The positivity rates in each group for DN4 were significantly different (p < 0.001), with a prevalence in symptomatic subjects of 56.3% (n = 9) among sFM individuals. A similar difference was also observed with the DNS total score (p < 0.001). NCM and MNSI did not disclose significant differences between the two groups. This finding seems to confirm the data regarding the prevalence of a neuropathic pain in sFM patients.Fibromyalgia syndrome (sFM) is one of the most common causes of chronic pain. This study aimed to assess the presence of small and large fiber impairment in fibromyalgic patients by applying validated scores used in the screening for diabetic neuropathy. The endpoints for the study were the assessment of neuropathy prevalence in sFM patients using the NerveCheck Master (NCM), the Michigan Neuropathy Screening Instrument (MNSI), the Diabetic Neuropathy Symptom (DNS) and the Douleur Neuropathique 4 Questions (DN4). The sample was composed of 46 subjects: subjects with sFM ( Among systemic diseases and painful extra-articular syndromes, Fibromyalgia or Fibromyalgic syndrome (sFM) is one of the most common causes of chronic pain. This holds true despite various prevalences between countries and ethnic groups, due to diverse diagnostic approaches . sFM is The etiopathogenesis of neuropathy in sFM is still unknown, although many authors claim that “neurobiological stressors” might be involved, especially if present during early life . HoweverThis was an observational pilot study conducted on patients recruited at the Internal Medicine ward of I Policlinico, University of Campania Luigi Vanvitelli, from February 2020 to January 2021. Subjects aged < 18 years, pregnant women and people affected by other forms of chronic pain and/or other forms of peripheral neuropathy  were excluded from the study. The study was approved by our local ethics committee and is in accordance with the 1976 Declaration of Helsinki and its later amendments.The primary endpoint for the study was the assessment of the prevalence of a neuropathy in the study population. The secondary endpoints aimed to assess: (i) the efficacy of the NCM for detecting a small or a large fiber impairment in sFM; and (ii) the utility of validated scores in diabetic neuropathy .Anamnestic data were collected from all patients. Furthermore, all subjects underwent clinical examination, routine biochemical exams , C-reactive protein, erythrosedimentation rate and specific rheumatological tests), and following tests and questionnaires: NerveCheck Master, MNSI, DNS and DN4. Moreover, patients with sFM were also presented with a questionnaire on the quality of life (QOL), the Short Form Health Survey (SF-36) and subjected to an evaluation using the Chalder Fatigue Scale and the Pain Visual Analogue Scale (VAS), according to the most recent diagnostic criteria ,28,29.Diagnosis of fibromyalgia was based on anamnestic data and clinical exam, in accordance with most recent guidelines, as discussed in the Introduction ,3. To beFor the evaluation of large and small fiber impairment and to evaluate the presence of symptoms/signs of neuropathy, the following tests were performed. Four different tests were performed using the NerveCheck Master (NCM) tool, evaluating, respectively, vibration, cold/warm and pain sensitivity. A subject was considered to have altered perception with a positive outcome to at least 2 tests. To evaluate vibration perception (VPT), the instrument is placed on the first joint of the big toe, and it emits 9 either true or false stimulations (from 2.7 to 6.4 V). The patient is then asked whether he/she perceives the stimuli or not. The test results are considered abnormal with a score from 0 to 3 and normal within the range 4–12. Regarding cold (CPT), warm (WPT) and pain (PPT) perception, they are evaluated by placing the thermode on the dorsum of the foot. Each of the CPT and WPT tests is repeated 6 times, with fluctuations in temperature (9.8–22.4 °C for cold and 37–44 °C for warm) or empty stimulations. Similarly, the test results are considered abnormal with a score of 0–2 and normal within the range 3–6. PPT assesses the pain threshold through a gradual warm stimulation. At the end of the exam, hyperalgesia is determined if the subject perceives pain before the NCM reaches 35 °C, hypoalgesia is determined if pain is perceived after the NCM reaches 47 °C and values between 36–46 °C determine normal algesia .In addition, the MNSI was performed. It is a validated instrument, generally used when a diabetic peripheral neuropathy (DPN) is suspected. It evaluates the appearance of feet and/or the presence of ulcerations , the presence of Achilles’ tendon reflex , the perception of vibration stimuli with a 128 Hz diapason and tactile sensitivity to 10 g monofilament . Peripheral neuropathy was defined as probable with a total score ≥ 2.5 .The Diabetic Neuropathy Symptom Score (DNS) was also employed. It evaluates the presence of sensitive symptoms at the foot level: burning, pain, tingling, numbness and walking instability. For each symptom, 1 point is assigned, if present. The test is positive with the presence of at least 1 symptom ,23.Finally, the DN4 questionnaire was used to observe the presence (or lack thereof) of symptoms/signs typical of DPN. Items from 1 to 7 are symptoms , while hypoesthesia to soft touch, to puncture and to skin friction (items 8–10), perceived at foot level, are classified as signs. One point is assigned to the presence of each symptom/sign, and the test is positive with a score ≥ 4 ,23,24.p-value of 0.05 was considered statistically significant. The relationship of each NCM score to the different tests for fibromyalgia was evaluated by univariate logistic regression models.The categorical variables were expressed as numbers and percentages, while continuous variables were expressed as median and interquartile range (IQR) or mean and standard deviation (SD), based on their distribution, according to the Shapiro–Wilk test. Between-group differences were assessed either by Fisher’s exact test or the chi-squared test in the case of categorical variables, and by the Student’s t-test or the Mann–Whitney U test in the case of continuous variables, based on their distribution. A Data were analyzed using SPSS version 24 software ) and STATA 15.5 software .n = 23) and healthy controls (HC) (n = 23). Overall, the study population consisted of all female subjects and no statistically significant difference was observed for age. Significantly higher levels of total cholesterol were observed in sFM patients as compared to HC (median 197.5 mg/dL (IQR 178.8–208.8) vs. 170 mg/dL (IQR 153–181.5); p = 0.009). LDL cholesterol, though slightly increased in the sFM subgroup, did not significantly change in the two groups. All other parameters were comparable. All data are described in The study sample consisted of 46 female subjects divided in two groups: subjects with sFM (p < 0.001), with a prevalence in subjects with altered DN4 of 56.3% (n = 9) among sFM individuals. A similar difference was also observed with the DNS total score (p < 0.001). Finally, the MNSI did not show significant differences between the two groups, considering both absolute values and prevalence of positivity. All data are reported in The study then focused on the evaluation of DPN tests. For the NCM, both the absolute score and the prevalence of positive patients in each test were evaluated. Both assessments did not disclose any significant difference between cases and controls. On the other hand, the positivity rate of each group for DN4 was significantly different  in sFM patients. Consistently with the sFM diagnosis, the VAS and the Chalder Fatigue Scale results were elevated, while the SF-36 showed a low total score. All data are reported in This study evaluated, for the first time, the utility of the NCM and other validated diabetic neuropathy screening scores in a population of sFM patients. In this setting, several authors have described the presence of an impairment of myelinated Aδ and small unmyelinated C fibers, thus defining a picture of small fiber pathology (SFP) ,31,32,33The NCM is a new tool able to detect signs of both large (by VPT) and small fiber impairment (by CPT/WPT and heat pain test). No significant difference emerged between HC and sFM patients. This result seems consistent with previous studies outlining QST in subjects with fibromyalgia, showing that there is not always a difference between patients with and without SFP, thus suggesting that SFP could have a negligible impact on somatosensory system function . MoreoveOriginally, the study set out to evaluate whether the MNSI, the DNS and the DN4, generally used to screen other conditions of neuropathy, could be useful to detect symptoms and signs of neuropathy in sFM.The MNSI allows for a large fiber neuropathy to be screened and is used to diagnose a probable DPN in diabetic subjects ,30. ThusThe DN4 and the DNS are validated scores used to detect neuropathic pain and screen a peripheral neuropathy in diabetic patients ,24,33. MAll the other tests used to evaluate psychic characteristics  were not associated with peripheral neuropathy scores. This observation could support the hypothesis for a different etiopathology of these phenomena .This study presents several limitations. Primarily, the small sample size, which does not allow to generalize the results of the observations. Secondly, there is a lack of a more specific tool to define the etiopathogenesis of the pain detected at DN4 and DNS, such as nerve conduction studies or skin biopsy, and of a comprehensive QST protocol to compare the results of NCM. Finally, the lack of a dedicated questionnaire, such as the small fiber neuropathy—symptoms inventory questionnaire (SFN-SIQ), which would have been useful to compare our results .The NCM and the MNSI, which were used for the first time in the evaluation of a neuropathy in sFM subjects, do not show significant differences compared to HC. These observations could be the expression in the absence of small and large fiber functional impairment as detected by the NCM, and from no signs of neuropathy at the MNSI in our cohort of sFM subjects. On the contrary, the DN4 and the DNS seem to show the presence of typical neuropathic pain in sFM subjects as well. However, the absence of a neurophysiological assessment and/or of skin biopsies did not allow us to better compare these results and to define the etiopathogenesis of the pain.Further studies are needed to better define the impairment of fibers in these patients and to clarify the role of scores validated in other conditions.


Prevention of chronic pain relies on accurate detection of at-risk patients. Screening tools have been validated mainly in (sub) acute spinal pain and the need of more generic tools is high. We assessed the validity of the French version of the short Örebro Musculoskeletal Pain Screening Questionnaire (ÖMPSQ) in patients with a large range of pain duration and localization.First, we re-analyzed data from a 6-month longitudinal study of 73 patients with (sub) acute spinal pain consulting in secondary line settings. Secondly, we performed a new 12-month longitudinal study of 542 primary care patients with (sub) acute and chronic pain in different localizations . The area under the receiver operating characteristic curve and cutoff scores were computed and compared for different subpopulations and ÖMPSQ subscores.Data from patients suffering from (sub) acute and chronic spinal pain consulting in both primary and secondary care settings confirmed the validity of the short French ÖMPSQ version and its subsets. In the primary care cohort, the performance of the questionnaire and its psychosocial subscore was variable but at least “fair” in most populations ((sub) acute and chronic, spinal and limb pain). Cutoff scores showed quite large variability depending on the outcome and the subpopulation considered.These results confirm the usefulness of the short French ÖMPSQ for prediction of the evolution of (sub) acute and chronic patients with spinal and limb pain, whatever its duration. However, increasing population heterogeneity results in slightly worse predictive performance and largely variable cutoff scores. Consequently, it might be difficult to choose universal cutoff scores and other criteria, such as patients’ values and the available resources for patient management, should be taken into account.The online version contains supplementary material available at 10.1186/s12891-021-04944-9. Chronic pain is one of the main public health burdens. It’s high costs – ranging from five to €32 billion worldwide per year for low back pain (LBP) , 2 – jusSeveral versions of the ÖMPSQ questionnaire have been validated  primary and secondary care settings, (2) (sub) acute and chronic pain and (3) spinal and non-spinal  pain.To this end, two patient cohorts were used. First, we re-analyzed data from previous work validating the French full ÖMPSQ , a 6-monWe applied the approach of Linton et al. , where iStudy participants were a convenience sample of patients suffering from non-specific (sub) acute low back or neck pain, presenting at the emergency facility or the outpatient consultation of the Physical and Rehabilitation Medicine department at the Cliniques universitaires Saint-Luc (Brussels). Inclusion criteria were the presence of pain for less than three months and a cumulated sick leave due to pain of less than 6 months in the past year. Exclusion criteria were inability to read and understand French and the presence of “red flags” . ParticiScoring for the short ÖMPSQ was performed according to previous studies , 9 by suThree outcome variables were derived from the ÖMPSQ , 9, 13: 2) indicated the strength of this relationship.Correlations between the full and short ÖMPSQ versions were evaluated using the Kendall rank-order correlation test. Correlation coefficients of 0.10-0.29 represented a weak correlation, coefficients of 0.30-0.59 represented a moderate correlation and coefficients of 0.60 and above represented a strong correlation , 40. TheAll analyses were performed using Microsoft Excel and IBM SPSS 23.0 software.This study was part of a large longitudinal study performed in general practice. Fifth-year medical students performing their one-month general practice internship  and their supervisors were offered to collaborate to this study. Detailed written instructions were provided and the investigators (AB and AS) were available for any questions. The study was approved by an independent ethical committee .To avoid interference with the beginning of the working day, we instructed the students to ask the third scheduled patient of every day to take part in the study. If the patient refused, the student could ask the fourth, and so on. Patients received information on the purpose and procedures of the study. They filled in an informed consent form, a questionnaire comprising demographic and lifestyle information, pain presence and localization (Axis I of the IASP taxonomy of chronic pain syndromes ), short One year later , the patients who agreed to be contacted again were sent an e-mail with a link to a secured online survey (Limesurvey ). The quInclusion criteria were to be the third patient to come to the general practice consultation, whatever the reason for the consultation. If the patient declined participation, the fourth patient was offered to participate, and so on.Exclusion criteria were age under 18, inability to answer questionnaires in French, and absence of a valid e-mail address.Descriptive statistics were used to present participant demographic and clinical characteristics. In order to assess potential selection biases, we compared the demographic and clinical data of the patients who responded at t1 (group A) to those who did not (group B). Data from patients suffering from pain attributed to cancer were excluded from further analysis.As participants did not complete the full 25-items ÖMPSQ, we could not use the same outcome variables as in the secondary care cohort. Several outcome variables were defined: presence of pain , items of the EQ-5D-5L and a composite “recovery score” computed as: [number of pain sites + pain intensity from item #2 of the short ÖMPSQ + 10-light work ability from item #3 of the short ÖMPSQ + 10-sleep quality from item #4 of the short ÖMPSQ]. This score could range from 0 (completely recovered) to 40 . For the ROC-analysis, outcome variables were dichotomized as follows: for the five dimensions of the EQ-5D-5L a score of 1–2 (no or slight problems) was considered good while scores of 3–5 (moderate to extreme problems) was considered as indicating bad health. The “recovery score” was considered as indicating good health if ≤ 12  or bad recovery if > 12.spinal pain, pain localized in the scapular girdle, upper or lower limb as limb pain and other pain localization  as probably non-MSKP. Data from patients with pain at more than one site were excluded to the analysis made according to pain localization .ROC curves and their confidence intervals (estimated by bootstrapping) of the short ÖMPSQ and its subsets were calculated for all outcomes, except for the “Autonomy” item of the EQ-5D-5L, which showed a ceiling effect (96% patients had no difficulties or slight difficulties). We calculated ROC curves for the total cohort, as well as for different subgroups according to pain duration and localization. Patients were classified as suffering from (sub) acute pain if their pain lasted less than 3 months and from chronic pain if it lasted longer. We considered pain localized in the cervical or lumbosacral regions as Statistical analysis was performed with Microsoft Excel and SAS JMP Pro 14.Out of 91 patients who entered the study at t0, 73 (80%) sent completed questionnaires at t6. Demographics were similar between dropout patients and those who completed the study. Patients who completed the study presented the following characteristics: mean age 42.2 ± 10.7 years, 56% females, 86% native French speaking, 88% had paid jobs and 15 years of education after age 6. Most patients had one painful site, 45% reported pain on 2 to 5 sites, 64% had pain for < 6 weeks, 30% had pain lasting from 6-11 weeks. Eighty per cent had less than 30 days off work. More details can be found elsewhere .Out of 433 medical students, 289 agreed to take part to the study. They approached 5815 patients, of which 3882 participated at t0 and 542 were included at t1 .The re-analysis of data from our previous secondary care cohort showed a high correlation between the total scores of the full ÖMPSQ questionnaire and its short version, as well as different subscores  for all three outcomes  acute pain, the short ÖMPSQ total and psychosocial subscores showed poor predictive abilities for pain outcomes  as well as anxiety/depression (EQ-5D-5L), and fair to good validity for functional outcomes . Items #7, #8 and their sum only showed poor to good predictive abilities for functional outcomes.In patients with chronic pain, the short ÖMPSQ and its subsets showed better predictive abilities than in patients with (sub) acute pain: fair results were observed for all outcomes for the total ÖMPSQ and the psychosocial subscore. Items #7, #8 and their sum usually showed poor validity, except for prediction of mobility, which was fair to good.As said in Methods, for this analysis, data from patients presenting pain in more than one site were excluded. Both in patients with only spinal or limb pain, the short ÖMPSQ total score and the psychosocial subscore showed poor to good results depending on the outcome variable. Items #7, #8 and their sum gave heterogeneous results, mostly of poor quality.Data concerning patients with only presumed “non-MSKP” should be interpreted with caution because of the small number of observations (n = 24). Results were heterogeneous, the ÖMPSQ and its subsets had a poor to good predictive validity, depending on the variable considered.For the short ÖMPSQ version, we propose two cutoff scores for each of the three outcomes, with either good sensitivity (80%) or good specificity (80%) to distinguish three groups of patients with low, intermediate, and high risk of chronicity.versus limb pain, both of which being probably mainly musculoskeletal. When expressed relatively to the maximal score of each subset, cutoff variability was much larger for items #7+#8 than for the psychosocial subscore, followed by the total short ÖMPSQ score . This suggests that cutoff determination is more sensitive to population differences when only a small number of risk factors is considered, as in the ÖMPSQ subsets.Data showed a large variability, depending on the population and the outcome variable chosen. Cutoff scores calculated for the secondary care population are lower than those observed for the primary care patients. Cutoff scores for patients with chronic pain tended to be higher than those for patients with (sub) acute pain. Cutoffs from the total short ÖMPSQ score showed only small differences when comparing patients with spinal pain Secondary and tertiary prevention of chronic pain require accurate identification of modifiable risk factors. In busy clinical settings, there is a need for simple tools allowing for the rapid detection of these factors. The ideal tool would be a short questionnaire, with generic cutoff scores, that could be used in a large range of disorders and clinical settings. In this perspective, the short ÖMPSQ, designed to evaluate patients with MSKP, but assessing most of the risk factors also identified in non-MSKP disorders, deserved further exploration.Our data show that the short French ÖMPSQ and its subsets had predictive properties comparable to those of the full French ÖMPSQ version in patients suffering from spinal pain in (sub) acute patients consulting in a secondary care setting. These properties were globally confirmed in a more heterogeneous population of patients consulting in a primary care setting, suffering from pain of variable duration  acute, and chronic) and localization . However, increasing population heterogeneity resulted in slightly worse predictive performance and more variable cutoff scores than in our first cohort. The short ÖMPSQ showed fair to good predictive performance for chronic pain patients. Data obtained for spinal and limb pain suggest that the short ÖMPSQ has an acceptable predictive validity for a large range of patients suffering from MSKP.These data are in line of those of the original validation of the short ÖMPSQ version  as well The choice of cutoff scores, which will influence patients’ treatment assignment, is an important but difficult process. In their original study, Linton et al.  proposedAn alternative to the use of rigid cutoff scores is to analyze patients’ answers to specific questions, alone or in combination with the total short ÖMPSQ score. The fair performances of single questions about patient’s expectations confirmed that the patient’s own beliefs are significant predictors of recovery , 46–48. The fair to good predictive performance of the short ÖMPSQ for chronic pain patients confirms that chronic pain is not a fixed state  and streTo our knowledge this is the first study that showed the interest of psychosocial subscore of the ÖMPSQ, in line with the observations made with the SBT. This observation confirmed therefore the importance of addressing psychosocial factors in the management of at-risk patients. However, the clinical efficiency of treatment assignment based on this psychosocial subscore remains to be tested and the moderate predicting value of this subscore indicates that other factors play a role in chronicity. Another important finding was the validity of the short ÖMPSQ to predict the evolution of patients with limb pain. Finally, we confirmed the validity of the short ÖMPSQ for patients with chronic pain, thus fostering a prognostic definition of chronic pain .This study has some limitations. (1) Participants in the secondary care cohort completed the full and not the short ÖMPSQ version. The impact of this is probably small, according to previous suggestions  and to tThe French version of the short ÖMPSQ and its subsets are useful tools for screening patients suffering from acute, subacute, and chronic spinal and limb pain. However, the choice of cutoff scores might be difficult and should integrate the clinical objectives  as well as the available therapeutic resources. We would advise clinicians not to stick to a single score but use this questionnaire as a guide to open a discussion with the patient, allowing a more detailed and enlarged assessment of his beliefs, behaviors and resources. The management decisions should integrate the results from this questionnaire to the context of the patient, his own objectives and the available resourcesAdditional file 1. Comparison of area under the receiver operating characteristic curves for various Örebro Musculoskeletal Pain Screening Questionnaire versions for three outcomes  in the secondary care cohort. Additional file 2. Comparison of area under the receiver operating characteristic curves between three outcomes  for different Örebro Musculoskeletal Pain Screening Questionnaire versions in the secondary care cohort.


Of 10 patients undergoing thoracotomy and treated with opioids, eight had a NRS of no more than 2, of which six had no chronic pain. Of the twenty-one patients who underwent VATS biopsy and were treated with opioids, fifteen had NRS no greater than 2, of which ten had no chronic pain. Subgroups of patients biopsied under mediastinotomy or video-assisted thoracoscopic surgery (VATS) and treated with thoracic epidural analgesia (TEA) or PVB were too small for such analysis.Chest pain following a trans-thoracic biopsy often has multiple etiologies, especially in patients with lymphomas. Pathological neuronal mechanisms integrate with an overproduction of IL-6, TNF-α, IL1-β by macrophages and monocytes, which amplifies inflammation and pain. In consideration of this complex pathogenesis, international guidelines recommend diversified analgesia protocols: thoracic epidural, paravertebral block, and systemic administration of opioids. This study reports an attempt to reduce chest pain and prevent chronic pain in 51 patients undergoing trans-thoracic biopsy for mediastinal lymphoma. The entity of pain, measured 72nd hour after biopsy by the Numerical Rating Scale (NRS), was compared with that seen at a 6th month checkpoint in 46 patients. The pain decreased in all cases. At the 6th month checkpoint, among 31 opioid-treated patients, none of the 16 patients with NRS < 6 within the 72nd hour post biopsy had developed chronic chest pain, while 8 of the 15 with higher values did ( Chest pain caused by a trans-thoracic biopsy is a complex pathophysiological entity, not exclusively dependent on trauma, but often caused by various etiological factors, especially in elderly patients with lymphomas or other neoplasms. Prolonged post-traumatic inflammation can induce persistent stimulation of the nociceptive pathways beyond recovery, thus generating chronic pain ,2,3,4,5.Thoracic incision is among the most painful types of incisions a patient can undergo , due to Thoracic epidural analgesia (TEA) is commonly considered the gold standard for limiting post-operative pain, as it has been shown to reduce the risk of persistent post-operative pain (PPP) more effectively than other measures; in some cases, however, it is contraindicated and in others it may not work . In addiThe origin of this pain has not been fully understood and alternative methods for postoperative pain control are considered of enormous interest ,42. PostSystemic opioid administration is the simplest and most common method of providing analgesia for postoperative pain, but this can be associated with several side effects, such as respiratory depression, sedation, nausea, and vomiting. The guidelines of the American Pain Society of Regional Anesthesia recommends multimodal analgesia protocols. In this regard, the Italian Society of Anesthesia Analgesia Resuscitation, and Intensive Care (SIAARTI) has adopted multimodal strategies since 2010 and has stressed the need to combine techniques of systemic and local anesthesia, and to reduce the use of opiates, a suggestion reaffirmed in 2019. Today we act at various levels, periphery, nociceptors, and afferent conduction pathways, trying to optimize the advantages of each drug and limit its side effects. The treatment begins at the time of the surgical incision, acting early on the nociceptive afferents, and then continues over time. The Cochrane meta-analysis of 14 studies with 698 patients undergoing thoracotomy, compared paravertebral block (PVB) with TEA and found no difference in the 30-day post-operative mortality rate, in the incidence of cases with excessive sedation and in the duration of the hospital stay; in terms of analgesic efficacy, PVB was comparable to TEA, but had a lower incidence of cases with hypotension, nausea, vomiting, itching, and urinary retention ,45,46,47The present study reports our attempts to reduce chest pain and prevent chronic pain in 51 patients undergoing transthoracic biopsy for suspected mediastinal lymphoma, with an open approach or with a minimally invasive approach such as video-assisted thoracoscopic surgery (VATS). The aim of this study was to highlight which of the surgical techniques and anesthetic choices  ,49 used Fifty-one consecutive patients undergoing transthoracic biopsy for suspected mediastinal lymphoma from April 2018 to October 2019 at the Department of Pain, AORN Dei Colli, Naples, Italy, were enrolled in this study. Needle biopsy is a common procedure for diagnosing anterior mediastinal tumors, but in some cases, only necrotic or fibrotic material is recovered and sometimes tumor samples are too small to allow diagnosis and a complete immunohistochemical typing. The present study includes only patients with mediastinal lymphoma. The age of the patients ranged from 57 to 84 years (median 68); 31 were males and 20 females. No patient had suffered from chronic chest pain or had undergone systemic analgesic therapy prior to trans-thoracic biopsy. Patients were followed by hospital doctors during hospitalization and entrusted to their family doctor after discharge with clear written instructions on how to continue the clinical follow-up and how to practice any occasional analgesic therapies. If deemed necessary by the family doctors, the patients were re-evaluated by the hospital doctors and then returned to the family doctor with clear written instructions on how to continue the clinical follow-up. Six months after the trans-thoracic biopsy, 46 of the 51 enrolled patients were re-evaluated by hospital physicians as outpatients.The thoracic pain was evaluated with the McGill Pain Questionnaire (MPQ) , recordiPatients with lymphoma were treated with chemotherapy after the histological diagnosis was made, in accordance with international guidelines. No patient underwent radiotherapy in the six months following surgery, as it was not necessary at that stage.All clinical procedures were performed in accordance with international guidelines and with the Helsinki Declaration of 1975, revised in 1983. The study was approved by the local Ethics Committees named: “Comitato Etico Universita’ Degli Studi Della Campania “Luigi Vanvitelli”-Azienda Ospedaliera Universitaria “Luigi Vanvitelli”-Azienda Ospedaliera Rilievo Nazionale “Ospedali Dei Colli”, Naples, Italy, with protocol number 263/2018.At the baseline visit, each patient signed an informed consent for the use of their data in clinical investigation, in keeping with the Italian lows on privacy.The surgical techniques for performing biopsy were open biopsy via anterior mediastinotomy  or VATS biopsy.Anterior Mediastinotomy: the procedure was performed in an operating room under general anesthesia and endotracheal intubation. The patient was placed in a supine position and a 4 cm incision was performed in the parasternal 2nd intercostal space. The cartilage of the third rib was removed with the preservation of the perichondrium and the mammary artery. Rib retractor was used to magnify surgical filed. The extra-pleural space was opened by blunt dissection to push the pleura away from the mediastinum and to gain access to the target lesion. Biopsies of the lesion were performed with standard biopsy forceps and tissue was evaluated for adequacy. At the end of the procedure, the cartilage was replaced, and the wound closed in layers. No chest drainage was placed.VATS biopsy: The procedure was performed with a single incision in the operating room, under general anesthesia and with selective endotracheal intubation. A 2–3 cm incision was made within the 4th intercostal space on the anterior axillary line and protected by a wound retractor. No rib retractor was used. This access was used for work tools and the camera. The lung was gently retracted to access the anterior mediastinum, and the target lesion was biopsied. The tissue samples thus obtained were evaluated for adequacy. At the end of the procedure a 24 French chest tube was inserted through the same incision and removed the next day.The anesthetic techniques used were TEA, PVB, and opioid analgesia.For TEA, patients were placed in a sitting position with the neck and upper back in flexion; the approach to the thoracic epidural space was performed using as superficial anatomical reference points to approximate the puncture site to the intended segment, the prominent spinous process of C7 and the lower edge of the scapula (T7). Skin anesthesia was performed with lidocaine 2% 3 mL; the 18 G Tuohy needle was advanced with the loss of resistance technique by means of an “air” syringe. Once the epidural space was found, ropivacaine 0.5% 6 mL was administered, and a catheter was placed and then fixed to the skin and connected to an elastomer for continuous administration of local anesthetic. The whole method was performed in a sterile condition. Four hours after the epidural anesthesia, ropivacaine 0.2% at 5 mL/h was administered intravenously for 72 h.For PVB, the injection of local anesthetic was administered at the T3 level with the patient in lateral position with the site of surgery on the top. The ultrasound probe was placed 5–6 cm from the midline in the craniocaudal direction and moved medially to identify the transverse process and parietal pleura. Eight ml of ropivacaine 0.5% were deposited in the space between the pleura and the costotransverse ligament by a 100 mm needle positioned out of plain. The same procedure was performed at the T4 and T5 level homolaterally. A catheter was placed at the T 4 level and connected to an elastomer for continuous administration of local anesthetic. The whole method was performed in a sterile condition. Four hours after blockade, ropivacaine 0.2% at 12 mL/h was administered intravenously for 72 h.Postoperative opioid analgesia consisted of the administration of morphine 20 mg per day and ketorolac 1 mg per kg per day for 72 h. Administration took place intravenously through an elastomeric system.Seventy-two hours after the surgical procedure, patients underwent pain treatment only “as needed”. Therapy consisted in the administration of an oral dose of paracetamol 1 g with the possible addition of oral ketorolac 30 mg in drops. The recommended daily dosage did not exceed 3 g of paracetamol and 60 mg of ketorolac. In patients who showed painful symptoms of NRS greater than 4 beyond 10 days from the surgical procedure, a treatment scheme was set up including the use of paracetamol (up to 3 g per day per os) and opioids . For patients who began to experience signs of mixed pain, not only nociceptive but also with neuropathic components, pregabalin  or gabapentin  were added. For patients who reported a further increase in the NRS value (greater than 5), tramadol was replaced with oxycodone , or transdermal fentanyl (up to 50 g/h) was added, always in combination with paracetamol and adjuvant drugs .Immediately after surgery, patients were encouraged to mobilize with movements of the upper and lower limbs, coordinated with the respiratory acts; as soon as was possible, each patient was encouraged to gradually increase the rhythm and number of movements with the assistance of a healthcare personnel.Hematologic blood tests were performed by routine methods. Serum HBsAg, total anti-HBc, anti-HBs, anti-HCV, and anti-HIV were detected by commercial immunoenzymatic assays as described in previous studies ,56,57,58p < 0.05). The Yates’ corrected chi-square test was used to assess whether NRS observed within the 72nd hour after biopsy could influence the onset of chronic chest pain, as recorded 6 months later.The Wilcoxon signed rank test was used to evaluate whether NRS and MPQ values recorded in individual patients 72 h after biopsy and 6 months later differ significantly  for one patient only, nine patients had NRS 8, twenty-five NRS 6, and ten NRS 1. The patient with NRS 10 had undergone VATS and was treated with systemic opioid analgesia during hospitalization. Of the nine patients with NRS 8, seven underwent VATS and two mediastinotomy; seven were treated with systemic opioids and two with PVB . Of the p = 0.001), with a large effect (r = 0.60); in the remaining two the initial NRS score of 6, remained unchanged. MPQ values were also significantly decreased  with a large effect (r = 0.55)  .p = 0.043), with a large effect (r = 0.64). The MPQ values were also significantly decreased at the 6-month checkpoint , with large effect (r = 0.64)  .p = 0.011), with a large effect (r = 0.59); this score decreased in 8 and persisted with the score 1 in the remaining one. The MPQ values also significantly decreased , with a great effect (r = 0.63)  .p < 0.01). At this checkpoint, eight of the 10 patients who underwent mediastinotomy and received opioids had an NRS no greater than 2 and six of these eight had no chronic pain  suggests some pain protection of VATS compared to mediastinotomy  after the surgical procedure as independent variables and VATS and mediastinotomy as dependent variables. Although not statistically significant, the odds ratio 0.77  is a complication of thoracic surgery, which, if not treated properly, can give rise to a chronic painful post-thoracotomy syndrome that usually reduces the quality of life, especially in patients with lymphomas. Scar pain, a complex entity of multifactorial origin, also has a significant impact, even in minimally invasive surgery. The prevalence of PTPS is described as extremely variable, ranging from 9% to 80% after mediastinotomy and from 5% to 33% after VATS.Effective perioperative pain management is crucial. TEA is considered the best postoperative pain therapy after mediastinotomy, but when this technique is contraindicated or fails, alternative therapies or pioneering solutions should be chosen ,62,63,64The systemic administration of opioids, the most common method of providing analgesia for postoperative pain for its intrinsic simplicity, is frequently followed by numerous adverse reactions, such as respiratory depression, sedation, nausea, and vomiting.It should also be noted that the Italian Group of Thoracoscopic Video Surgery suggests that all patients undergoing trans-thoracic biopsy should receive local anesthetic administration with one of the techniques used as an integral part of the VATS analgesic protocol. VATS is generally associated with a lower number of perioperative complications and a reduction in hospital stays. This makes it preferable in general, regardless of the level of anesthetic risk . AlthougWe should not forget that the pain due to thoracic surgery has a multifactorial origin, and therefore, it is not surprising that a less invasive surgical procedure may be followed by intense symptoms and vice versa, independently from the anesthetic techniques used ; of thisThe anesthetic techniques for pain control and early mobilization used in the present study were useful for most enrolled patients. Indeed, none of them developed infectious complications or sustained post-operative pain, less than a third developed clinically significant chronic pain, and impaired pulmonary ventilation was observed only in one patient unable to perform early mobilization. The observation that out of 31 opioid-treated patients none of the 16 patients with NRS < 6 by the 72nd hour after biopsy developed chronic chest pain, while 8 of 15 with higher values did, supports the opinion we have acquired in conducting the study that, in cases with more intense pain, it is useful to improve the anesthetic treatment already in the first days after the biopsy.We admit that our data should be considered preliminary because 51 patients may not be quite enough, given the necessary diversifications in surgical and anesthetic choices. However, we believe that our model of integrated clinical practice between hematologists, surgeons, and anesthetists might be borrowed in clinical practice.We admit that the present study has some limitations. In fact, pain is a subjective perception which, even if measured with accredited international scales, remains self-declared. Furthermore, many cofactors are implicated in determining pain intensity and duration as patients age. Our patients were predominantly elderly, occupational activity, level of education, level of pain perception, co-pathologies, and many others already listed in this paper. Another limitation is the small size of the sample studied, which however, for the results obtained, we think it may be sufficient to stimulate the setting up of large multicenter studies.


A significant number of chest pain patients had previous cardiac imaging tests (CIT) performed before being presented to the Emergency Department (ED). The HEART  score has been used to risk-stratify chest pain patients in the ED, but not particularly for patients with CIT performed. We aim to modify the current HEART score with the addition of most recent CIT findings (referred to as HEART2 score), to predict a 30-day major adverse cardiac event (MACE) among ED chest pain patients, compare the performance accuracy of using HEART versus HEART2 score for 30-day MACE outcome predictions, and further determine the value of HEART2 in a subset group of ED chest pain patients .This is a single-center observational study. We included chest pain patients with HEART scores calculated during their index ED visits. A modified HEART2 score was developed with the addition of CIT findings as one of the HEART2 components. Patients were divided into three groups, including low (≤ 3), moderate (4–6), and high-risk HEART/HEART2 scores (≥ 7). MACE occurrence of a patient with different risks of HEART and HEART2 scores and overall performance accuracy of HEART versus HEART2 score predicting MACE outcomes were compared.We included a total of 9419 chest pain patients at ED, among which one out of five patients (1874/9419) had previous CIT performed. Fewer (38.2%) of such patients had low-risk HEART scores in comparison to 55.5% of low-risk HEART2 scores (p < 0.001). The MACE outcomes were similar in low-risk HEART patients compared with low-risk HEART2 patients . The overall performance accuracy of using the HEART2 score to stratify chest pain patients with previous CIT was better than using the HEART score’s .Using the HEART2 score might be suitable to stratify low-to-moderate risk chest pain patients at ED with a similar 30-days MACE occurrence compared to the HEART score. More importantly, with the use of similar low-risk criteria (HEART2 ≤ 3), over 45% more chest pain patients with previous CIT performed could be discharged directly from ED.The online version contains supplementary material available at 10.1186/s12872-022-02528-6. The HEART  score has been used widely to risk-stratify chest pain patients in the Emergency Department (ED). It has been well validated in many studies –3. ChestOne previous study reported that recent negative CIT results would predict the low risk of cardiac ischemia with a median follow-up of 35 months regardless of their initial risks of ACS . Such fiModification and expansion of the current HEART score have been reported in previous studies , 17. SomAn accurate scoring system will help standardize clinical practice, minimize healthcare disparity, and improve patient quality control. The HEART scoring system has been proven to risk-stratify ED chest pain patients in general successfully. However, the current HEART scoring system may still have its limitation and cannot risk-stratify accurately due to the diversity of ED chest pain patients. Since a significant number of ED chest pain patients had previous CIT findings, it is necessary to modify the current HEART scoring system by including the CIT findings to improve the performance accuracy of these patients. Meanwhile, the performance accuracy of the HEART score should maintain the same among other ED chest pain patients without the CIT findings. Thus, we believe such a modified HEART scoring system may have broader applications.In this study, we aim to (1) develop a modified HEART score, HEART2, by adding the previous CIT findings as an extra scoring component to predict 30-day MACE outcome among ED chest pain patients, (2) compare the performance accuracy of using HEART versus HEART2 score for 30-day MACE outcome predictions, and (3) further determine the value of HEART2 in a subset group of ED chest pain patients—ones with previous CIT findings.This was a single-center retrospective study. JPS Health Network is a publicly funded tertiary referral center, which is also a level one trauma center, a chest pain center, and a comprehensive stroke center. JPS Health Network Emergency Department (ED) has annual patient volume of approximately 120,000–130,000, among which, chest pain is one of the most common chief complaints. In January 2017, we built in a HEART clinical decision tool in the electronic health record (EHR) to recommend using such a tool for risk stratification and disposition guidance. Considering the physician judgements and discretion always exceed the decision tool, using tool to determine cardiac risk and disposition was not mandatory. The HEART scores were calculated upon the patient’s presentation to the ED in the EHR. This study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for studies involving human subjects. The regional Institutional Review Board approved this study with a full waiver of informed consent .All patients aged 18 or older who presented to the study ED with the chief complaint of chest pain or chest pain mimics  between January 1, 2017, and December 31, 2019, were screened. We included all patients who had HEART score calculated with at least one EKG and one troponin test done in the ED. In our ED, we used conventional troponin I (cTn I). If multiple HEART scores reported during patients’ hospital stay, only the initial HEART score assessed by ED providers and documented on ED notes was used for data analysis. If multiple HEART scores were documented by different ED providers during patients’ ED stay, we chose the last HEART scores that documented on ED notes prior to patients’ departure from ED. We excluded patients who (1) left the ED against medical advice (AMA), eloped, or left without being seen (LWBS), (2) directly transferred to other facilities, transferred to the heart catheterization lab, or expired at the ED, and (3) who did not have one troponin tested during their indexed ED visits. In addition, all patients were expected to follow up within 30 days of discharge from the ED or hospitalization. For patients who had missed information on 30 days follow-up, imputed data were used for the analysis .We collected patients’ basic demographics  and clinical variables . A detail explanation of general variables had been reported previously .Cardiac imaging tests (CIT) consist of stress tests and heart catheterizations in this study. Stress tests included exercise treadmill stress test, exercise stress echocardiography, dobutamine stress echocardiography, pharmacologic nuclear Lexiscan (Regadenoson) examination, and nuclear exercise stress testing with myocardial perfusion imaging. If multiple CIT were performed in the past, the most recent ones performed were reviewed. Two independent reviewers reviewed all stress tests and heart catheterization results after completing training with cardiologist and senior emergency physicians. Briefly, Stress test results were categorized as: (1) low-risk, (2) moderate-risk, (3) high-risk, and (4) inconclusive. Positive stress test findings refer to moderate-risk and high-risk categories. Heart catheterization tests were categorized as: (1) normal/no intervention, (2) interventions, and (3) recommend further procedures. Positive heart catheterization findings refer to performing interventions or recommending further procedures. A detail description on CIT reviewing decisions were reported previously .Our primary outcome is short-term (30 days) MACE outcomes. MACE referred to acute myocardial infarction (AMI), coronary revascularization by the percutaneous coronary intervention (PCI) with or without additional interventions, coronary artery bypass graft surgery (CABG), and all-cause mortality. ICD-10 code was used for determining AMI, and procedure code was used for PCI/CABG determinations. Our secondary outcome is ED disposition .Approximately 37.6% of the patients in this data sample had no follow-up information, and therefore their 30-day MACE outcomes were not observed. We thus manipulated the missing values as previously reported . BrieflySince nearly 20% 1874/9419) of chest pain patients from this study had at least one CIT performed in the past, a modified HEART scoring system has been derived. It is based on the previous results of negative CIT findings within a certain timeframe having few MACE outcomes , 19, 20, of chestChi-square test with Data retrieval and validation was described in the previous report . DescripSince the HEART2 score mainly affected ED chest pain patients with previous CIT findings, a sub-cohort analysis was done only on these patients. We calculated the HEART2 score on each sub-cohort chest pain patient. The performance accuracy of HEART and HEART2 scores were again compared.The reporting of this study conforms to the STARD statement (STAndards for Reporting Diagnostic accuracy studies) .From January 1, 2017, to December 31, 2019, HEART scores were calculated prospectively among 9673 chest pain patients at the study ED. A further screening excluded patients who were transferred directly to emergent catheterization laboratories or other facilities, patients who expired at the study ED, who signed AMA, eloped, or LWBS. Thus, a total of 9419 patients were included in the final analysis  . Among aAt present, ED chest pain patients with the previous CIT performed are over-investigated. Though not accounting for the majority of ED chest pain patients, such a cohort may use significant healthcare resources . FrequenIn an emergency care setting, we believe that using the HEART2 score does not burden ED physicians for patient evaluation. They would need only to incorporate patients’ previous CIT findings that have already resulted. With the broad use of electronic health records, such findings are easy to find and review. The same categories of differentiating low-risk versus moderate-to-high risk chest pain patients make it easy for ED physicians to remember. Higher HEART2 scores indicate a higher risk of short-term MACE occurrence, similar to the HEART scores . The onlFirst, given the nature of retrospective study design, patient selection bias, incomplete data, missing data cannot be avoided entirely, although our data were collected directly via electronic medical records. Second, the abnormal findings of CIT were determined based on charts reviewed by two independent reviewers, and even though our results reached a high level of agreement, variability may still occur. Additionally, the study hospital did not provide coronary CT angiography, therefore, such CIT was not included in this study. Third, though chest pain patients with low-risk HEART2 scores  can be safely discharged from ED with similar MACE occurrence in comparison to patients with low-risk HEART scores, the MACE occurrence rate may still exceed some ED physicians’ comfortable zone due to high medical-legal risks. As always, physician discretion should always exceed any scoring systems. Even with the ED discharge, such patients might still require closer clinical follow-ups. Lastly, we used this modified HEART2 score to risk-stratify low-risk recurrent chest pain patients in a single center with our unique patient population. Such findings might only be applied to this cohort. A large-scale multicenter prospective study is warranted for external validation.In conclusion, using the HEART2 score at Emergency Department might be suitable to stratify low-risk chest pain patients with previous cardiac image tests performed with a similar 30-day MACE occurrence compared to the HEART score. More importantly, when similar low-risk HEART score criteria were used on HEART2 scores, over 45% of chest pain patients with previous CITs could be discharged directly from the ED.Additional file 1. Table S1: General and Clinical Information in ED Chest Pain Patients with Previous Cardiac Imaging Tests Performed. Table S2. Performance accuracy comparisons between HEART and HEART2 score predicting MACE outcomes.


Opioid consumption during surgery and in the PACU was not significantly different. Need for patient-controlled analgesia postoperatively was significantly lower in the group receiving an ESP block (p = 0.010). Length of stay in hospital was reduced from 3.23 days (IQR 1.1) in the control group to 2.74 days (IQR 1.6) in the study group (p = 0.012). Adding an erector spinae plane block to the analgesic regimen for posterior lumbar interbody fusion surgery seemed to reduce postoperative pain and length of hospital stay.Postoperative analgesia in patients undergoing spinal fusion surgery is challenging due to the invasiveness of the surgical procedure and the frequent use of opioids preoperatively by many patients. Recently, the erector spinae plane (ESP) block has been introduced in our clinical practice as part of a multimodal pain strategy after posterior lumbar interbody fusion surgery. This is a retrospective case–control study evaluating the analgesic efficacy of the ESP block when added to our standard analgesic regimen for posterior lumbar interbody fusion surgery. Twenty patients who received an erector spinae plane block were compared with 20 controls. The primary endpoint was postoperative pain, measured by the numeric rating scale. Secondary outcome measures were opioid use, postoperative nausea and vomiting, and length of stay. Postoperative pain scores in the PACU were lower in patients who received an erector spinae plane block ( Postoperative pain management in spinal fusion surgery is challenging and usually includes administration of extensive amounts of opioids2. This can cause well known side-effects, such as respiratory depression, sedation, nausea, vomiting, and constipation. These side-effects can lead to a longer hospital stay and a worse patient experience4. Even with opioids, pain is not always sufficiently managed. Inadequate pain control increases cardiac and respiratory complications, delays mobilization, increases the length of hospital stay and may increase the risk of developing a chronic pain syndrome5.Patients can experience severe postoperative pain after spine surgery. A study comparing pain intensity on the first postoperative day in 179 different surgical procedures ranked spinal fusion surgery at second place, after open reduction of calcaneus fractureThe above mentioned complications indicate the need for a multimodal analgesic approach to posterior lumbar interbody fusion (PLIF) surgery with an increasing role for novel regional anesthesia techniques. Until recently, regional anesthesia techniques have not been used on a regular basis in PLIF surgery as an immediate postoperative neurological examination is required. This examination of the motor and sensory function of the spinal cord eliminates spinal and epidural analgesia as suitable pain treatments. Novel interfascial plane blocks, such as the erector spinae plane (ESP) block, generate regional analgesia without interference of spinal cord function and are therefore suitable for spinal surgery pain management.6. Using ultrasound, local anesthetic is injected below the erector spinae muscle group 7. This causes a sensory blockade over the antero- and dorsolateral thorax by blocking ventral and dorsal rami of the spinal nerves. Recent case reports suggest a positive effect of an ESP block on pain for multiple indications including vertebral metastases, lumbar transverse process fractures or following lumbar spine fusion and scoliosis surgery11. An ESP block has a very low risk of complications, as sonoanatomy is easily recognizable and there are no structures in close proximity at risk of needle injury12. The transverse process acts as an anatomical barrier and avoids needle insertion into the pleura or vessels, thus preventing a pneumothorax or hematoma. Moreover, the needle is relatively far from the vertebral canal, which means the risk of spinal cord injury is very low. In a pooled review, which yielded 242 reported cases between 2016 and 2018, only one adverse event (a pneumothorax) was reported13. An ESP block preserves bladder function and motor neuron function enabling early mobilization. Since motor function is unaltered, immediate postoperative neurological evaluation of spinal cord function is possible.The ESP block was first described in 2016We hypothesized that for patients undergoing PLIF surgery, adding an ESP block to standard anesthesia treatment might provide additional analgesia and reduce the need for postoperative opioids. We implemented this block in our clinical practice in 2018. This study aimed to retrospectively evaluate pain scores during the first 24 h post-surgery. We examined the effect of the ESP block on opioid consumption during the first 24 h post-surgery, the occurrence of postoperative nausea and vomiting (PONV), the need for patient-controlled analgesia (PCA) and length of stay (LOS) as secondary outcome parameters. Complications registered as part of standard registration of care were evaluated as well.This is an observational retrospective case–control study. It was approved by the Medical Research Ethics Committees United  (document number W20.100). The study was performed in accordance with the Declaration of Helsinki  and in accordance with the Medical Research Involving Human Subjects Act (WMO) and Good Clinical Practice guidelines. We followed the STROBE  guideline to report this study.From September 2019 until the end of January 2020, we performed the ESP block in 20 patients undergoing PLIF surgery. These blocks were performed by anesthesiologists with clinical expertise in regional anesthesia. During the preoperative consultation, informed consent was obtained for supplementary analgesia by ESP block. The study patients were the last 20 patients who underwent PLIF surgery at the moment we decided to undertake this evaluation. Twenty controls were selected from an earlier period (June 2017–January 2018), when use of the ESP block or any other local anesthetic was not part of standard care for this procedure. All patients in this study were treated by the same two surgeons. Consent for the anonymous use of the data of all patients was obtained by a letter asking for permission, according to national general data protection regulation and in consultation with the hospitals’ privacy officer.The goal of PLIF surgery is to decompress painful nerve roots and permanently immobilize adjoining vertebrae of the lumbar spine. The indications for PLIF surgery were persistent radicular pain due to either spondylolisthesis, lateral foraminal stenosis, failure of previous neurosurgical decompression, or a combination of the above. All patients underwent conservative treatment before surgery i.e. physiotherapy, oral analgesics, sleeve infiltration and/or pulsed radiofrequency therapy.14. Access was obtained in supine position on Wilson frame through a midline incision followed by subperiosteal dissection of the spinal musculature until the transverse processes of corresponding vertebrae were reached. Titanium pedicle screws  where placed before laminectomy and decompression of affected nerves was performed. After discectomy, PLIF cages  and autologous bone were introduced between the denuded endplates of the disc space. Nerve decompression and introduction of PLIF cages was always performed in cooperation with a neurosurgeon. Pedicle screws were fixed to titanium rods thus obtaining a rigid 360 degree fixation. Fascia, subcutis and skin were closed separately with dissolvable stitches. There was a no drain policy.All operations performed by a surgical team comprising of an orthopedic and a neurosurgeon. The PLIF procedure was first described in 1944 and has evolved to the current method as described in a review by MobbsPatients were permitted to walk 4 h postoperatively. They were discharged home when able to walk the stairs and if pain was manageable with oral analgesics.Preoperatively, all patients were given an intravenous (IV) canula and received oral administration of paracetamol if contra-indications were absent. Standard monitoring as advised by the American Society of Anesthesiologists (ASA) was applied. After completing the safety procedures, general anesthesia was induced. Patients were placed in prone position for surgery. Patients received sufentanil at induction and during surgery. Some patients received a bolus of morphine at the end of surgery, depending on the preference of the attending anesthesiologist.After surgery, patients were admitted to the post anesthesia care unit (PACU). In the PACU, patients were clinically assessed routinely for postoperative complications. Numeric rating scale (NRS) scores for pain and presence of PONV were documented by the PACU nurses. In case of a NRS pain score of more than 3, the patient received intravenous boluses of morphine until pain relief (NRS < 4) was achieved. This was performed according to the standard hospital’s postoperative pain protocol.Patients were discharged from the PACU when Aldrete’s scores were 8 or above, NRS pain scores 3 or lower, and PONV was absent or adequately treated. On the ward, a medical assessment including NRS pain scores was documented by the nurses at set intervals. All postoperatively administered medication was documented in the clinical file.17. Therefore, we chose to perform the ESP block at the lowest thoracic level.The ESP block was performed by administering local anesthetic beneath the erector spinae muscle group. In a lumbar ESP block, local anaesthetics may spread to the lumbar plexus resulting in motor weakness as demonstrated in radiologic studies6. By using ultrasound  with a high-frequency curved array probe , the erector spinae muscles were identified in relation to the transverse processes of T12. The probe was placed 2–3 cm lateral to the vertebral column, in longitudinal alignment. A 10-cm 21 gauge ultrasound-needle  was inserted in-plane in a cephalad to caudal direction. After bone contact with the transverse process was obtained, the needle was retracted slightly. Hydrodissection with normal saline (NaCl 0.9%) was performed to identify and open up the correct plane. After confirmation of correct placement of the needle, a dose of 20 mL of ropivacaine hydrochloride was injected. The same procedure was performed on the contralateral side.The ESP block was performed after induction of anesthesia and after placement of the patient in prone position for surgery. The ESP block was performed as described by Forero et al.Patients over 70 kg received 200 mg ropivacaine (40 ml), patients 50–70 kg received 150 mg ropivacaine (40 ml), and patients under 50 kg received ropivacaine 3 mg/kg (40 ml).18. In the PACU, only morphine was administered and therefore not converted to OME.All data were collected from the hospital’s patient data management systems. Preoperative data were collected from the preoperative anesthesia screening and the surgical consultations. During surgery, registration of medication and procedures regarding analgesia and anesthesia was performed by the attending anesthesiologist. Nurses on the PACU and surgical ward documented the patient’s condition as part of standard practice. We collected data from 4 different time points postoperatively: at the PACU and after 6, 12 and 24 h postoperatively. We compared both groups by calculating the oral morphine equivalent (OME) of all opioids used during surgeryOur primary outcome was postoperative NRS pain scores. Secondary outcome parameters were opioid use, PONV, and LOS. Continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR), depending on normality. Categorical demographic variables were reported as a number or a percentage.p-value < 0.05 was considered statistically significant when comparing the two groups. We have calculated the effect size for nonparametric data using r = z/√N, as described by Fritz, Morris and Richler (2012). The effect size was calculated such as the r proposed by Cohen (1988); 0.5 for a large effect; 0.3 for a medium effect and 0.1 for a small effect. Statistical analyses were performed using SPSS, version 25 .Differences in normal distributed continuous variables between groups were tested using an independent T-test. Differences in not-normal distributed continuous variables between groups were tested using a Mann–Whitney U-test. Differences in categorical variables between groups were tested using a Fisher’s exact test. A Informed consent was obtained from all individual participants included in the study.The demographic data including age, sex, ASA classification, BMI, history of spine surgery, number of levels, and length of surgery, were equally distributed between the two groups Table .Table 1Dp = 0.040, with a medium effect; r =  − 0.330). On the ward, NRS pain scores were comparable between the 2 groups after 6 h , 12 h  and 24 h .Postoperative NRS pain scores in the PACU were lower in patients who received an ESP block . The percentage of patients needing patient-controlled analgesia postoperatively differed between the groups . Patients who did not need a PCA pump, received intermittent oral opioids (oxycodone). There was no registration of the amount of morphine used by patients who had a PCA pump. Therefore, the collected data did not allow for a meaningful comparison between the PCA and oral analgesic group. There were no ESP block related complications mentioned in the charts. One case of ileus was registered in the ESP block group. This patient needed PCA with intravenous morphine postoperatively and was limited in mobilization due to wound leakage.PONV occurred in 2 cases (11.1%) in the control group, compared to 0 cases in the ESP block group -protocols in the last decade. A retrospective study found a reduction from 6.7 days in 2012–2013 to 4.8 days in 2016–2017 for posterior lumbar spine fusionOur data show that the time spent in the operating theatre did not differ between the groups, as the ESP block is easily performed while the surgeon is scrubbing in for surgery. As the ESP block was performed after general anesthesia was induced, there was no patient discomfort during performance of the block. Implementation of this block as standard care was easy in our center and we did not find disadvantages for our patients.This study has two limitations. Firstly, this is a small-scale retrospective clinical evaluation. Hence, sample size was not a priori powered and our conclusion cannot be generalized. Secondly, staff followed our in-house protocol which allowed a more liberal anesthesia regimen and resulted in less detailed data registration compared with a strict study protocol.Implementing the ESP block for PLIF surgery as standard care in our center has caused a significant reduction in postoperative pain and length of hospital stay, most likely by allowing earlier mobilization. As we have increased our experience with the ESP block, these results encourage us to perform a large prospective, randomized clinical trial to further establish the role of the ESP block in PLIF surgery.Supplementary Information


Painful osteoarthritis is common in elderly patients, and low-dose radiotherapy has been demonstrated to provide effective symptomatic treatment. We examined the analgesic effects of low-dose radiotherapy for osteoarthritis in the elderly aiming to reveal potential differences in the response rates relating to increasing age.A retrospective analysis was performed at two university hospitals including elderly patients (≥ 65 years) undergoing radiotherapy for osteoarthritis between 2008 and 2020. Pain intensity and response were quantified using the numerical rating scale (NRS) and the Pannewitz score. Age groups were defined for young old (65–74 years), older old (75–84 years), and oldest old patients (≥ 85 years).p < 0.001 for t0–t1, t1–t2, and t0–t2). At t1, 1.5% exhibited a Pannewitz score of 0 (no pain), 58.5% of 1–2 (less pain), 36.1% of 3 , and 3.9% of 4 (worse pain), while at t2, pain response shifted towards 6.9% (0), 58.6% (1–2), 28.1% (3), and 6.3% (4). Pain response did not differ between age groups at t1 (p = 0.172) or t2 (p = 0.684). In addition, pain response after re-irradiation (n = 384 sites) was 61.0% and was comparable between age groups (p = 0.535).In all, 970 patients with 1185 treated sites and a median age of 76 years were analyzed. Mean NRS was 66 at baseline (t0), 53 after radiotherapy (t1), and 44 at first follow-up (t2) (Low-dose radiotherapy results in pain reduction in about two-thirds of treated sites with no difference relating to increasing age, showing that radiotherapy is an effective analgesic treatment for osteoarthritis even at advanced ages. Osteoarthritis is a common disease especially in the elderly that is becoming more frequent in developed countries due to an increasing life expectancy . OsteoarDue to the anti-inflammatory effects of small doses of ionizing radiation, low-dose radiotherapy is commonly used in patients with painful osteoarthritis, especially in central and Eastern Europe . The advA plethora of studies have reported analgesic effects of low-dose radiotherapy for osteoarthritis, but these studies mostly did not focus on the important subgroups of elderly patients –25. NeveWe therefore aimed to analyze the effects of linear accelerator-based low-dose radiotherapy in a large cohort of elderly osteoarthritis patients treated at two university hospitals.The Independent Ethics Committees of University of Freiburg (reference no. 150/20) and University of Heidelberg (reference no. S‑040/2018) approved this study. Patients who received low-dose radiotherapy for osteoarthritis between 2008 and 2020 and were ≥ 65 years at the time of radiotherapy were included. Low-dose radiotherapy was applied for painful osteoarthritis of the large joints, i.e., the knees, hips and shoulders, as well as the small joints, i.e., the wrist, fingers, thumbs, ankle, and feet, following the guidelines of the German Society of Radiation Oncology . Radioth2 test was performed to examine whether the re-irradiation rate was different between the age groups. Statistical significance was assumed for p < 0.05. IBM SPSS Statistics software version 25  and GraphPad Prism software version 8  were used for statistical analyses.Wilcoxon signed-rank tests were used to compare NRS values between the time points. Mann–Whitney U (2 groups) or Kruskal–Wallis tests (≥ 3 groups) were performed to compare the pain response measured by the Pannewitz score. A χn = 858, 72.4%). Median body mass index (BMI) was assessable for 270 patients and amounted to 27.7 kg/m2 (range 16.0–52.1 kg/m2). Most common treatment sites included knees , hands , and feet . The majority of patients were treated with NSAIDs prior to radiotherapy , and a considerable percentage of patients had also received prior intraarticular corticosteroid injections . The most common treatment scheme was 6 × 1 Gy , while 6 × 0.5 Gy was less frequently used .A total of 970 patients with 1185 treated lesions were analyzed. As some patients were treated for separate joints at different time points, patient characteristics are related to the total number of sites . By only analyzing patients with information at t0, t1, and t2, the mean NRS difference amounted to −12.3 (±15.4) between t0 and t1 and −21.0 (±23.9) between t0 and t2.Directly upon completion of low-dose radiotherapy, 18 patients (1.5%) exhibited a complete pain relief (Pannewitz score = 0), 693 (58.5%) reported a partial response (Pannewitz score = 1–2), 428 (36.1%) unaltered pain (Pannewitz score = 3), and 46 (3.9%) increases in pain, therefore resulting in a response rate (Pannewitz score 0–2) of 60.0% at t1 . Both at t1 and t2, there were no significant differences regarding patients’ NRS between the different age groups . Similarly, the Pannewitz score was found to be similar between the different age groups of elderly osteoarthritis patients: 6 (1.1%), 325 (59.7%), 195 (35.8%), and 18 (3.3%) young old patients exhibited Pannewitz scores of 0, 1–2, 3, and 4, respectively at t1. This was comparable to the distribution in the older olds  and oldest olds  . At t2, there also were no significant differences regarding Pannewitz scores between the three age groups (p = 0.684). The overall pain response rates (Pannewitz score = 0–2) at t2 were 68.0%, 64.0%, 61.5% for the young olds, older olds, and oldest olds, respectively.Following a common subdivision approach for the elderly population, we divided our cohort into young olds (65–74 years), older olds (75–84 years), and oldest olds (≥ 85 years) and compared pain response rates among the three age groups Fig. . Initialp < 0.001, Mann–Whitney U test). However, there were no differences in the mean NRS decline between male and female patients at t1 (p = 0.271) or t2 (p = 0.610). As shown in previous prospective trials for other benign diseases, there was no difference in the analgesic efficacy between single doses of 1 Gy and 0.5 Gy  [p = 0.970, t2: p = 0.192, Kruskal–Wallis test). Neither at t1  nor at t2 (p = 0.380), patients with previous NSAID intake had a different pain response as indicated in the Pannewitz score distribution. Similarly, previous intra-articular corticosteroid administration had no effect on patients’ pain response . Patients with obesity (BMI > 25 kg/m2) exhibited similar NRS declines both at t1  and at t2  compared to patients of normal weight. Likewise, pain responses as measured with the Pannewitz score were not different between overweight and normal-weight individuals .We furthermore analyzed the role of patient gender, radiotherapy fractionation, and osteoarthritis location on the pain response Fig. . Prior t U test) . The difp = 0.805, χ2 test; Fig. p = 0.256, Kruskal–Wallis test). At the first follow-up after the second course , Pannewitz score distribution was similar to t3: 3.6% of patients had a Pannewitz score = 0, 57.4% a Pannewitz score = 1–2, 36.4% a Pannewitz score = 3, and 2.6% a Pannewitz score = 4, leading to a pain response rate of 61.0% after re-irradiation that was comparable between the age groups .We also investigated whether there were differences in the frequency of second radiotherapy courses depending on patient age. A total of 384 s radiotherapy courses (32.4%) were applied in our cohort. Re-irradiation rates did not differ between the different age groups and amounted to 33.3% in the young olds, 32.0% in the older olds, and 30.6% in the oldest olds , low-doAlthough a placebo effect cannot be ruled out, it should be considered that low-dose radiotherapy is commonly applied for patients after multiple previous therapy attempts, therefore considering a rather intensively pretreated patient cohort with a long disease history. Increasing pain response rates between t1 and t2, as seen in our study, would also rather be untypical for a pure placebo effect. It may further be hypothesized that elderly patients with favorable pain response after low-dose radiotherapy would rather omit the follow-up consultation at t2, thereby biasing the results towards lower pain response rates. In turn, patients that exhibit equal or even more intense pain after radiotherapy could be maybe more likely to keep the appointment at the follow-up consultation to receive a second course.Although low-dose radiotherapy is a widely used treatment modality for osteoarthritis in central and Eastern Europe and numerous retrospective analyses have demonstrated the pain-relieving effects of this therapy, two randomized, double-blind, sham-controlled studies could not confirm superior analgesic effects of low-dose radiotherapy for knee and hand osteoarthritis compared with sham treatment , 38. HowAlthough providing real-world data of low-dose radiotherapy for painful osteoarthritis in a large cohort of elderly patients, our analysis has limitations: For instance, about half of patients failed to present for the first follow-up appointment; therefore, information on patient’s pain intensity at t2 of these patients are missing. Second, we had insufficient data about patients’ long-term pain response, as patients were not routinely re-assessed over the following years. However, previous analyses rather have shown that pain response is augmented with increasing duration and that the full analgesic effect of low-dose radiotherapy is most pronounced at later time points .To the best of our knowledge, this is the largest study of elderly osteoarthritis patients treated by low-dose radiotherapy. Our data demonstrate that low-dose radiotherapy is an effective treatment in elderly patients with osteoarthritis, resulting in pain improvement in two of three cases. As we could not detect reduced analgesic efficacy in the older/oldest old patients, our data suggest that there is no upper age limit for radiotherapy. As the risk for tumor induction is decreasing with advancing age, low-dose radiotherapy may even have a more prominent role in this population.


Background: Osteoarthritis (OA) is imposing substantial burdens on individuals and society with the aging population. Cortex Daphnes patch is widely used for symptomatic knee OA in China with a satisfying clinical efficacy; however, there is scant clinical evidence supporting its use. To evaluate its efficacy, we conducted a multicenter, non-inferiority, randomized, parallel-group study comparing Cortex Daphnes patch with topical nonsteroidal anti-inflammatory drugs in patients with knee OA (NCT02770950).Methods: A total of 264 symptomatic knee OA patients were treated with Cortex Daphnes or indomethacin cataplasms applied to affected sites once daily for 2 weeks. The primary outcome was improvement in knee pain on walking as assessed using a visual analog scale (VAS). The non-inferiority margin based on the full analysis population was set as –5 mm on the pain VAS. The secondary outcomes were changes of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, WOMAC scores for pain, function and stiffness, the 36-item Short Form Health Survey (SF-36), and global assessment of knees by the patients. Responder rates for pain VAS, WOMAC total score, and WOMAC pain were also included in the secondary outcomes.Results: The Cortex Daphnes patch was non-inferior to indomethacin cataplasms for the primary outcome with a group difference (Cortex Daphnes patch–indomethacin cataplasm) of 2.1 mm ; similar results were found in the per-protocol population. For all other outcomes, no significant differences were found in the full analysis set or in the per-protocol analysis set, except the responder rates for WOMAC pain was higher in the Cortex Daphnes patch group than in the indomethacin cataplasm group  in the per-protocol analysis set. Overall, 28.8% patients in the Cortex Daphnes patch group and 9.8% in the indomethacin cataplasm group reported treatment-related adverse events, the vast majority of which were mild-to-moderate skin irritation, resulting in only 3.8 and 0.8% of patients dropping out, respectively.Conclusion: The Cortex Daphnes patch, which provides satisfactory analgesic efficacy and enhances the physical function of the knee, as well as improving quality of life, may be a promising alternative to knee OA. Osteoarthritis (OA) is a progressive disease of joints, common in middle and old age, that leads to joint capsule and ligament contracture, resulting in joint pain and functional impairment, as well as social and economic burdens . The joiTraditional Chinese medicine has been accepted as a complementary therapy for knee OA, owing to its effects on relieving pain and improving functions of knee joint . TopicalAccording to Chinese medicine theory, the function of Cortex Daphnes herb is to remove blood stasis and relieve pain, removing cold-wind and dredge collaterals. It is used to treat headache, stomach ache, bruises, limb numbness, joint pain, and others. Although Cortex Daphnes patch has been widely used to treat arthritis in China, there have been few clinical studies reporting its effect and safety. The first published clinical study of Cortex Daphnes patch was in the 1980s, reporting the effects of pain relief in Chinese patients with soft tissue injury . Only onThe aim of the present study is to evaluate whether Cortex Daphnes patch has the potential to be a valuable topical intervention for patients with knee OA. For this reason, we conducted a multicenter, non-inferiority, randomized controlled trial to compare the safety and efficacy of the Cortex Daphnes patch to indomethacin cataplasms for the treatment of knee OA.Cortex Daphnes is majorly derived from the field-grown root bark and stem bark of Daphne giraldii Nitsche., which were collected in the plateau region of Gansu Province, China, and processed as described in the standard of Chinese medicinal materials in Gansu Province . The maiThis was a multicenter, randomized, active controlled trial with duration of 2 weeks to evaluate the efficacy and safety/tolerability of Cortex Daphnes patch in patients with symptomatic knee OA. The study was conducted at eight sites in China from May 2016 to December 2017.Among those NSAIDs used for local treatment of OA, topical administration of indomethacin has been widely prescribed for pain in China. According to package instructions, the dose of indomethacin cataplasm was one patch for one site once daily for 24 h.Participants were all outpatient patients who visited doctors complaining of knee pain. Patients were aged 40–75 years who met the 1995 American College of Rheumatology combined clinical and radiographic criteria for knee OA  and had This was a multicenter and active-controlled design. Using the block randomization method, a random number table was generated by an independent third party, the Clinical Evaluation Center of China Academy of Chinese Medical Sciences, using SAS 9.4 software . The randomized assignment sequence was placed in a sealed opaque envelope and was kept by the scientific research management department of the research unit and can be reproduced upon request. Eligible patients were randomized 1:1 to either Cortex Daphnes or indomethacin cataplasm topical treatment. Prior to recruitment, study investigators, site staff, and patients were blinded to the details of the allocation sequence. In order to avoid patient’s preference for treatment method, we discussed all the interventions (the Cortex Daphnes patch and the indomethacin cataplasm) involved in this study with each participant, and informed them that all the treatments may benefit them. Furthermore, we asked a staff member not to discuss the intervention with participants when dispensing the medicine. The therapeutic and side effects were evaluated by a trained staff member of each site who was blinded to group allocation.The study included a screening visit to determine eligibility, a baseline visit, and a 2-week visit. Patient-reported outcome measures were collected at baseline and at the 2-week visit. Unscheduled visits were also possible at any time during the study treatment if required.The primary outcome was change in the patient’s global assessment of pain intensity score from baseline to posttreatment. The Patient’s Global Assessment of Pain Intensity score employed a 100-mm VAS pain scale evaluating knee pain when walking flat (0 for no pain and 100 for pain as bad as it could possibly be) . The secSafety evaluations included monitoring of adverse events (AEs), treatment discontinuations, measurement of skin irritation, and the assessment of clinical laboratory investigations. Skin irritation intensity evaluation criteria were used to record adverse skin events, which were the most commonly expected side effects. According to these criteria, the degree of the irritation symptoms including erythema, edema, and pruritus, were divided into mild, moderate, and strong irritation and were assessed by a trained physician . The spePatients whose eligibility was confirmed at the baseline visit were randomly assigned to treatment with one or the other intervention. During the treatment period, participants were instructed to apply the Cortex Daphnes patch or the indomethacin cataplasm  onto clean skin overlying the affected sites on both knees every night and keep it in place for 24 h. The standard operation procedure for the application of Cortex Daphnes patch has been established. As shown in No other treatments for knee OA were permitted during the treatment period: systemic and topical NSAIDs; opioid analgesics; acetaminophen; oral and intra-articular injection of corticosteroids; intra-articular knee injections ; surgical or physiotherapeutic therapies; acupuncture; and aspirin. All AEs were recorded in detail and were monitored regularly until properly resolved or the condition was stable.The sample size was determined using the primary endpoint of the change of VAS pain score. The literature showed that the effect for Cortex Daphnes patch with the same primary endpoint was 44.6 mm (SD: 33.4 mm) and it was 35.3 mm (SD: 30.4 mm) for indomethacin cataplasms at week 2 . AssuminStatistical analyses were performed using SAS version 9.4 . The full analysis set (FAS) and per-protocol (PP) analysis set were analyzed. The FAS population included all participants who were randomized and underwent the assigned treatment. Non-inferiority of the primary endpoint (change of VAS pain score of Cortex Daphnes patch vs. indomethacin cataplasm) was determined if the lower limit of the 95% CI for the difference was not less than the cutoff value of -5 mm. The changes of primary and secondary endpoints at week 2 from baseline were analyzed using an analysis of covariance (ANCOVA) model with the treatment group and the study center as factors and the baseline score as a covariate. The point estimate, the least squares (LS) means, and the two-sided 95% CI based on the ANCOVA model were provided for the difference between treatment groups. The 30% responders were defined as patients who experienced a 30% reduction of WOMAC pain score, WOMAC total score, and VAS score from baseline for each respective outcome. A p-value of <0.05 was considered statistically significant. All patients who received at least one dose of the study drug were included in the safety set (SS). Incidence of AEs, treatment-related AEs, and discontinuation rate due to AEs were compared between the two groups using the Pearson chi-square test and Fisher’s exact model.All patients were Chinese. Among 292 patients with symptomatic knee OA who were initially screened, 264 eligible patients were enrolled and constituted the FAS population. There were no statistically significant differences between the groups with respect to demographic and baseline clinical characteristics . There wIn the FAS population, the LS mean changes from baseline in the pain VAS score at week 2 was –25.4 mm in patients receiving the Cortex Daphnes patch and –23.3 mm in patients receiving indomethacin cataplasms. The treatment difference (Cortex Daphnes patch–indomethacin cataplasm) in the FAS population was 2.1 mm and the two-sided 95% CI for the treatment difference was –2.1–6.4 mm. In the PP population, the result was similar (treatment difference and two-sided 95% CI: 3.8 [–0.6 to 8.2] mm). The lower limit of the 95% CI was –5 mm, which indicates that Cortex Daphnes patch was non-inferior to indomethacin cataplasm for the treatment of Chinese patients with knee OA.In the FAS population, there were no significant differences between groups with respect to any secondary endpoint after 2-week treatment . The LS In the FAS population, no differences between groups were significant in terms of responder rates for pain VAS, WOMAC total score, and pain subscale (p > 0.05) . In the AEs are displayed in The severity for skin AEs of erythema, itching, and edema are summarized in Current international and Chinese guidelines support the use of topical NSAIDs as an early treatment option for symptomatic relief of the management of knee OA . DespiteOur results suggest that the Cortex Daphnes patch can effectively relieve the symptoms of knee OA, in line with the findings of previous clinical studies. Cui et al. demonstrated that a 2-week regimen of Cortex Daphnes patch could relieve pain, swelling, and restricted movement in patients with knee synovitis when compared with infrared radiation therapy . A randoin vivo and in vitro experiments. Pharmacological activity experiments showed that prostaglandin E2 generation was inhibited by extract of Cortex Daphnes by inhibiting the expression of cyclooxygenase-2 (Our findings show that Cortex Daphnes patch has a favorable anti-inflammatory analgesic effect. In recent years, daphnetin, coumarins, lignins, flavonoids, diterpenes, and other chemical components have been isolated and identified from Cortex Daphnes. Daphnetin, the main phytochemical component of Cortex Daphnes, has provided dramatic improvement in percutaneous absorption results genase-2 . An animgenase-2 . Daphnetgenase-2 .In recent years, more than 250 chemical constituents have been identified from the genus Daphne. The most important classes of compounds obtained from this genus include coumarins, flavonoids, lignans, terpenoids, and several other less common groups  CoumarinFortunately, those skin side effects were mostly mild in severity, were transient, and did not require intervention. Moreover, the skin reactions may be alleviated after discontinuation of the Cortex Daphnes patches. These findings suggest a rest time for skin is needed when using the Cortex Daphnes patch, and the components containing the Cortex Daphnes patch should be changed to be milder and less irritating.There are some limitations with respect to the design of this non-inferiority study. First, the completely different physical characteristics and smell between the Cortex Daphnes patch and the indomethacin cataplasm prevented double-dummy design from being applied. Nevertheless, considering that those two medicines and their topical simulators could not be used on the knee simultaneously, or even used separately on each knee, an enormous difference in efficacy might result in a substantial decline in compliance with the treatment plan. Therefore, to ensure the reliability of evaluation measurements, instead of using the double-dummy design, a staff member who dispensed the investigational medicine was trained not to discuss the intervention with participants, and the therapeutic effects and side effects were evaluated by another blinded trained staff member. Second, its long-term efficacy remains unclear due to a paucity of follow-up. Third, we did not pay attention on the average time for skin irritation after medication and relevant data need to be supplemented in the following Cortex Daphnes patch-related research.The Cortex Daphnes patch exerts favorable effects in decreasing knee pain and improving joint function for patients with knee OA, especially with mild-to-moderate knee OA, which were non-inferior to the therapeutic effects of a recognized treatment for knee OA. The clinical evidence presented here highlights the promising therapeutic efficacy of the Cortex Daphnes patch for the treatment of pain and symptoms associated with knee OA, particularly as part of a changing healthcare landscape that seeks to identify effective and safe plant medicines to treat chronic pain.