus, and temporal pole. Metabolic connectivity analysis further showed that amygdala co-activation with the hippocampus was reduced in the group with poor pain control and preserved in the groups with no or minor pain and good pain control. The increased although imbalanced activity of the medial temporal regions may represent poor pain control in patients with cancer. The number of patients who used anxiolytics was higher in the group with poor pain control, whereas the usage rates were comparable between the other two groups. Therefore, further studies should investigate the relationship between psychological conditions and pain in patients with cancer and analyze the resultant brain activity.Trial registration: This study was registered at clinicaltrials.gov on 9/3/20 (NCT04537845). The actual etiology of cancer pain remains poorly understood owing to the various potential direct and indirect causes4, which has resulted in approximately one-fourth to half of the patients with cancer reporting cancer-pain undertreatment7.Pain is one of the most prevalent symptoms in patients with cancer. Overall, 55% of patients with cancer experience pain during treatment, and the prevalence increases up to 80% depending on the stages or sites of the cancer8, and chronic pain also frequently coexists with anxiety and depression9. The limbic system integrates information from the sensory and affective components of pain and anxiety, which include the limbic lobe, hippocampal formation, amygdala, septal area, and hypothalamus11. The altered response of the amygdala to chronic pain may further affect the functional brain networks related to interoception, emotion, and cognitive status, all of which may result in maladaptive pain perception13. Elucidating the cortical representation of cancer pain perception and the differences in cortical responses between well-managed and poorly-managed chronic cancer pain could further improve our understanding of the central mechanism of chronic cancer pain and lead to potential treatments.Evidence suggests a strong interaction between pain and emotion, that is, negative emotions can worsen pain experiences14 and serve as a functional neuroimaging tool to investigate brain areas and metabolic connectivity in various pain conditions18. Our previous animal study on cancer-induced bone pain confirmed the reliability of FDG-PET for cancer pain investigations19. However, the utilization of FDG-PET in patients with cancer pain had been limited to a small-group study20 with results that were difficult to interpret because of the various types of cancers and other clinical conditions included in the sample.Therefore, we investigated the resting-state brain activity of patients with cancer reporting various intensities of perceived pain by analyzing 18F-fluoro-2-deoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) images acquired for routine clinical examination purposes. FDG-PET images can be used for quantitative evaluations in clinical oncologyWe investigated signature cortical responses reflecting good or poor pain control by comparing the cortical activity of 80 patients with cancer across three groups of perceived pain intensities and on pain control statuses based on analgesic use. We hypothesized that cancer pain activates the amygdala and limbic system compontents involved in pain-emotion interactions and that this activity is inhibited in patients who are appropriately treated with analgesics. We also investigated differences in the cortical metabolic network emerging from these medial temporal regions within other resting-state networks to determine the functional organization in conditions of good and poor control of chronic cancer pain. The working hypothesis is that the pain-related changes in the metabolic network may also be ameliorated under the good pain control conditions.24. Patients with brain metastases based on brain magnetic resonance imaging or CT and patients without a pain rating on the day of the PET scan were excluded. Data collected for analysis included age, sex, cancer diagnosis, pain condition including location, pain score, medication, and FDG-PET/CT findings of the patients.Patients who underwent FDG-PET/CT between March 2015 and July 2020 at the National Taiwan University Hospital were retrospectively enrolled. This study was approved by the institutional ethics committees of the National Taiwan University Hospital and conducted in accordance with the Declaration of Helsinki. The requirement for informed patient consent was waived owing to the retrospective nature of the study. We included patients diagnosed with head and neck squamous cell carcinoma or esophageal cancer who completed a PET/CT study for the clinical indication of cancer staging. These cancer types were selected because they share a cancer cell origin, clinical risk factors, and genetic alterations in tumorsWe divided the patients into three groups: patients treated with analgesics with good pain control , patients treated with analgesics with poor pain control , and patients with no or ignorable pain and not receiving analgesic treatment   or Biograph mCT .25). The FDG uptake value of each voxel was normalized based on the whole-brain activity for each image20.PET image analysis was performed using MATLAB  and Statistical Parametric Mapping . We extracted the head region from the raw PET scans for each patient from the original Digital Imaging and Communications in Medicine files and reconstructed the three-dimensional images of cerebral FDG uptake. The individual images were co-registered and normalized to the standard stereotactic space in reference to a standardized FDG-PET template -corrected threshold of p < 0.05 within the cerebral region. Since the prevalence of anxiolytic use was higher in the AP group, we also tested another ANOVA model with the same pain status factors and included anxiolytic use as a covariate. However, we could not include the anxiety severity in the current retrospective study owing to the lack of data.We first conducted voxel-based, one-way analysis of variance (ANOVA) on the data to compare the brain activities among the groups. After determining the cortical regions that corresponded to the main effect of the pain status , we performed multiple-comparison analyses to localize the cortical regions demonstrating different activities between group pairings. The initial voxel threshold was 26. Metabolic connectivity determines regionally connected areas of the resting brain from static FDG-PET images collected from multiple participants. It determines the cortical connectivity with the strength of co-activation or deactivation between regions based on a conjugate increase or decrease in the cerebral metabolic rate of glucose27. We defined three seed regions obtained from the main effect analysis in the one-way ANOVA that differentiated the resting-state brain activity of the three groups. More specifically, the seed regions were defined as: (1) the anatomically parcellated region in the anatomical automatic labeling (AAL) atlas showing a significant main effect of enhanced glucose metabolism across groups, (2) volume exceeding 30 voxels, and (3) present in the cerebral cortex. The mean normalized FDG uptake values of these seed regions were used as independent variables in a general linear model to determine voxels that covaried with activity in the seed regions across patients. After obtaining the t-value map in the regression analysis, we extracted regions showing significant metabolic connectivity under the statistical criterion of FWE-corrected p values < 0.05 with a cluster-size threshold of k > 30.Second, we investigated voxel-wise metabolic connectivity in the brains of patients from each group using interregional correlation analysis35, we investigated the metabolic connectivity from the seed regions occurring within the brain regions of the default mode network (DMN), salience network (SN), and central executive network (CEN). The triple network of DMN, SN, and CEN was investigated based on the causal relationship between the aberrant interactions within and between these networks and neuropsychiatric illnesses36. Cortical regions within the triple network were defined according to previous studies39. Brain masks representing each network were prepared using either the AAL3 atlas40 or Brodmann atlas implemented in the WFU PickAtlas41 .Based on the reported engagement of pain status in the resting-state brain networksp < 0.05. Statistical analyses were performed using MedCalc version 19.8 .We used one-way ANOVA or the chi-square test to examine differences in patient demographics among the groups. Multiple comparisons were corrected with the Scheffe test. Data were considered statistically significant at p < 0.001, Table p < 0.05). However, there was no statistically significant difference between the AG and the AP or N groups. The type of analgesic used showed a significant difference between the AG and AP groups (p < 0.001), while the strength of the opioids used and duration of opioid treatment were comparable. The number of patients who used anxiolytics was higher in the AP group (p < 0.05) while the usage rates were comparable between the AG and N groups.Age, sex, and cancer stage did not differ among the N, AG, and AP groups. The pain score (NRS) was significantly different between each group pairing p < 0.00, Table 1One-way ANOVA showed the statistically significant main effect of enhanced glucose metabolism in the bilateral amygdala, right inferior temporal gyrus, and right temporal pole (TP) Fig.  in the pMultiple comparisons demonstrated significant differences in activity between the AP and other groups Fig. . Howeverp < 0.001. Multiple comparisons also demonstrated increased bilateral amygdala and TP activity in the AP compared with the other groups .The main effect in the left amygdala and right TP remained after anxiolytic use was included in the ANOVA model at the lower statistical threshold of uncorrected Figure Metabolic connectivity from the TP seed showed mostly similar patterns of autocorrelation and correlation with neighboring regions within the TP regardless of patient group Fig. . Additiop < 0.001, the co-deactivation and co-activation with amygdala seed regions were observed within the CEN and SN regions, respectively, in all groups. The AG group showed more distributed co-deactivation within the CEN regions and co-activation of the insular cortex within the SN regions than that in the N and AP groups . Moreover, the recurrence rate of anxiolytic users was 45% , indicating that the anxiolytic use and recurrence rates may not be associated. These results support the fact that pain is the most common symptom of cancer, especially when cancer recurs49, as well as to the physical pain itself52. Recent studies support the significant role of the amygdala and hippocampus in enhancing pain perception under anxiety53 and regulating anxiety56. Our results suggest that the altered resting-state activity of these medial temporal lobe regions may be caused by cancer pain and associated psychological stress.The enhanced activity found in the amygdala and hippocampus of patients with poorly controlled pain relative to those without pain could therefore represent the neural response to the emotional stress caused by cancer pain59 including pain processing60. Functional connectivity analyses also support the involvement of the TP in modulating brain regions associated with the sensory-discriminative and affective-motivational aspects of pain, including the insula and amygdala, in patients with chronic pain60 and generalized anxiety disorders61. Our observation of enhanced TP activity in patients with uncontrollable cancer pain may thus imply maladaptation of the central circuitry of pain perception and increased anxiety.The TP is involved in various cognitive and psychological processes62. The specifically determined metabolic connectivity observed between the amygdala and anterior hippocampus supports the previous functional magnetic resonance imaging-based functional connectivity reported in healthy participants55. The metabolic hypoconnectivity between the amygdala and hippocampus in the AP group suggests a maladaptive response to prolonged pain or stress-induced hyperalgesia64. The coactivation of the amygdala and hippocampus may suggest good control of pain or anxiety in patients with cancer pain.Metabolic connectivity analysis further revealed hippocampal co-activation with the amygdala seed regions in the AG and N groups but not in the AP group. The hippocampus and parahippocampal gyrus are part of the medial temporal subsystem of the DMN, which is involved in self-inspection and monitoring of the internal environment65, our results suggest an antagonistic relationship between emotional responses in the amygdala and its regulatory responses in these frontoparietal regions in patients with good pain control32.The metabolic connectivity analysis also revealed significant co-deactivation with amygdala seed regions found in the bilateral angular gyrus within the DMN, bilateral IPL regions associated with the DMN and CEN, and right DLPFC within the CEN, which were observed exclusively in the AG group. Reflecting the essential roles of the angular gyrus, IPL, and DLPFC in the cognitive regulation of emotional responses66 therby affecting limbic system activity67. However, the included patients may have experienced similar emotional stress, as they had all been recently diagnosed with cancer or recurrence and underwent FDG-PET to determine the cancer stage. Furthermore, all three groups of patients used benzodiazepines for anxiety. Patients in the N and AP groups also took zolpidem, and one patient each took zopiclone, mirtazapine, quetiapine, and flupentixol/melitracen in the AP group. The reduced statistical significance of the perceived pain intensity-related activity in the medial temporal regions in patients taking controlled anxiolytics suggests a moderate effect of anxiety on the metabolic network in patients with severe cancer pain. However, the anxiety severity should be included to precisely investigate the effect of anxiety on the cortical activity related to cancer pain. Further prospective studies should incorporate information on anxiety and depression intensity to disentangle anxiety-related neural correlates from pain-related symptoms. Second, the type of analgesics was significantly different between the AG and AP groups. However, the effect of analgesics on cortical activity may have been minor because perceived pain intensity was not significantly different between users of weak and strong opioids in the AG and AP groups and the total durations of opioid use were comparable between the groups. However, various opioids may alter cerebral activity, which requires further investigation to identify the pharmacological mechanisms in cancer pain. Third, metabolic connectivity maps were only qualitatively compared since the metabolic connectivity analysis provided only a single connectivity map per group. Further studies should employ normal control data to determine the individual alternations in the metabolic connectivity architecture relative to control metabolic connectivity maps68 for between-group comparisons.This study had several limitations. First, the psychological history, depression, and anxiety status of the patients were not available in this retrospective study. The perceived intensity of anxiety may varied among individualsPET imaging in patients with head and neck squamous cell carcinoma or esophageal cancer demonstrated the potential involvement of cancer pain in enhancing temporal lobe activity, especially in the amygdala, hippocampus, and TP regions. Since these regions are strongly involved in emotion and interoception, further studies should investigate the relationship between psychological conditions and pain in patients with cancer and analyze the resultant brain activity.Supplementary Information.


To evaluate the effect of hard stabilization splints (HSS), counselling and exercise therapies, respectively, for the painful temporomandibular disorder (TMD) in patients seeking for orthodontic treatment through magnetic resonance imaging (MRI) and clinical examination.n = 43) comprising of patients treated with HSS, counselling and masticatory muscle exercises; the control group (n = 44) comprising of patients treated with counselling and masticatory muscle exercises alone. All patients had orthodontic therapies after the first treatment phase. The joint pain and clicking of all patients were recorded via clinical examination. MRIs of HSS groups were taken before (T0), after the first phase (T1), and after the orthodontic treatment (T2). Parameters indicating the condyles and articular discs were evaluated. Clinical symptom (pain and clicking) changes among T0, T1 and T2 time point were detected in the two groups respectively. The significant differences between HSS and control groups, as well as between male and female were tested at T1 and T2. Position changes of condyles and discs in HSS group among T0, T1 and T2 were detected in male and female respectively.Eighty-seven TMD patients were divided into two groups according to their therapies: the HSS group (P > 0.05). Clicking decreasing was not statistically significant. After the whole orthodontic periods, the TMJ pain relapsed in female of the control group, and the number of female’s pain joints was more than male’s (P < 0.05). In the HSS group, the posterosuperior movements of discs and the anteroposterior movements of condyles were recorded in closing position (P < 0.05). After the whole orthodontic periods, female’s disc-condyle angles increased, the discs to HRP distance decreased and condyles to VRP distance increased when compared with the data of T1 (P < 0.05).After the first treatment phase, there was no difference in the decrease of facial pain between the two group, as well as between male and female in the two groups (For the orthodontic patients with painful TMD, HSS combined with counselling and exercise therapies before orthodontic treatment could provide pain relief. HSS is helpful to improve the position and relation of discs and condyles. In addition, male's prognosis is better than female's in terms of stability. Temporomandibular disorder (TMD) is a common condition and frequently encountered disease in oral system, which is a general term for a group of diseases involving masticatory muscles, peripheral nervous system, and temporomandibular joints (TMJs) . Main syThe pathogenesis of TMD has not been fully clarified, which is related to psychosocial factors, immunity, occupational strain, TMJ overload and its anatomical factors and so on . OcclusaThe conservative therapy of TMD mainly include occlusal splint therapy, counselling, exercises, massage, manual therapy, which are considered as the first choices treatment for TMD pain because of their low risk of side effects . ExercisThe reality is that many patients seeking for orthodontic treatment do have some TMJ clinical symptoms, such as pain, friction and clicking. In orthodontic clinics, in order to alleviate the clinical symptoms of some patients with obvious TMJ pain, sometimes HSS, counselling or exercises therapy are used before orthodontic treatment to relieve TMJ symptoms and reduce TMJ discomfort , 19. HowThe whole dynamic process from HSS, counseling, exercise therapies to the end of the occlusal reconstruction about TMJ symptoms are relatively rare. The aim of this study was to explore whether HSS combined with counselling and exercises has additional benefit in relieving TMJ pain, whether HSS will increase long-term efficacy stability in the following orthodontic treatment, to explore what the HSS dose to disc-condyle position. The null hypothesis is that no difference in efficacy would be found between HSS therapy and counselling, exercise therapies, as well as between male and female. This study could provide some references clinically.This retrospective study selected 20 to 30-year-old adults with painful TMD as the experimental object, and was done at the Xiangya Stomatological Hospital of Central South University with 41 males and 46 females. The samples were consecutive patients with detailed and complete clinical data who started the treatment after 04–2020 and ended before 06–2020. Subjects were selected according to the following criteria: (1) Meeting the diagnostic criteria for TMD research (RDC/TMD) [Centric relation (CR) occlusion was performed by one hand induction directly by the same clinician and recorded by Delar wax. Then, occlusion records were transferred to the Germany SAM articular and the splints were produced on this CR position Fig. .Fig. 1HaPatients of HSS group were asked to wear HSS throughout night plus 4 h during the day, being 2 h in the morning and 2 h in the afternoon for 4 months. Clinicians have the HSS adjustably grinded on each subsequent visit . In addition, counselling and masticatory muscle exercises were also implemented during the period. The control group implemented counselling and masticatory muscle exercises alone.Fixed orthodontic treatment was used to all patients after the first treatment phase. Class I occlusion was achieved at the end of the orthodontic therapy and modified Hawley’s mechanical retainers were used for each patient. The implementation of treatment for all patients was performed by one clinician.In the section of radiographic data, Authors should add the information weather or not the patients wore, as this, see:T0), immediate post-splint (T1) and post-orthodontics (T2) of the patients in HSS group were accessed with closings and the greatest openings respectively. All MRI data were calibrated and obtained by the same observer with patients not wearing fixed retainers, as retainers may blur and cause distortions to the image [MRIs of three different stages in the whole treatment procedures including pre-splint  TMJ pain: The degree of TMJ pain, including masticatory and joint area, was assessed for signs and symptoms according to Mehra and Wolford (7) and Kurita et al. [TMJ clicking: Whether there was joint clicking and the number of joints with clicking at a et al.  Visual aT0, T1 and T2time point. An independent sample t-test was used to test significant differences between HSS and control groups, as well as between male and female. To assess the reliability of these measurements, 30 subjects were randomly chosen. All measures were duplicated by the investigator R.N. An intraclass correlation coefficient (ICC) was used to determine the intraobserver reliability of the measurements through reliability analysis in SPSS. Reliability was divided into three categories: poor (ICC < 0.40), fair to good (0.40 ≤ ICC ≤ 0.75), and excellent (ICC > 0.75) [All data were analyzed by IBM SPSS Statistics 21 software. Kolmogorov–Smirnov analysis and Fanchazzi analysis were used for the homogeneity of variance test and normal distribution, and statistical significance was established at α = 0.05. One- and two-way analysis of variance (ANOVA) with Tukey tests was used to detect clinical symptom changes among  > 0.75) .P < 0.05 shows that each set of data conforms to homogeneity of variance test and normal distribution. And the intra-observer reliability of the measurements of all descriptions using SPSS software was excellent, with ICC’s ranging from 0.821 to 0.898. The retrospective power was from 0.791 to 0.932.Kolmogorov–Smirnov analysis and Fanchazzi analysis with all The subjects in both the HSS and control groups that were examined according to RDC/TMD criteria showed none of the patients were diagnosed with Disc displacement without reduction, with limited opening.T1 period, after which there was no statistically significant change at the T2 period. In contrast, the changes of TMJ pain in the control group had statistical significance at both T1 and T2, with pain relief at T1 and pain recurrence at T2. There was no difference between the T0 and T2 periods in TMJ pain in control group. At the T1 period, the VAS value and number of pain joints in HSS and control groups decreased, and the difference between the two groups was not statistically significant. At the T2 period, the VAS value and number of pain joints in the control group increased, which was significantly greater than that of HSS group .None of HSS, counselling and exercise therapies could alleviate the TMJ clicking. There was a significant TMJ pain relief in both groups. However, pain relief in the HSS group was mainly concentrated at the T2 period of the control group, the difference in the number of pain joints and VAS value was statistically significant . The VAS value of male (2.14 ± 1.05) was smaller than that of female (4.33 ± 1.57), and the number of pain joints of male (9) was also less than that of female (30).There were no statistically significant differences in numerical comparisons between all male and female in the HSS group. At the P < 0.05). The disc-condyle angles also decreased (P < 0.05). These outcomes indicated that the discs showed posterosuperior movements and condyles showed anterosuperior movements immediately after HSS treatment in all HSS group’s patients. At the T2 period, female’s disc-condyle angles increased, the discs to HRP distance decreased and condyles to VRP distance increased when compared with the data of T1 (P < 0.05), which meant that there was a tendency to relapse back to discs’ original position. The good news was that the statistically significant difference in (T2-T0) period was still showed in female (P > 0.05). In opening position, the movement of discs and condyles had no statistically significant difference, as well as disc-condyle angles. The MRIs in typical cases was showed in the Fig. Both in male and female, the discs to HRP distance significantly increased and to VRP distance significantly decreased after the HSS treatment in closing position  The surface of the posterior tooth area of HSS is flat and smooth, which can ensure no interference in mandibular movement and prevent condyles from being locked by ICP . The anterior tooth area of HSS forms the guiding surface of mandibular anterior and lateral movement, which will ensure a balance in mandibular anterior and lateral movement, and gradually restore TMJ to a comfortable condition . (2) EttOn the other hand, male had a more stable efficacy in both clinical examinations and MRI results when compared with female’s. We don't really know exactly why things turned out as they did, but we hypothesized some possible reasons for the phenomalea. (1) In clinical practice, normal disc-condyle relations are often not restored, and the temporary stability of disc-condyle relations partly result from the reconstruction of joint discs, which can be helped by HSS. TMJ pain will occur again if such reconstruction—more difficult for female—is not successful. Isberg  suggesteThere are certain limitations of this retrospective analysis. First, the research has a relatively small sample size due to the strictly controlled inclusion criteria and the required integrity of the research data. Second, it is difficult to use a blind method in retrospective analysis, and the bias is inescapable. Third, the research lack of long-term tracking of clinical efficacy on TMD, which need to be implemented in the future. However, taking the clinical symptoms and MRI results into consideration, we analyzed the influence of gender factor and treatment methods on the clinical efficacy. The useful conclusion could still provide some clinical references.T0 and T2. These results indicates that both in male and female, HSS might improve disc-condyle relations in short-term, but long-term observation and a more adequate statistical analysis are needed.In general, this study suggests such HSS can relieve the pain of masticatory muscles for the orthodontic patients with painful TMD, especially for female. Besides, although there was a slight increase in disc deviation after orthodontic treatment in female, there was still statistical significance in all descriptions between In addition to treating painful TMDs, some clinicians think HSS also have the function of clarifying mandibular positions and assisting orthodontic diagnosis. In view of the possible relationship between the CO-CR incompatibility and the TMD, it is particularly important for clinicians to determine accurate orthodontic diagnosis under favorable TMJ condition for patients with TMJ symptom. Clinicians’ treatment goal is to achieve coordinated static and functional occlusion, and to limit CO-CR deviation within a certain range as much as possible . UnfortuFor the orthodontic patients with painful TMD, HSS combined with counselling and exercise therapies before orthodontic treatment could provide pain relief. In addition, male's prognosis is better than female's when without HSS therapy.HSS is helpful to improve the position and relation of discs and condyles. However, there was a tendency to relapse back to discs’ original position, especially in female. Careful and long-term monitoring of the condyle and disc may be needed after splints and orthodontic therapies.