Thoracic epidural analgesia is commonly used for upper gastrointestinal surgery. Intrathecal morphine is an appealing opioid-sparing non-epidural analgesic option, especially for laparoscopic gastrointestinal surgery.Following ethics committee approval, we extracted data from the electronic medical records of patients at Royal North Shore Hospital  that had upper gastrointestinal surgery between November 2015 and October 2020. Postoperative morphine consumption and pain scores were modelled with a Bayesian mixed effect model.n = 300), laparoscopic (n = 120) or laparoscopic converted to open (n = 7) upper gastrointestinal surgery. The majority of patients undergoing open surgery received a neuraxial technique  compared to a minority in laparoscopic approaches . Intrathecal morphine was superior over non-neuraxial analgesia in terms of lower median oral morphine equivalent consumption and higher probability of adequate pain control; however, this effect was not sustained beyond postoperative day 2. Thoracic epidural analgesia was superior to both intrathecal and non-neuraxial analgesia options for both primary outcomes, but at the expense of higher rates of postoperative hypotension  and substantial technique failure rates (32%).A total of 427 patients were identified who underwent open (We found that thoracic epidural analgesia was superior to intrathecal morphine, and intrathecal morphine was superior to non-neuraxial analgesia, in terms of reduced postoperative morphine requirements and the probability of adequate pain control in patients who underwent upper gastrointestinal surgery. However, the benefits of thoracic epidural analgesia and intrathecal morphine were not sustained across all time periods regarding control of pain. The study is limited by its retrospective design, heterogenous group of upper gastrointestinal surgeries and confounding by indication.The online version contains supplementary material available at 10.1186/s13741-023-00324-0. Opioids are a mainstay of perioperative pain management, but opioid-related side effects may limit dosing and negatively impact on recovery. Furthermore, in the context of an opioid epidemic and abuse crisis, measures to minimise opioid use following hospital discharge is a priority  protocols following upper gastrointestinal surgery  we undertook a retrospective cohort analysis in patients who underwent upper gastrointestinal surgery over a 5-year period (between November 2015 and October 2020) at Royal North Shore Hospital, a 900-bed tertiary facility, in Sydney, Australia. Billing codes were used to identify patients within the electronic medical record to include those who had elective open or laparoscopic upper gastrointestinal procedures including: hepatectomy, gastrectomy, pancreatectomy, oesophagectomy, pancreatoduodenectomy, splenectomy, diaphragmatic or hiatus hernia repair, or bariatric surgery.For our primary endpoints, pain scores were recorded using the 11-point numerical rating scale where zero indicates no pain, and 10 the worst pain imaginable , type 2: most extensive major  or type 3: other major .The primary outcomes for this study were differences in pain scores and daily cumulative oral morphine equivalent dose until 72 h postoperatively for the patients grouped into either thoracic epidural analgesia, intrathecal morphine, or non-neuraxial analgesia cohorts. A difference of 10 mg oral morphine equivalent consumption was considered clinically relevant. Pain scores of four or less were considered to reflect adequate pain control  and entered into a REDCap database hosted at Northern Sydney Local Health District. Preoperative data collected included: age, sex, American Society of Anesthesiologists (ASA) physical status, timing of surgery, and surgery type. Intraoperative data collected included: surgical approach (open or laparoscopic), analgesic technique, dose of intrathecal morphine (if used), ease of neuraxial placement (if used and indicated), dose and types of intraoperative analgesia, and extubation/ventilation status at conclusion of the surgical procedure. Postoperative data included: patient disposition, duration of high dependency unit stay, worst resting and dynamic pain scores in the recovery unit as well as on postoperative days 0 to 3 recorded by the ward nurses, oral morphine equivalent dose administered while in the recovery unit, daily cumulative oral morphine equivalent dose until postoperative day 3, obtained from the PCA and medication chart, duration of hospital stay, opioid prescription on discharge home, and occurrence of opioid related side effects including: itch, nausea and/or vomiting requiring treatment, sedation or respiratory depression requiring naloxone or airway intervention, urinary retention, ileus, hypotension requiring fluids or vasopressor, or death having occurred prior to the date of data extraction.Our detailed statistical analysis approach is included in the additional material. In brief, post-operative morphine requirements, resting pain scores and dynamic pain scores over the 4 post-operative time points were modelled separately with Bayesian generalised mixed effect models. In this retrospective cohort sample, each patient can have up to 4 data points across the post-operative period. With 427 patients, the data set had 1664, 1548 and 1252 data points for postoperative morphine requirement, resting pain score and dynamic pain scores, respectively, that are potentially highly correlated. The generalised mixed effect model was chosen as the modelling approach as it allows within-patient, across time-points correlations to be accounted for.Our modelling approach allows bespoke specifications to the models according to what we understand about the properties of a particular outcome that we are interested in. For example, for postoperative morphine requirements, we would expect it to be highly skewed and its distribution to be not normal. We would also expect the morphine requirements over the postoperative period to be non-linear. From clinical experience, with different intra-operative analgesic techniques and with different surgical extent and approaches, we would also expect that some patients may not need opioid at all postoperatively. This may give rise to a bi-modal distribution of postoperative morphine where there is a second peak of an excess of zero opioid dosing. These more realistic properties of morphine requirements have been incorporated in our modelling by specifying a hurdle-lognormal link and using natural splines.Pain scores, on the other hand, are arguably not numerical scores that can be added, subtracted or averaged between different patients. They are ordinal values where the interval between a pain score of 0 to 3 is not necessarily the same as a pain score difference between 6 and 9, but a pain score of 0 is considered less than a pain score of 1, and a pain score of 1 < 2 < 3…. < 10. We have thus chosen to specify our resting and dynamic pain score mixed effect models with an ordinal cumulative link.. Two kinds of adjusting variables were included—those intrinsic to the patient such as age, gender, and their ASA physical status classification, and those extrinsic to the patient such as the surgical procedure conducted, and the surgical approach chosen. We are interested in how these “extrinsic” variables may affect the opioid requirements or the pain scores over the postoperative period, hence in our modelling approach we have included additional interaction terms against time.The adjusting variables were collected a priorip values, confidence intervals and the concepts of type I/II errors  framework that use a number of tools for interpretation such as For postoperative morphine requirements  and laparoscopic (n = 127) upper gastrointestinal surgery at the Royal North Shore Hospital between November 2015 and October 2020. Most patients were ASA physical status 2 or 3 across all cohorts  and intrathecal morphine 21%), versus non-neuraxial (21%). By contrast, 85% of patients who underwent laparoscopic surgery had non-neuraxial analgesic management. The predominance of patients undergoing pancreatoduodenectomy (84%) or oesophagectomy (96%) received thoracic epidural analgesia. Most patients (87%) undergoing less extensive procedures, such as hiatus hernia repairs, were more likely to receive non-neuraxial analgesia as their primary analgesic modality, and rarely received intrathecal morphine (8%) or thoracic epidural analgesia (5%)  98 60–120) mg, compared to the non-neuraxial 50 (IQR 30–100) mg and thoracic epidural 20 (IQR 20–60) mg analgesia groups  and open (− 6.0 mg [− 31.9 to 22.4]) surgeries  However, specific to postoperative day 0, the probability of a clinically relevant reduction in opioid consumption for laparoscopic surgery was 92%  were more frequently 0 for intrathecal morphine and thoracic epidural analgesia, the latter remaining 0 until postoperative day 2. Thereafter, dynamic pain scores were more frequently greater than 5 in both the intrathecal morphine and thoracic epidural analgesia groups.The ups Fig. . Rest parest  − 0.09 to 0.08) and dynamic  pain, according to extent of surgery or surgical approach (Tables rest pain control was evident on postoperative day 0 and 4% reduction (− 0.16 to 0.09) on postoperative day 1. Reversal in favour of the non-neuraxial group was evident by postoperative day 3. Subgroup analysis by surgical approach and type of surgery had similar results. An early benefit of intrathecal morphine at reducing the probability of poorly controlled dynamic pain scores (0–20% reduction) is evident across all types of surgery and approaches, with reversal in favour of non-neuraxial analgesia by postoperative day 3.Overall, simulation of allocation from a non-neuraxial technique to intrathecal morphine, or vice versa, had minimal impact on the probability of poorly controlled rest pain overall by 8% (-0.16 to -0.01), with the greatest impact on day 0 (− 21% [− 0.35 to − 0.10])  and open (6% [− 0.14 to 0.22]) surgery. This finding is similar when the movement between analgesia types is considered in reverse.Where a non-neuraxial technique is chosen, simulation of movement to thoracic epidural analgesia is predicted to reduce the median probability of poorly controlled 0]) Fig. . No diffdynamic pain was found when moving from non-neuraxial to thoracic epidural analgesia ] following pancreato-duodenectomy and oesophagectomy, however, there is no difference from postoperative day 1 onwards. When calculating the reverse transition from thoracic epidural to non-neuraxial, the benefit remains until postoperative day 2. Similar findings are seen for type 3 surgery.A 12% reduction (− 0.21 to − 0.02) in the overall probability of poorly controlled sia Fig. . The imprest pain by 7% overall (− 0.16 to 0.02), whilst increasing it by 7% when the reverse is considered (− 0.01 to 0.15)  in favour of thoracic epidural analgesia was seen until postoperative day 2 when considering the reverse movement between analgesia groups.Simulation of allocation of patients from the intrathecal morphine to thoracic epidural analgesia is predicted to reduce the probability of median poorly controlled 15) Fig. . In the dynamic pain is − 10% (− 0.22 to 0.00) when simulating movement from intrathecal morphine to thoracic epidural analgesia, with consistent findings until postoperative day 3 and when simulating the reverse movement, from thoracic epidural analgesia to intrathecal morphine  compared to the thoracic epidural analgesia 6%, 2%, and 7%) and non-neuraxial groups  , intrathecal morphine (93%), non-neuraxial (58%), where they also remained for longer. The median (IQR) high dependency unit length of stay for thoracic epidural analgesia was 3 2–4) days, intrathecal morphine was 1 (1–2) day, non-neuraxial analgesia was 1 (0–1) days  were used more frequently in the non-neuraxial group, which may also have contributed to this observed difference in opioid requirements.Simulation of the impact of movement to thoracic epidural analgesia, from either intrathecal morphine or non-neuraxial analgesia, resulted in a clinically relevant reduction in oral median morphine equivalent dose with narrow credible intervals. This finding was consistent irrespective of surgical approach, postoperative day, or extent of surgery and similarly increased oral median morphine equivalent required when we simulated movement in the opposite direction, from thoracic epidural analgesia to the alternative analgesic techniques. The overall probability of reaching a predefined clinically significant difference in median oral morphine equivalent dose greater than 10 mg in favour of thoracic epidural analgesia was consistently high, ranging between 88–100%, and greater than 75% when analysing based on extent of surgery at all time points. The only variation from this was during the early postoperative period following laparoscopic surgery, where the probability in favour of intrathecal morphine finding a difference in median morphine equivalent dose requirements greater than 10 mg ranged between 46 and 47%.Whilst overall there was no clinically significant difference in opioid consumption between non-neuraxial analgesia and intrathecal morphine, the probability of reaching pre-defined clinical significance in the early postoperative period (up to the end of postoperative day 1) was more than 88%, reflecting the efficacy of intrathecal morphine, albeit its finite duration of action, and warrants consideration of mechanisms or analgesic techniques to extend its duration of effect. The change is similar regardless of the surgical approach and surgery categories.rest pain control until postoperative day 3, and dynamic pain control until postoperative day 2 in both thoracic epidural analgesia and intrathecal morphine groups. Despite multimodal analgesia being utilised more frequently in the non-neuraxial group, poorly controlled dynamic pain  was most frequently found at all time points in this cohort  was smaller compared to non-neuraxial (2–18%) analgesia, but generally more consistent until postoperative day 3. Compared to non-neuraxial analgesia, the probability of poorly controlled pain on postoperative day 0, favoured intrathecal morphine across all subgroup analyses, again likely reflective of the pharmacodynamics of neuraxial delivered morphine. Data extending beyond 72 h following surgery was not collected; hence, the incidence and impact of rebound pain on pain scores or opioid consumption following cessation of thoracic epidural analgesia in those patients with functional epidurals is unknown.Overall, the advantage of thoracic epidural analgesia over intrathecal morphine and non-neuraxial cohorts in reducing the probability of poorly controlled rest or dynamic pain between thoracic epidural analgesia and non-neuraxial analgesia was determined from postoperative day 3 regardless of surgical extent. This likely relates to the lower-case complexity in the non-neuraxial group with faster recovery following surgery, however, an alignment with thoracic epidural analgesia failure commonly occurring on day 3 is another potential cause.It is noteworthy that no difference in the probability of poorly controlled Pain scores and opioid consumption alone are inadequate surrogate markers for patient comfort and quality of recovery, which is ultimately what we are trying to optimise. Patient satisfaction or levels of distress related to pain or side effects need to be incorporated into future clinical trials for a more encompassing outcome assessment beyond simple numeric rating scales. These various effects include things as simple as pruritus and extend to a broader analysis of patient comfort in line with the Standardised Endpoints in Perioperative Medicine initiative  and institutional preference. The strength of predictions relies on the data points entered, with more uncertainty when there are fewer supporting data points.With a lens of identifying strategies to reduce opioid requirements and perioperative complications, our analysis of a large retrospective cohort observed potential positive impact with improved postoperative pain by integrating neuraxial techniques across varying major abdominal surgeries and operative approaches. Prospective, multicentre studies are required to provide further, evidenced-based, guidance on the appropriate management of these patients undergoing major surgery with direct comparisons of thoracic epidural analgesia and intrathecal morphine justified amongst patients undergoing similar surgical procedures. Measurement of patient comfort related parameters, methods to extend the duration of intrathecal morphine effect, and utilisation of alternative regional techniques within a multimodal analgesia strategy would also be informative.Additional file 1. a Post-operative morphine requirements. b.  Post-operative rest pain. c Post-operative dynamic pain.


Research on the use of Acceptance and Commitment Therapy (ACT) for patients with degenerative lumbar pathology awaiting surgery are limited. However, there is evidence to suggest that this psychological therapy may be effective in improving pain interference, anxiety, depression, and quality of life. This is the protocol for a randomized controlled trial (RCT) to evaluate the effectiveness of ACT compared to treatment as usual (TAU) for people with degenerative lumbar pathology who are candidates for surgery in the short term. A total of 102 patients with degenerative lumbar spine pathology will be randomly assigned to TAU (control group) or ACT + TAU (intervention group). Participants will be assessed after treatment and at 3-, 6-, and 12-month follow-ups. The primary outcome will be the mean change from baseline on the Brief Pain Inventory (pain interference). Secondary outcomes will include changes in pain intensity, anxiety, depression, pain catastrophizing, fear of movement, quality of life, disability due to low back pain (LBP), pain acceptance, and psychological inflexibility. Linear mixed models will be used to analyze the data. Additionally, effect sizes and number needed to treat (NNT) will be calculated. We posit that ACT may be used to help patients cope with the stress and uncertainty associated with their condition and the surgery itself. Chronic pain is considered a multidimensional experience, and it is accepted that both the intensity and the characteristics of pain are influenced by the individual’s cognitive processing . ChronicSpecifically, ACT maintains that language is at the base of psychological problems, making it inevitable that under certain conditions thoughts and sensations arise that can be experienced as annoying. The fact of being verbal also makes it easier for people to become entangled in fighting against their own private events, and to persist in them even though the results of such struggles are often counterproductive. Using metaphors, paradoxes, and experiential exercises, people learn to be in touch with thoughts, feelings, memories, and sensations, both those previously feared and avoided and any others that arise. In this way, people learn the ability to recontextualize these private events, clarify what matters to them in their lives—what deep down and radically they value—and gain commitment to the necessary changes in the action ,11.Low back pain (LBP) is a problem that affects around 11 to 84% of the general population at some point in their lives ,13. TherDegenerative low back conditions, such as spinal stenosis and facet arthrosis, lead to chronic pain, impairment, and reduced quality of life . The preAccording to the International Association for the Study of Pain (IASP), CPSP is defined as chronic pain that develops or increases in intensity after a surgical procedure and is categorized as secondary chronic pain . AlthougThe first step in addressing this type of pain, as well as the disability and suffering it entails, is to identify the modifiable and protective causal risk factors that predict the CPSP. The identification of psychological risk and protective factors for CPSP will serve for the development and implementation of psychological interventions to prevent and/or manage CPSP . ExpandiThere is a growing understanding of the important role that psychological interventions can play in reducing negative affect, avoidance behaviors, and pain perception after surgery. Specifically, ACT allows patients to learn to expand their ability to experience and accept pain, including the negative thoughts and feelings that inevitably arise when pain is present. Physical pain sensations, as well as patient psychological reactions to them, are observed in a neutral, non-reactive manner, while focusing on improving motivation and commitment to engage in personally meaningful, achievable, and goal-oriented activities. This is practiced without engaging in problematic avoidance behaviors, which typically worsen pain and limit functioning. Patients become more psychologically flexible and learn to adapt their behavior in a way that allows them to live a rich and meaningful life . FinallyThe present work describes the design of a randomized controlled trial (RCT) comparing the effectiveness of preoperative ACT versus treatment as usual (TAU) to improve pain interference in patients subjected to surgery for degenerative lumbar pathology. Considering the above evidence, we hypothesize that participants who engage in ACT will have greater improvement in quality of life and less disability and pain interference compared to participants who do not engage in ACT. The objectives of this RCT are the following: (a) to analyze the effectiveness of ACT as an adjuvant to TAU to improve pain interference (primary outcome); (b) to examine the effectiveness of ACT for improving pain intensity, anxiety, depression, pain intensity, quality of life, functional status, kinesiophobia, pain catastrophizing, psychological flexibility, and pain acceptance (secondary outcomes); and (c) to explore the differences between responders and non-responders in terms of sociodemographic and clinical characteristics.ClinicalTrials.gov, accessed on 5 December 2022, with the NCT number NCT05634122. Patients in both arms will receive TAU as it is commonly provided by the Spanish National Health System [This study is a 12-month RCT that follows the guidelines of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)  and the h System .d of 0.64 and 0.73 for pain interference (BDI) at post-treatment and at follow-up, respectively [The sample size was estimated through R with R Studio using the package “pwr.t.test” version 4.3.0. This sample size was determined to achieve a power of 80%, a significance level of 5%, and a treatment effect size based on Cohen’s ectively . Consideectively ,49,50,51Patients who have been scheduled for surgery in the Spine Unit and who have been diagnosed with degenerative pathology that also present psychosocial risk factors for CPSP, as determined by screening questionnaires, will be assessed by the Pain Unit psychiatrist starting June 2023 and will be recruited if they meet the selection criteria. Inclusion criteria will be (a) age 18–80 years, (b) adequate understanding of Spanish or Catalan, (c) meeting the diagnostic criteria for the LBP/degenerative low back pathology that indicates a candidate for first surgical treatment according to the clinical history  , (d) preExclusion criteria will be (a) cognitive impairment  that, in the clinician’s opinion, prevents them from participating in therapy, (b) presence of chronic pain not related to the diagnosis of LBP that indicates a candidate for surgical treatment, (c) not presenting psychosocial risk factors for CPSP, (d) being involved in litigation or pending legal claims for compensation, (e) having a severe or decompensated psychiatric disorder  that, in the clinician’s opinion, prevents participation in therapy, (f) suicidal ideation, (g) consumption of toxic substances in abuse/dependence, except for smoking, and (h) having a surgical indication for lumbar surgery that involves reintervention.The principal investigator (J.R.C.-A.), through an initial interview, will provide a general description of the study to patients with an indication for lumbar surgery interested in participating who met the eligibility criteria. Prior to random assignment to treatment (TAU or TAU + ACT), informed consent forms will be collected, which will include a general description of the characteristics of the interventions. Patients will also be informed that their participation will be voluntary and that they may withdraw at any time, with the guarantee that they will continue to receive their TAU. ACT will be performed by the psychiatrist (J.R.C.-A.) who is trained and accredited in ACT linked to the hospital’s Pain Unit, who has years of experience in individual and group management with this therapy at the level of patients with psychiatric comorbidity and chronic pain. The psychological intervention will be delivered before the participants have undergone surgery. At present, for our current protocol, in the context of the heterogeneity of the applications of perioperative psychological therapies in the studies published to date, it is not clear if patients who are candidates for surgery can benefit more from psychotherapeutic interventions in the preoperative period, in the postoperative period, or combined. In addition, the exact number of sessions and the adequate time to obtain improvement is unknown . In our This research will be carried out in accordance with the ethical standards established in the Declaration of Helsinki of 1964 and was approved by the Ethics Committee of the hospital (PR(ID) 2021/9998/I). Patient data will be treated confidentially, ensuring that only the research team can access this information after recoding the name and personal identity number. Only the principal investigator (J.R.C.-A.) will have access to the patient’s code key, which, in accordance with current data protection legislation in Spain, will be kept separately in a secure place. Participants will be assigned to the intervention group (TAU + ACT) or control group (TAU) using an SPSS v25 randomization list. Patients will be evaluated through 5 visits: 1 baseline visit (Visit 1), another visit after the ACT intervention (Visit 2), and other visits at 3, 6, and 12 months after surgery . The RCT flowchart is presented in Inititation of patient recruitment: June 2023;End of patient follow-up period: December 2024;Publication of results: June 2025.ACT is a new form of cognitive behavioral therapy (CBT) with a specific focus on mindfulness and acceptance of difficult emotional experiences. It is an evidence-based behavioral therapy that has been found to be effective in treating chronic pain . This thThe control group (TAU) in this study primarily consists of medication prescription and routine follow-up according to the symptoms of each patient. Patients in the control group may also receive ACT treatment if deemed appropriate and recommended by healthcare providers after the study is finished, if they so choose.Participants in the intervention group (TAU + ACT) and the control group (TAU) will complete the instruments described below. The This will be used to gather general and clinical information about the patient, including age, educational level, marital status, and years since the diagnosis of LBP, among others.The baseline visit of the study will include a clinical examination by a psychiatrist (J.R.C.-A.) from the Pain Unit of Hospital del Mar  to diagnose mental disorders, using ICD-10 diagnostic criteria and following the usual protocol of the Pain Unit psychiatrists. The examination of the patients by the orthopedic specialist and neurosurgeons of the Spine Unit of the Hospital del Mar will be used to diagnose disorders at the level of the lumbar spine and the type of surgical intervention, using ICD-10 diagnostic criteria, which will be recorded in our protocol.The Brief Pain Inventory (BPI) ,64 is a The Hospital Anxiety and Depression Scale (HADS) ,66 is a The Pain Catastrophizing Scale (PCS)  is a scaThe Tampa Scale of Kinesiophobia (TSK-11SV) ,69 is a The Chronic Pain Acceptance Questionnaire (CPAQ) ,71 consiThe Psychological Inflexibility of Pain Scale (PIPS) ,73,74 coThe SF-12 Health Questionnaire (SF-12)  is compoThe Oswestry Low Back Pain Disability Scale (OLBPDQ) ,77 is a t test or their non-parametric equivalents , depending on the characteristics inherent to the variables under study. The Chi-Square test or Fisher’s exact test will be used, as appropriate, for categorical variables. The Bonferroni correction will be applied in all post hoc tests. In all statistical tests performed with the outcome variables, a statistical significance level of 0.05 will be used. In adherence with CONSORT recommendations, potential baseline differences in sociodemographic and clinical characteristics are considered irrelevant after randomization and, as a result, were not included as covariates in the analyses of RCT outcomes.Data analyses will be carried out using the statistical packages SPSS v26.0, R with R Studio v4.0.2, and MPlus v7.4. Comparative analyses of continuous data will be performed using the Student’s d. A 5% significance level will be used in all 2-tailed tests, applying the Benjamini–Hochberg correction for multiple comparisons .The main analysis will compare the effect ACT compared to TAU on the primary outcome (pain intensity and pain interference at 12-month follow-ups). All data analyses will be carried out following an intention-to-treat (ITT) principle, that is, regardless of protocol adherence. Then, we will compute analysis of the primary outcome post-treatment and analysis of the secondary and treatment process outcomes at post-treatment and at 12-month follow-up. The analyses will be replicated from a per-protocol approach. Multi-level, linear mixed models will be created using the restricted maximum likelihood method for the estimation of parameters. The effect sizes will be calculated according to Cohen’s t-tests for categorical and continuous variables, respectively.To determine the clinical significance of improvements on the primary outcome (BPI), patients will be classified into two categories: responders and non-responders. Considering the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations, a 1-point reduction in the pre–post and pre-follow-up BPI total score are used as a criterion for establishing clinically significant improvement . This caClinicalTrials.gov, accessed on 5 December 2022) according to CONSORT guidelines. The interest is to explore the benefits of ACT applied before surgery in degenerative lumbar pathology to improve the results in pain and functionality in patients with a high risk of developing chronic pain.The present work describes the design and protocol of an RCT that aims to assess the effectiveness of ACT compared to TAU in patients with degenerative pathology of the lumbar spine who are candidates for surgery. The protocol for this RCT was designed using SPIRIT recommendations and registered in a clinical trial database  of the PSMAR, there is a long tradition of care in the use of different group therapy programs in the adult population receiving inpatient and outpatient care. As part of this process, psychological group therapies are carried out in the hospital setting of the PSMar Pain Unit, which are aimed at improving coping with chronic pain by applying a therapeutic protocol based on ACT. We have adapted our ACT protocol that we use for patients with chronic pain to a pre-surgical protocol of 8 sessions in a group format, encompassing both a behavioral psychotherapeutic intervention and pain psychoeducation. Psychological intervention covers many key areas, including identifying personal functioning goals, observing, and describing physical pain and the difficult thoughts and feelings that come with pain, identifying avoidance behaviors and analyzing when they exacerbate pain, distress, anxiety, and dysfunction and noting the impact on pain of engaging in worthwhile activities gradually, with acceptance in mind.Predicting prognosis in patients scheduled for surgery for LBP, by means of pre-assessment tests, could be efficient to apply in complementary treatment modalities, and thus prevent chronification of pain and worsening of functionality. Therefore, the objective of our study will be to test ACT in an RCT to better understand its impact in the short medium, and long term on the pain intensity, pain interference in activities of daily living, quality of life, mood, and pain disability. We will explore if applying ACT with an online preoperative program of 8 sessions, lasting 90 min, is effective, as well as analyzing patient adherence. We will investigate whether the results underscore and corroborate the possible benefits of integrating psychology services in multidisciplinary teams to prevent the incidence, intensity, and disability of CPSP. In our study, we will stratify the patients who have undergone ACT based on the number and type of psychological factors of CPSP presented, to see if there are significant differences.It is hoped that ACT will improve the results in variables studied in relation to chronic pain in this population at high risk of postsurgical LBP. This study is justified because of the importance of identifying these psychosocial prognostic factors, and to be able to intervene with them, to improve the clinical outcomes of surgical treatment in patients with chronic degenerative LBP. The purpose is to apply ACT to improve these outcomes. Of the patients who are candidates for lumbar surgery, those with a high fear of movement (kinesiophobia), a high level of catastrophism, and the presence of anxiety and depression will be screened to focus the intervention on them. The ACT program has been designed to develop skills and tools with patients to enable them to regulate themselves in the face of pain, fear of movement, catastrophizing, anxiety, and depression. By applying this intervention, we will seek to improve pain acceptance and psychological flexibility with the idea of improving catastrophizing, kinesiophobia, anxiety, depression, quality of life, and overall personal functioning of people with chronic pain both before and after surgery, as measured by the degree of pain interference (primary endpoint of our study).Predicting the prognosis in patients scheduled for surgery for LBP, through previous evaluation tests, could be efficient to apply them to complementary treatment modalities and thus prevent the chronification of pain and the worsening of functionality. People with chronic degenerative LBP who are candidates for surgery, with higher rates of catastrophizing, anxiety, depression, and fear of movement (kinesiophobia) will present a higher risk of chronic pain and a worse prognosis in relation to the efficacy of surgical treatment. We posit that participants receiving ACT will have greater improvement in pain intensity, pain interference, and quality of life, and less disability than participants receiving only TAU. It is hoped that ACT can improve the results in the variables studied in relation to chronic pain in this population with a high postsurgical risk of LBP.Finally, we would like to mention that including TAU alongside an intervention in a clinical trial is not only important from a scientific perspective, but also from an ethical one. It is necessary to consider the patient’s perspective and ensure that they receive the appropriate treatment and the best possible care. In some cases, TAU may be the best available treatment for a given condition. In addition, this helps to prevent patients in the clinical trial from being subjected to unnecessary risk by receiving only the experimental intervention without having the standard treatment option.Nevertheless, including TAU alongside an ACT in an RCT may introduce different types of biases that could affect the interpretation of the results. Confounding bias can make it difficult to separate the effects of treatment as usual from the effects of the experimental treatment. To minimize the biases that may arise when including TAU alongside an intervention in our RTC, we will carefully monitor variables that could explain the study results, such as patient characteristics  and intervention characteristics . Monitoring these variables (which are collected in the RCT battery of measures) can help us to improve the validity of the study results.A two-arm RCT is planned to address the potential effectiveness of ACT compared to TAU.ACT postulates the need to abandon efforts to control aversive thoughts or feelings and accept them as they are. It also promotes a commitment in a valuable vital direction for the person in relation to detecting and promoting actions that bring them closer to the important things in their life; this is useful in a life with meaning.It is hoped that ACT can improve the results in the various variables studied in relation to chronic pain in this population with a high postsurgical risk of LBP.This study represents the attempt to combine psychological therapy with lumbar spine surgery for degenerative pathology:


Background: Orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes mainly characterized by painful attacks localized in facial and oral structures. According to the International Classification of Orofacial Pain (ICOP), the last three groups  are cranial neuralgias, facial pain syndromes resembling primary headache syndromes, and idiopathic orofacial pain. These are often clinical challenges because the symptoms may be similar or common among different disorders. The diagnostic efforts often induce a complex diagnostic algorithm and lead to several imaging studies or specialized tests, which are not always necessary. The aim of this study was to describe the encountered difficulties by these patients during the diagnostic–therapeutic course. Methods: This study was based on the responses to a survey questionnaire, administered to an Italian Facebook Orofacial Patient Group, searching for pain characteristics and diagnostic–therapeutic care courses. The questionnaire was filled out by patients affected by orofacial pain, who were 18 years and older, using a free online tool available on tablets, smartphones, and computers. Results: The sample was composed of 320 subjects (244F/76M), subdivided by age range . Most of the patients were affected by OFP for more than 3 years The sample presented one OFP diagnosis in 60% of cases, more than one in 36.2% of cases, and 3.8% not classified. Trigeminal neuralgia is more represented, followed by cluster headaches and migraines. About 70% had no pain remission, showing persisting background pain (VAS median = 7); autonomic cranial signs during a pain attack ranged between 45 and 65%. About 70% of the subjects consulted at least two different specialists. Almost all received drug treatment, about 25% received four to nine drug treatments, 40% remained unsatisfied, and almost 50% received no pharmacological treatment, together with drug therapy. Conclusion: To the authors’ knowledge, this is the first study on an OFP population not selected by a third-level specialized center. The authors believe this represents a realistic perspective of what orofacial pain subjects suffer during their diagnostic–therapeutic course and the medical approach often results in unsatisfactory outcomes. Orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes mainly characterized by painful attacks localized in facial and oral structures . The IntFor these reasons, it seems useful to analyze the diagnostic and therapeutic process of a group of NFDP subjects, not selected by clinical services but by a patients’ association, trying to understand not only their clinical features but also the involved diagnostic examinations  and the several adopted therapeutic strategies. Our aim was to describe the difficulties encountered by these patients during the diagnostic–therapeutic process  to adopt more effective strategies in the future.Investigations for this transversal study were carried out by a research group, called GIMDO , which includes several researchers from different affiliations interested in the study of orofacial pain.This study was based on the responses to a survey questionnaire administered to an Italian Facebook Orofacial Patient Group , aimed to determine pain characteristics and the diagnostic–therapeutic care process. Patients in this social group interact with each other, exchanging advice on specialists, specialized centers, and treatments, and often inviting specialists to discuss with them in webinars. One of the authors CA.C was invited to one of these webinars, so it was possible to establish a collaboration. To be admitted into the social media group, all members had to declare to be affected by TN or other non-dental facial pain. The questionnaire was filled out by patients aged 18 years or older who suffer from orofacial pain using a free online tool on tablets, smartphones, and computers and was conducted between March and April 2021.The questionnaire was submitted via a link, which was sent by the host of the Facebook group to all members. As a preliminary step, they were asked to give written online consent to the processing of their answers, given anonymously, and to declare that they were over 18 years old; otherwise, the online system would not allow them to continue. Given the descriptive purpose of this study, inclusion criteria were age and being enrolled in the Facebook group, while exclusion criteria were the presence of dental or myofascial syndromes as the first diagnosis and neoplastic diseases. No statistical power calculation was conducted prior to this study, but the sample size was based on the available data.The sample of potential subjects to be interviewed consisted of 468 subjects active in the Facebook group. They answered the questionnaire in 320 subjects equal to 68.4%.According to local ethical policies, no formal approval by the hospital ethics committee was needed.The group of patients was from different regions of Italy. In more detail, participants were divided into four groups. The first group included subjects who affirmed to be affected by TN as their only diagnosis (group A), the second comprised subjects with TN and other comorbidities such as headache, migraine, different neuralgia, etc. (group B), the third comprised subjects with a pathology that caused facial pain without TN, and the fourth included subjects without a specific diagnosis. Overall, the entire examined population was composed of 320 subjects, of whom 76 were male and 244 were female, most of whom were aged between 46 and 55 years.The Orofacial Pain GIDMO Survey consisted of a list of 45 questions divided into 7 sections to which all the participants replied using a free online tool. Some of the questions required a yes/no answer and the next one had to be answered only if there was a positive answer to the previous one (close questions). Others were multiple-choice and often, more than one answer was allowed, or an alternative could be added (open questions). In the final part of the questionnaire on the level of pain and satisfaction with the diagnosis, treatments, or degree of side effects, the median and range of the scale used are given. The first section included general subject information such as age, gender, region, and diagnosis. The second and fourth parts focused on pain clinical features, whereas the fifth and sixth parts regarded diagnostic and therapeutic paths. The third and seventh parts were composed of scores ranging from 0 (poor) to 10 (excellent) on a rating system about the acme in pain and intensity of interictal pain, in addition to the degree of treatment and diagnosis satisfaction. The questionnaire was prepared ad hoc. Its administration did not exceed 20–30 min, as evidenced by the administration of some employees.Two doctors  examined the questionaries using ICOP diagnostic criteria  to indepData analyses were conducted using Microsoft Office Excel, version 16. The median and confidence intervals were used when we were interested in showing measures of central tendency and dispersion of the study population. Percentages were used when we wanted to show the partition of the whole population.The sample was composed of 320 subjects . They were divided into age ranges . The population was distributed throughout Italy, with 152 subjects from the north, 53 from the center, and 139 from the south and islands, while three patients declared that they lived outside Italy. Most of the patients had been affected by OFP for more than 3 years .The sample showed one OFP diagnosis in 60% of cases, more than one in 36.2% of cases, and 3.8% were not classified. TN was the most represented, followed by cluster headache (CH) and surprisingly, migraine. The absence of persistent idiopathic facial pain (PIFP) was even more surprising. Analyzing the global sample, we observed that most subjects had no remission of pain, interestingly, across the several groups of disorders; in about 30% of cases, the pain showed an intermittent course with free pain remission periods; continuous pain associated with acute exacerbations was prevalent. It was not characterized by sudden onset and end, showing a point median equal to 8/10 on the Visual Analogue Scale (VAS) during acute crisis. The persisting background pain was described with a median of 7 on the VAS point; the background pain was less defined, while the acute pain was predominantly defined as burning or throbbing. Almost all patients did not report important vegetative signs, such as vomiting. The pain was strictly unilateral in 85% of cases. Interestingly, about 65% of the subjects reported pain irradiation beyond the face, such as to the back, neck, ears, etc. Autonomic cranial signs during the pain attack, in oscillating percentages, were present between 45% and 65%, except for facial sweating, which was present in less than 20% of cases. Cutaneous triggers were reported by 61% of patients.About 40% of the patients identified a triggering cause of pain, such as trauma, herpes infection, surgical and radiotherapy treatment, or especially, dental treatments.The interview also evaluated which and how many specialists were consulted before and after. Neurologists and dentists were the first to be consulted; however, several specialists were met in various ways. About 70% of the subjects consulted at least one other doctor, and more than 30% at least two others. Frequently, more than one exam was prescribed from the beginning, and about 50% directly underwent a brain or maxillofacial MRI. About 70% of patients received a diagnosis at their first visit, but curiously, about 30% of this group received more than one diagnosis at the first visit. The initial diagnoses did not exactly match the final diagnoses in which the patients were placed, with 26% continuing to have more than one final diagnosis. Overall, 10% still did not have a diagnosis, and finally, there was a group of about 15% of patients whose diagnosis had been matched between 3 and over 5 times.The last part of the questionnaire was related to the treatment of orofacial pain in this group. Almost all (more than 95%) received drug treatment. About 25% had between four and nine drug treatments prescribed, but 40% remained unsatisfied, and almost half received nonpharmacological treatment, of which about 50% were in association with drug therapy. About 35% of patients received more than one non-pharmacological treatment, and almost 8% received between four and eight non-pharmacological treatments (which are listed in the table). Finally, when patients were asked to rate their degree of satisfaction (both drug therapy and non-drug therapy) on a scale between 0 and 10, the median of responses was 5, apart from the side effects from drug therapies, which had a median response of 8. The reported results are shown in Upon analyzing the responses, we divided them into three diagnostic groups, and we found that the first group of patients with trigeminal neuralgias had no diagnosis at their first visit in 26.3% of cases. About 80% of these patients consulted multiple specialists, and the diagnoses were changed more than once for about 39% of patients and more than twice for about 20% of patients. Almost all subjects were prescribed pharmacological therapy, and more than 50% were unsatisfied with their first diagnosis and prescribed therapy. About 77% of patients reported discomfort from side effects. Non-pharmacological therapies were used by about 57% of the sample, and about 75% were satisfied with their treatment, but about 58% reported discomfort from these therapies.The second group included 53 subjects with reported TN together with other orofacial pain syndromes. In this group, 41% had no diagnosis at their first visit, about 50% consulted multiple specialists, and the diagnosis changed more than once for about 67% of patients and more than twice for about 30% of patients or remained without a specific diagnosis. Almost all subjects were prescribed pharmacological therapy (about 92%), and about 68% were unsatisfied with their first diagnosis and prescribed therapy, with more than 70% reporting discomfort from side effects. Non-pharmacological therapies were used by about 57% of the sample, and about 47% were satisfied with the treatment, although about 46% reported discomfort from these therapies.The third group was grouped with other orofacial pain syndromes not associated with trigeminal neuralgia (131 subjects). We observed that about 30% of patients in this group had no diagnosis at their first visit, and the first-consulted doctor was typically the family physician, in contrast with the other two groups. About 58% consulted multiple specialists, and the diagnosis changed more than once for about 39% of patients and more than twice for 12.1% of patients, or they remained without a specific diagnosis. Almost all subjects were prescribed pharmacological therapy (about 97%), and about 58% were unsatisfied with their first diagnosis and prescribed therapy, with more than 60% reporting discomfort from side effects. Non-pharmacological therapies were used by about 45% of the sample, and about 40% were satisfied with their treatment, but about 44% reported discomfort from these therapies.The post hoc analysis of the orofacial pain diagnosis was performed by three researchers to evaluate whether the diagnoses assigned by the patients themselves were modified based on their responses to the questionnaire about the reported features of orofacial pain syndromes.This analysis showed a significant reduction in idiopathic trigeminal neuralgia diagnoses, as more than 40% of them were reclassified as symptomatic trigeminal neuralgias, following mainly dental disorders or dental surgical interventions. The diagnoses of migraine and CH were slightly reduced, and the diagnosis of tension headache was reduced by almost 50%. However, idiopathic persistent facial pain diagnosis remained rare (with only three probable cases).Facial pain sufferers often go from one specialist to another without finding good relief for their pain ,6. TheseTo establish and organize an adequate diagnostic path within the health system, it is essential to know which current diagnostic–therapeutic stages patients suffering from orofacial pain frequently face and whether they are satisfied with the type of attention and care received ,5,6,7,8.To begin, it is critical to note that, as expected, trigeminal neuralgia is the most common manifestation in our sample, accounting for around 40% of cases. Surprisingly, the sample includes approximately 20% of cases characterized by primary migraine and tension headaches. This incidence far exceeds the rates described in the previous literature, where migraines with prominent facial involvement and tension headaches are considered extremely rare .On the other hand, the recent scientific literature shows that primary headaches can involve the lower half of the skull in about 10–20% of cases ,5,8,9. T1.The common knowledge of primary headaches among patients and doctors with a preparation not particularly aimed at orofacial pain of non-dental origin can lead to overestimating these diagnoses. In the case of PIFP, its lack of knowledge and the absence of specific characteristics can lead to a strong underestimation, even in a sample of patients selected for orofacial pain to enroll in a specific group ;2.It is also possible that patients with PIFP, precisely because of the poorly defined characteristics of their disorder, tend not to join an association to which they think they do not belong. However, this suggests that the patient, though receiving a correct diagnosis, has not received an appropriate elucidation from the referring physician and, therefore, is not able to receive help from these patient associations. The patient probably misses the significance of the disorder, leading the patient to further wander between different specialists and treatments.Even more interesting is the almost complete absence in our sample of persistent idiopathic facial headache (PIF), which accounts for a significant proportion of clinical cases at specialized centers ,11,15. TAnother explanation lies in the possibility that several of these diagnoses are incorrect, as stated in the first point. However, considering that we did not find a geographical prevalence, the problem of diagnostic classification and knowledge of these disorders is a common issue. On the other hand, it should be remembered that the first ICOP  classifiTherefore, it is not surprising that recent studies show the poor response of these patients to different pharmacological therapies and consultation with different specialists, often without real multidisciplinary teamwork ,16,17.Another point of interest raised from the data is that our sample reported receiving multiple diagnoses, with the final diagnosis often consisting of more than one. The sample was subdivided into four groups: isolated trigeminal neuralgia, trigeminal neuralgia, and other primary orofacial pain, two primary orofacial pain without trigeminal neuralgia, and a small group that continues to have no specific diagnosis. These results are not easy to understand due to the type of origin of the data, which is uncontrollable. However, they underline the possible important confusion of patients regarding the origin of their orofacial pain. Although it cannot be excluded that there are real coexistences of two primary forms of orofacial pain in the same patient, it cannot be denied that patients and doctors may have trouble evaluating this pain in a specific frame for each case.In an attempt to better understand these data, each questionnaire was subjected to a group of researchers trained in the use of the two classifications  to seFinally, the sample confirmed the results of the literature ,8 as subOur data clearly suggest that an important update for health workers on these disorders is necessary to avoid troubled diagnostic procedures. The low degree of satisfaction found in our sample on the interventions carried out confirms these considerations. Research carried out on the general population and on the population belonging to a highly specialized clinic in these disorders would help to understand which are the greatest removable obstacles to effective treatment.Furthermore, these data show how primary headaches in adulthood can have an orofacial localization, as already seen in pediatric ages ,14, so tFinally, our study’s generalizability may be limited as it is based on a particular population within a specific health system, which may make recognizing these disorders difficult. Finally, the generalizability of our study may be limited because it is based on a specific population within a specific health system, which may make identifying these conditions challenging. However, the literature demonstrates that the cited issues are shared by all Western countries .Future research on clinical and general populations may help to establish a well-defined diagnostic and therapeutic pathway. Our data suggest the need for an integrated multidisciplinary intervention among different specialists, avoiding isolated therapeutic diagnostic attempts but facilitating communication between different specialists. Our multidisciplinary group’s next step will be to propose an integrated therapeutic diagnostic pathway and validate it on clinical populations.The findings of this study, such as the high prevalence of primary migraine and tension headaches and the low prevalence of persistent idiopathic facial headache, have important implications for the diagnosis and treatment of orofacial pain. Clinicians should be aware of these patterns and use them to guide their diagnostic and treatment decisions. For example, patients with primary migraine or tension headaches may benefit from medications such as triptans and nonsteroidal anti-inflammatory drugs, while those with persistent idiopathic facial headache may escape to the medical diagnosis, while these disorders require instead more specialized treatment approaches.


Fibromyalgia is a chronic musculoskeletal disorder characterized by generalized pain, which is also known as “muscular rheumatism” in Chinese medicine. We undertook this systematic review to evaluate the effectiveness of non-pharmacological traditional Chinese medicine (TCM) combined with conventional therapy on pain, health status, depression, and the quality of life of fibromyalgia patients.Studies were retrieved from five electronic databases  with publication date up to August 2022. We included randomized controlled trials examining the effects of a combination of non-pharmacological TCM and conventional therapy on pain intensity, health status, depression, and quality of life.1 = −1.410, P < 0.01; pressure pain threshold WMD2 = 0.830, P < 0.001, respectively). Significant differences in pain assessment were also observed between the two groups after a long-term follow-up (12 months) . The combination therapy group also showed a greater reduction in fibromyalgia impact questionnaire than the control group after a long-term follow-up . Depression and pain-related quality of life showed no difference between groups .Four randomized controlled trials with 384 fibromyalgia patients met the inclusion criteria. Results of the meta-analysis showed that non-pharmacological TCM combined with conventional therapy exerted significant positive effects on alleviating pain at the post-intervention time point than conventional therapy only (visual analog scale WMDNon-pharmacological TCM combined with conventional therapy may be more effective in alleviating pain and improving health status than conventional therapy only. However, it remains some concerns over the safety and clinic application.Identifier: CRD42022352991. Fibromyalgia is a chronic musculoskeletal disorder characterized by diffuse pain, fatigue, and sleep disturbances Clauw, . It has Conventional therapy, which is a multidisciplinary and non-invasive treatment, is the preferred choice for fibromyalgia patients according to the guidelines in different countries  is also considered as an effective alternative therapy in managing fibromyalgia recommended by the latest two practice guidelines  proved to be effective  and the work adheres to PRISMA guidelines  Participants: patients over 17 years of age with a diagnosis of fibromyalgia according to the American College of Rheumatology (ACR) criteria or the ACTTION-American Pain Society Pain Taxonomy (AAPT) criteria. (2) Interventions: non-pharmacological TCM combined with conventional therapy. (3) Comparisons: conventional therapy in treating fibromyalgia . (4) Outcome measures: Primary outcome measures: Pain intensity: visual analog scale (VAS), and pressure pain threshold (PPT) Fischer, . SecondaStudies were excluded if they were: (1) Self-reported diagnosis without clinical confirmation. (2) Participants in the combination therapy group were treated concomitantly with herbal medicine. (3) Participants in the control group received TCM treatment.Two reviewers (ZC and LC) independently screened the enrolled articles through title and abstract screening and full-text reading. Extracted data included: source, setting and language, study type, demographics, symptom duration and severity of fibromyalgia, interventions, outcome measures, adverse events, time points, and overall dropout rate. Disagreements were resolved through discussion with a third reviewer (QD).The methodological quality of the included studies was evaluated using the Cochrane Risk of Bias Tool 2.0 (Rob 2.0). Grading of Recommendation Assessment, Development, and Evaluation (GRADE) was used to assess the quality of the evidence. JL, YS, and HY performed the quality assessment.I2 ≤ 50%, which represented low to moderate heterogeneity, while a random-effects model was used when I2 > 50%, to reduce the impact of substantial heterogeneity. The results would be presented as weighted mean difference (WMD) or standardized mean difference (SMD) and 95% confidence interval (CI) with a significance value set as 0.05.Data analysis was performed using Review Manager . A fixed-effects model was used for the quantitative analysis if The flow diagram of the study selection was provided in The baseline characteristics of enrolled patients, a summary of outcome measures, and adverse events in included studies were shown in This review included 4 articles published from 2003 to 2016, and data from 4 studies were included in the meta-analysis. All included studies were RCTs in English. In total, 197 patients were allocated to the combination therapy group and 187 patients received control intervention.The duration of intervention for fibromyalgia patients ranged from 8 weeks to 3 months, and the frequency of treatment ranged from once to twice a week. Patients in the combination therapy group were treated with non-pharmacological TCM in addition to conventional therapy. Non-pharmacological TCM treatment included Qigong     and afte = 0.0%) .P < 0.001, I2 = 0.0%) and after a long-term follow-up .PPT was assessed in two studies    . However= 42.0%) .P = 0.36, I2 = 0%).After removing the study from Vas et al.  based onRegarding the assessment of depression, Astin et al.  used BDIThe study from Vas et al.  showed tP = 0.500, I2 = 0.0%)   . The res = 0.0%) .Two studies reported pain-related quality of life using the bodily pain score of the SF-36  and after a long-term follow-up . The results are presented in Compared to the control group, the pooled data showed no more improvement in the bodily pain score of the SF-36 in the combination therapy group after intervention  in pain improvement in patients with fibromyalgia. A consensus statement indicated that a 1.0 cm reduction in the 10 cm VAS may represent a “minimal” or “little” change in chronic pain, while a 2.0 to 2.7 cm reduction may be more clinically meaningful , post-acupuncture pain, post-acupuncture bruising, post-acupuncture vagal symptoms, and increased pain in low back and hips in Qigong exercise  and acupoints  were employed in these studies. The high methodological heterogeneity may restrict the possibility of inferences from the present results and subgroup analysis could not be conducted due to the limited number of studies. A standardized intervention protocol should be developed in the future. Second, two of the included studies showed a high risk of bias due to a high overall dropout rate. Improving the acceptance and comfort of TCM intervention may be a feasible plan to reduce the dropout rate. Future studies should focus on stretching and relaxation after exercise to reduce pain. Online guidance or supervision may be a key way to enhance the adherence of fibromyalgia patients to TCM. Third, although there was a more significant decrease in pain intensity in the combination therapy group than in the control group, it remained unclear whether the effect size reached MCID. Hence the effect of combination therapy on relieving pain should be interpreted with caution and the calculation of MCID in pain measurements warrants further research.Non-pharmacological TCM combined with conventional therapy may be more effective than conventional therapy only in alleviating pain and improving the health status of patients with fibromyalgia. A long-term effect of non-pharmacological TCM combined with conventional therapy was also found in the treatment of pain and health status. However, our results should be applied to the clinic with caution due to the limited number of included studies, methodological heterogeneity, and potential adverse events. To increase the safety and adherence to non-pharmacological TCM, future studies should add stretching and relaxation after exercise and provide online supervision to fibromyalgia patients during the intervention.The original contributions presented in the study are included in the article/LC and ZC conceived the idea and contributed to the writing of the manuscript and screened the enrolled articles and completed the data extraction. LC, JZ, and QW performed the literature search. JL, YS, and HY assessed the risk of bias and the quality of the evidence. LC, ZC, and JL conducted the statistical analyses and interpreted the results. QD and XZ revised the manuscript and gave guidance throughout the process of this study. All authors read and approved the summited and final version of the manuscript to be published.


Kinesiophobia is an excessive, irrational, debilitating fear of physical movement and activity caused by a sense of vulnerability to pain or re-injury, which can have a direct impact on physical functioning and mental well-being of patients. This paper aims to provide reliable support for future in-depth research on kinesiophobia through scientometrics and historical review. Studies on kinesiophobia published from 2002 to 2022 were retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer were used to conduct bibliometric analysis of the included studies and map knowledge domains. Keywords were manually clustered, and the results were analyzed and summarized in combination with a literature review. A total of 4157 original research articles and reviews were included. Research on kinesiophobia is developing steadily and has received more attention from scholars in recent years. There are regional differences in the distribution of research. Chronic pain is the focus of research in this field. A multidisciplinary model of pain neuroscience education combined with physical therapy based on cognitive–behavioral therapy and the introduction and development of virtual reality may be the frontier of research. There is a large space for the study of kinesiophobia. In the future, to improve regional academic exchanges and cooperation, more attention should be given to the clinical applicability and translation of scientific work, which will be conducive to improving the quality of life and physical and mental health outcomes of kinesiophobia patients. The latter can have a range of physiological and psychological consequences that promote the development of ineffective states and exaggerated pain perceptions, allowing fear to be maintained or exacerbated. In 1990, Kori et al introduced the term “kinesiophobia,” which refers to an excessive, irrational and debilitating fear of physical movement and activity caused by patients who feel vulnerable to painful injury or (re)injury. Cognitive-behavioral model of fear of move/(re)injury argues that when a painful experience is interpreted as a threat, it leads to the belief that exercise causes pain and risk of reinjury, leading to avoidance behavior and withdrawal from activities that may cause painful and uncomfortable situations. Knapik et al developed a new perspective by defining kinesiophobia as the fear of experiencing physical or psychological discomfort. The negative effects of kinesiophobia on patients are both physical and psychological. Over time, long-term avoidance or avoidance behaviors may lead to adverse outcomes such as disability, disuse and psychological stress,6 and may also affect rehabilitation outcomes by weakening rehabilitation motivation and exercise compliance. Review of the literature revealed that in addition to patients with chronic back pain, who commonly experience kinesiophobia, other diseases accompanied by pain, such as Parkinson disease, fatigue, heart disease, temporomandibular joint disease, scoliosis, and even asthma and stroke may also lead to kinesiophobia.–12 Due to the diversity and complexity of the risk factors and neurophysiological mechanisms of kinesiophobia,,14 which have a profound impact on the physical and mental health and quality of life of patients,,8 in-depth understanding and analysis of kinesiophobia remains a top priority in future work to develop more targeted and effective screening, prevention and treatment strategies. Ultimately, the health outcomes and quality of life of kinesiophobia patients may be improved, and the burden on family and society may be reduced.In 1983, Lethem et al CiteSpace and VOSviewer are popular software for mapping knowledge domains and have been widely used in scientometrics research.,17 We mapped the country/region co-occurrence network and institution co-occurrence network with CiteSpace, conducted co-citation analysis and keyword burst analysis, and mapped the author co-occurrence network and keyword co-occurrence network with VOSviewer. The distribution, knowledge structure, research topics and trends of kinesiophobia research were revealed. Along with a historical review of artificial clustering results, we provide a comprehensive and objective analysis and summary of the topics discussed in this field in the current study.To understand the knowledge base of kinesiophobia research in the past 20 years, identify research hot spots and the evolution of this field, explore potential trends of future research, and provide references and support for future research on kinesiophobia, we conducted a scientometric analysis of the field of kinesiophobia research. Maps of knowledge domains show the relationship between the development and the structure of scientific knowledge as the object of knowledge domains. These maps are not only a visualization but also a serialized knowledge pedigree, showing a large number of implied complex relations such as networks, structure, crossovers, evolution or derivation among knowledge units or knowledge groups, and these complex relations can give rise to new knowledge.Ethical approval is not required for this study because it is conducted based on secondary data.The citation data of this study were retrieved from the Web of Science Core Collection (WoSCC), Science Citation Index Expanded database (SCI-E). The topic search strategy was as follows: TS =((Pain-Related Activity Avoidance) OR  OR (Pain Related Activity Avoidance) OR (Fear of Movement) OR (Movement Fear) OR (Movement Phobia) OR  OR  OR Kinesiophobia OR Kinesophobia OR Kinetophobia). The publication time range was as follows: 2002-01-01 to 2022-12-31. Other qualifications: Original article or reviews were included if published in English. Finally, a total of 4157 citation records were identified for inclusion. Files were downloaded in as plain text files, and the record content was “Full Record and Cited References.” In this way, the data were sorted for use with visual analysis software. The process of this study is shown in Figure ,19 The items analyzed in this study include category, country/region distribution and institute distribution based on CiteSpace maps of knowledge domains, co-citations, keywords with citation bursts, and keyword co-occurrence based on VOSviewer, supplemented by artificial clustering and a historical review and discussion. Some parameters of CiteSpace were set as follows. The time slice was set at 2002 to 2022, and each year was considered 1 slice. The node type was selected from the items mentioned above. The selection criterion for each slice was as follows: Top N = 50 . VOSviewer was run to read the downloaded bibliographic database file and create a map. “Author” and “author keywords” were selected in the cooccurrence analysis unit, and “full counting” was used as the counting method. In addition, the impact factor (IF) and H-index were introduced into the relevant analyses to ensure a comprehensive analysis of scientometric results.The bibliometric analysis was performed with the help of the visual analysis software CiteSpace 6.2.3 (64-bit) and VOSviewer 1.6.19 (0), both of which are applications written in Java.Based on the citation data from the WOS database, the total number of publications on kinesiophobia has increased substantially in the past 20 years. Although there were slight fluctuations in growth, the overall trend is increasing , George SZ , and Meulders A  were the only core authors (within the last 20 years). These authors have published a considerable number of studies, which are widely cited and provide important reference and support for other scholars and future research. Table Price Law is an important reference standard used in bibliometrics to determine the core authors in a research field.Pain had the largest number of publications , followed by European Journal of Pain  and BMC Musculoskeletal Disorders . The journals with the top impact factors (IF) were Pain (IF = 7.4), Scientific Reports (IF = 4.6), and Archives of Physical Medicine and Rehabilitation (IF = 4.3). PLoS One (H-index = 404) had the highest H-index. This was followed by Pain (H-index = 282) and Scientific Reports (H-index = 282). Eleven of these journals were from the United States, and 6 were from the United Kingdom. According to the available information, the number of publications on kinesiophobia in journals is generally small, and many studies in this field were published in journals with low impact factors, which suggests that there is indeed room for future research on kinesiophobia. The distribution of the main categories of publications is shown in Figure Table –23 Tampa Scale for kinesiophobia,,25 pain-related fear and disability,,26 and intervention measures for kinesiophobia.,28 Five articles were cited more than 50 times. The most frequently cited article was “The fear-avoidance model of musculoskeletal pain: Current state of scientific evidence.” This article reviewed the current status of scientific evidence for each component of the fear-avoidance model, emphasizing the role of pain-related fear in the initiation of low back pain, the development from acute to chronic low back pain, and the maintenance of persistent pain. Vlaeyen J.W.S., one of the core authors according to the previous analysis, had 4 papers on the list. The author review of the treatment of kinesiophobia discussed the difference between in vivo exposure and general graded activity, reporting a related trial. Finally, the authors observed improvements in pain-related fear and catastrophizing levels only during exposure treatment in patients.Articles with high co-citation frequency in the specified time period were considered to have an important impact on the research field under discussion in the time period of interest. These important articles, discovered through visualization, are useful for our following historical review. With the help of CiteSpace, we generated a co-citation map Fig.  and extrKeywords are the distillation of the core content of an article, reflecting the focus of the article and the authors. Keyword cooccurrence analysis can indicate the hot spots and frontiers of a research field. VOSviewer was used to generate the keyword knowledge map Fig. , and 534CiteSpace can identify large changes in a certain variable over a specific time period through burst detection, and this fluctuation can be used to reflect deeper changes. By taking the “burstiness” keywords as the detection object, the research hotspots in a specific research field and the rise and fall of a specific research direction can be identified to a certain extent. Figure According to the bibliometrics results, research on kinesiophobia has steadily increased, with a large increase since 2020. Regarding the subject categories and publication types of kinesiophobia research, a wide number of subjects are related, which may be due to kinesiophobia complex pathogenesis, wide range of patients, profound impact on patients’ physical and psychological outcomes, and increasing attention to mental health. These ideas were verified by manual clustering of keywords. However, from the multidimensional analysis of the total number of publications; the distribution of countries, institutions, and journals; and the core authors in the past 20 years, the field of kinesiophobia still has space for exploration, and in-depth research is needed. The United States has conducted more research related to kinesiophobia than other countries, and Kori, who first proposed “kinesiophobia” is a neuroscientist from the United States. Well-known institutions such as Harvard University, the State University System of Florida, the University of California system and Harvard Medical School have been the main contributors to kinesiophobia research in the United States. In Europe, Masstricht University (Netherlands), KU Leuven (Belgium) and the University of London (England) are representative institutions. The University of Sydney and the University of Queensland in Australia are also representative institutions, while research in other regions may be lagging behind.,30 He and his team have examined the role of unpredictability in the generalization of somatic symptoms and disease behavior, with a particular focus on the competition between avoidance and reward-seeking tendencies. George, S.Z. from the United States also proposed hypotheses and carried out studies on the potential effects of fear avoidance or phobia, possible effective interventions, and measurement of psychological characteristics.–34 However, one important question is why more studies on kinesiophobia have been published in journals with lower impact factors? There may still be a lot of work to do. As more researchers become interested in kinesiophobia, the situation is likely to be improved, and more findings will provide high-quality, convincing and scientific evidence for clinical practice. It is important not to ignore the academic exchanges and cooperation among countries/regions, institutions and scholars.JWS Vlaeyen, PhD, full professor at KU Leuven and Maastricht University, is one of the scholars with important contributions to the study of kinesiophobia. His main research interests/expertise include the behavioral, cognitive and motivational mechanisms that transform common acute aversive feelings (pain) into chronic physical symptoms and disability.,35 established a cognitive-oriented pain-related fear model based on previous findings. The following discussion may help interpret this model. The negative evaluation of pain and its consequences is a precursor to pain-related fear. For example, pain catastrophizing is an exaggerated negative psychological response to harmful stimuli. People with high levels of negative emotions are more likely to be hyperalert to any threat and therefore more likely to develop fear. In addition, overestimation of pain may also make fear more likely. Fear of pain will affect physical performance, and avoidance behavior is one of the consequences, leading to reductions in patients’ daily activity. Long-term avoidance and inactivity will also affect the skeletal muscle and cardiovascular system, which may be result in symptoms of disuse, leading to worsening pain and disability. Another problem with avoidance is emotional disorders, such as depression and frustration, and negative emotions can indirectly affect avoidance by exacerbating the fear of pain. Patients are thus trapped in a vicious cycle of avoidance, disability, and increased pain.To understand the mechanism of kinesiophobia, one must understand the fear avoidance model. In 1995, Vlaeyen et al According to the cognitively oriented fear model mentioned above, judgments of potential danger may also come from false threat signals, and such responses may be maladaptive, such as avoidance behaviors or fear of activities. Threat signals are transmitted to the lateral amygdala after being perceived; subsequently, they are transmitted to the central nucleus and to the nucleus accumbens, after passing through the basal nucleus, thereby generating physiological, emotional, and behavioral responses related to fear. The posterior portion of the amygdala is involved in the descending pain regulatory system, which controls pain-related emotion, behavior, and motivation.–39 Studies have found that areas such as the amygdala, insula, anterior cingulate cortex and hippocampus play an important role in fear acquisition, and the amygdala is also crucial for fear extinction and learning of safety.,41 Meier et al found that phobic movement was positively correlated with the brain activity of fear-related brain areas such as the amygdala and insula. The differential effect of kinesiophobia in patients with chronic low back pain and pain-free subjects is reflected in the extended amygdala and its connection with the anterior insula. Genzel et al reviewed previous studies and found a large amount of evidence to support the effect of rapid eye movement sleep on amygdala-related memory processing; that is, the amygdala-hippocampal-medial prefrontal network involved in fear memory showed the strongest activity during rapid eye movement sleep. In general, the neurobiological mechanism of pain-related fear and kinesiophobia is extremely complex, and comprehensive research of the brain circuit and its synapses, neuronal interaction and physiological encoding of information will help us to develop new strategies for the prevention and treatment of kinesiophobia.In addition, neurobiological studies of threat processing and fear memory have indicated new directions and are highly important for understanding the pathogenesis of fear and pain-related fear. Due to the plasticity and adaptability of the brain, previous traumatic or threatening experiences will make the brain respond faster to threats in the future.,6,35,44 Pells et al recruited 67 patients with sickle cell disease to evaluate and analyze kinesiophobia, pain, and psychological distress and found that patients with a higher severity of kinesiophobia had a higher degree of pain and psychopathology. This may be because the avoidance behavior and pain induced by kinesiophobia will reduce patients’ resources for coping with stress and thus lead to greater psychological distress. A study from Turkey examined the impact of kinesiophobia on lymphedema, upper limb function, depression/anxiety, and quality of life in breast cancer survivors. The study involved 81 breast cancer patients , all of whom had undergone cancer-related surgery within the previous 6 months. The results of the survey showed that 25 (30.8%) had kinesiophobia. In addition, kinesiophobia in breast cancer survivors increased the risk of depression/anxiety and decreased upper limb function. No correlation between kinesiophobia and quality of life was observed in this study, which may be due to the sample size and assessment tools. To explore the correlation of kinesiophobia with pain, disability and quality of life in patients with chronic musculoskeletal pain, Luque-Suarez et al conducted a systematic review of 63 studies with 10,726 participants and found that there was strong evidence of an association between the severity of kinesiophobia and pain intensity and disability as well as moderate-quality evidence that the severity of kinesiophobia is associated with lower quality of life and greater disability. Given that kinesiophobia in patients with various diagnoses of pain is more widely discussed, further scientific research on the adverse effects of kinesiophobia on the physical and psychological aspects of patients is needed.One of the main features of fear is the avoidance of perceived threats, leading to reductions in daily activities, poor performance, disability or muscle disuse. Numerous studies have confirmed that kinesiophobia is an important predictor of disability and psychological stress in patients with various types of pain that may impact their quality of life. The original TSK consists of 17 items scored on a 4-point Likert scale ranging from 1 (strongly disagree) to 4 (strongly agree), with a total score ranging from 17 to 68. The higher the score is, the higher the patient fear of exercise. If the score exceeds 37, the patient is considered to have kinesiophobia. Later studies confirmed the validity and reliability of the TSK.,47 Woby et al designed a short version of the TSK (the TSK-11) by removing 6 items with poor psychometric characteristics from the original version . The results in a sample of 149 patients with chronic low back pain showed that the TSK-11 had good internal consistency, responsiveness and construct validity equivalent to the TSK, while taking less time to complete. Subsequently, some scholars included data from 1109 patients with work-related upper limb diseases in confirmatory factor analysis, and the results showed that the 2-factor model of the TSK-11 consisting of somatic focus and activity avoidance had the best fit. This is consistent with the findings of Tkachuk and Harris. Therefore, the TSK-11 tends to be more recommended. Other measures of fear of movement/(re)injury include the Fear-Avoidance Beliefs Questionnaire, Kinesiophobia Causes Scale, and Fear-Avoidance Components Scale. Although the reliability and validity and cross-cultural adaptation of existing measurement tools had been extensively studied, most of these studies were based on low back pain, chronic skeletal muscle pain, or fibromyalgia.,46,49,50 However, with the development of medicine, the study of kinesiophobia had long been associated with a variety of different types of pain-related diagnoses.–12 We believe that special measurement tools for kinesiophobia for special diagnoses can be one of the directions of future research.The Tampa Scale for Kinesiophobia (TSK), developed in 1991, is a common measure of fear of movement/(re)injury. As kinesiophobia is the result of interactions among physiological, psychological and social factors, interventions are challenging as they need to adopt a multidisciplinary strategy addressing physiological and cognitive-behavioral aspects.,52 Studies have proven that the multidisciplinary model, which combines psychological and cognitive aspects to help patients change their incorrect beliefs and perceptions and master effective health management methods, as well as a hierarchical activity plan and training courses led by therapists, can improve patients’ health outcomes by changing patients’ kinesiophobia beliefs, reducing pain catastrophizing and increasing pain self-efficacy.,54 With the development of medical technology and interdisciplinary methods, more potentially effective methods have been discussed, such as exposure intervention based on behavioral observation, exposure intervention based on VR technology, eye movement desensitization and reprocessing therapy. On the other hand, more research and translation are needed.Previous studies have found that pain education for patients with pain-related fear may promote behavior change, but actual experience is more persuasive than hearing this information only; patients with kinesiophobia may benefit from graded exposure to sports and activities they previously avoided.,59 Physical activity and rehabilitation exercise are effective ways for stroke patients to restore their physical function and improve their health outcomes. However, a review of the literature indicated that there are few studies on kinesiophobia in stroke survivors. Wasiuk-Zowada et al published a study on the occurrence of kinesiophobia in patients with neurological diseases in 2021; their study included 50 stroke patients, 81 multiple sclerosis patients and 61 Parkinson disease patients. Enrolled patients with stroke were generally in stable condition, were assessed at least 5 days after stroke onset, and had a modified Rankin Scale score of 2 or 3. The results showed that 128 people (66.67%) had severe kinesiophobia, and the incidence of kinesiophobia in stroke patients was close to 80%. In addition, Bąk et al conducted a cross-sectional study of 152 elderly patients with ischemic stroke in Poland, reporting that kinesiophobia was present in 78% of the patients. Sertel et al found that the balance score and fall efficacy score of stroke patients were negatively correlated with the severity of kinesiophobia. It is well known that fall and balance problems are the most common problems in stroke patients. Loss of balance in stroke patients weakens fall efficacy or the confidence that they will not fall. After developing a fear of falling, they will adopt escape strategies and reduce physical activity, resulting in a decline in physical function and balance confidence, which in turn will increase the risk of falling and the avoidance of exercise. Ultimately, it will hinder the functional recovery and the improvement in ability to independently perform daily activities of patients. Therefore, further research on kinesiophobia in stroke survivors is necessary and promising.In the manual clustering of keywords, the appearance and combination of balance, falls, fear of falling and stroke attracted our attention. Subsequently, we reviewed much of the relevant literature and formulated a new perspective. Stroke is a disease that threatens human health, and more than 13.5 million people experience stroke every year. Most stroke patients have different degrees of dysfunction in language, movement and perception. The maintenance and exacerbation of the fear state is associated with an exaggerated perception of pain. Pain-related fear can lead to negative coping or avoidance behaviors,,65 which may eventually cause related functional disuse or disability.,66 Studies have found that 56%–72% of chronic pain patients are affected by kinesiophobia,,68 and most of the scientific work on the treatment of kinesiophobia has focused on chronic pain disorders, especially low back pain and neck pain. This is consistent with the results of our bibliometric analysis. At present, research on kinesiophobia has extended beyond low back pain to other diseases associated with chronic pain or the development of chronic pain due to kinesiophobia, such as fibromyalgia, osteoarthritis, Parkinson disease, and even stroke and postoperative recovery.,69,70According to the keyword co-occurrence and citation burst maps, chronic pain is the key research object and research hotspot of kinesiophobia, especially low back pain. This suggests that it is important to investigate and synthesize relevant evidence. The topic of chronic pain and kinesiophobia has been studied for a long time. Initially, the “fear-avoidance” model was proposed to explain the cause and process by which musculoskeletal pain developed into chronic pain syndrome in patients. Kinesiophobia involves not only a simple fear of exercise but also a complex and multifactorial mindset derived from the belief of vulnerability. It is one of the potential psychological factors leading to the deterioration of patients’ physical function and is also closely related to mental health disorders, which seriously affect the rehabilitation outcomes and quality of life of patients. Therefore, the identification and intervention of kinesiophobia is an important project and challenge in the field of mental health. Since avoidance behaviors caused by fear occur in anticipation of pain, excessive anticipation of pain, catastrophizing and related negative beliefs need to be transformed. Pain neuroscience education (PNE) is an effective way to alter patients’ pain beliefs and deepen their understanding of pain by educating them about neurobiology, neurophysiology, pain processes and performance. Finally, this method ensures that the patient understands that the movement or exercise that causes pain is safe and that the patient has the confidence to perform the activity.,73 A meta-analysis showed that the combination of PNE and exercise for chronic musculoskeletal pain resulted in greater short-term improvements in pain, disability, kinesiophobia, and pain catastrophizing compared with exercise alone. From the psychological and physiological aspects, PNE is an effective psychotherapy, and the combination of PNE and various forms of physical therapy as a treatment for kinesiophobia is worth exploring. Similarly, sex, age, and education level may be associated with kinesiophobia severity; thus, the diverse and personalized PNE method may become an option with future research.,75 Another promising approach is VR. In 2017, Yelvar published a study on the short-term efficacy of VR combined with physical therapy on pain, function and kinesiophobia in patients with subacute and chronic nonspecific low back pain and reported positive experimental results. Gulsen et al also showed that compared with simple exercise therapy, exercise training combined with VR led to significant improvements in patients’ pain, kinesiophobia and mental quality of life. Previous studies have reached similar conclusions. A 2013 meta-analysis of 11 randomized controlled trials involving 488 subjects showed that the use of VR technology can reduce the severity of kinesiophobia in patients with chronic low back pain. The study also found that nonimmersive VR was more effective than fully immersive VR. VR combined with exercise was more effective than VR alone. VR technology has potential therapeutic applications for kinesiophobia, but future studies containing more details, such as specific scenario designs for different diagnoses, details of treatment, safety, and supervision, are needed.Further exploration of keywords with citations can identify possible future research trends. Pain neuroscience education, mental health and VR research were late to emerge but quickly resulted in a super-strong citation burst. This suggests that these 3 topics may be the research frontier in this field in the next few years. First, with the development of society, people have higher requirements for health care. Health involves not only good physical condition but also good mental health and quality of life. The “bio-psycho-social” medical model proposes that diseases should be understood from the biological level to the psychological and social levels to identify the determinants of diseases, provide a reasonable treatment, and develop a health care model.In this study, the bibliometric tools CiteSpace and VOSviewer were used to analyze studies on kinesiophobia included in the WOSCC and published in the past 20 years. Cooccurrence analysis was conducted on the countries/regions, institutions, authors and keywords in this field to understand the basic knowledge structure of research in this field. Second, artificial clustering based on keyword cooccurrence was conducted; the literature was reviewed to summarize the pathogenesis, adverse effects, measurement tools and intervention strategies of kinesiophobia; and potential research directions were proposed. Finally, combined with previous work, co-citations and keyword bursts, we objectively and comprehensively summarized research hotspots and trends. We believe that this study can provide an important reference for future scientific work on kinesiophobia.It is clearly a limitation that the data in this study were derived only from the SCI-E database of the WOSCC, which prevented us from considering the full context of this research field. However, the SCI-E contains a large amount of kinesiophobia-related research data, ensuring the quality of the literature, and our results are still scientifically reliable. Next, we will learn to retrieve and export data from more databases, to improve this shortcoming and to compare analytic results.We would like to thank the editor and anonymous reviewers for their helpful comments on early versions of this manuscript.Conceptualization: Linzhang Li, Yan Sun.Data curation: Hua Qin.Formal analysis: Linzhang Li, Jun Zhou, Xiaojuan Yang.Funding acquisition: Yan Sun.Methodology: Linzhang Li, Aiying Li, Jin Zhang.Supervision: Yan Sun.Validation: Linzhang Li.Visualization: Linzhang Li, Yan Zhang.Writing – original draft: Linzhang Li, Hua Qin.Writing – review & editing: Aiying Li, Jin Zhang.