To establish a predictive model for pain response following radiotherapy using a combination of radiomic and clinical features of spinal metastasis. This retrospective study enrolled patients with painful spine metastases who received palliative radiation therapy from 2018 to 2019. Pain response was defined using the International Consensus Criteria. The clinical and radiomic features were extracted from medical records and pre-treatment CT images. Feature selection was performed and a random forests ensemble learning method was used to build a predictive model. Area under the curve (AUC) was used as a predictive performance metric. 69 patients were enrolled with 48 patients showing a response. Random forest models built on the radiomic, clinical, and ‘combined’ features achieved an AUC of 0.824, 0.702, 0.848, respectively. The sensitivity and specificity of the combined features model were 85.4% and 76.2%, at the best diagnostic decision point. We built a pain response model in patients with spinal metastases using a combination of clinical and radiomic features. To the best of our knowledge, we are the first to examine pain response using pre-treatment CT radiomic features. Our model showed the potential to predict patients who respond to radiation therapy. The rate of pain relief after radiotherapy is estimated to be 60%2, meaning 40% of patients do not get adequate pain relief after radiation therapy. It may become possible to select the patients who do not benefit from radiotherapy, if we can predict the degree of pain relief after therapy. In a report on predictive clinical models, the World Health Organization performance status (PS), numerical rating scale (NRS), and primary tumor site were important factors for predicting pain relief3. However, this model did not exhibit high performance, thus better predictive models of performance are needed for clinical use.Radiotherapy is widely used for pain relief associated with painful bone metastases and was performed in 12.5% of all radiotherapy treatments in Japan4. Furthermore, a database of clinical information can be created and machine learning techniques such as random forests (RF), an ensemble classifier which classifies data using decision trees and facilitates the validation and evaluation of the classification accuracy of a set of predictors6, can be used to improve the accuracy of diagnosis and prediction of prognosis after treatment8."Radiomics” is an image analysis method involving the extraction of multiple features from medical images. By analyzing a specified area and many radiomic features from CT, MRI, PET and other images, it is possible to identify the tumor genotype and phenotypeHerein, we sought to develop better diagnostic methods to determine pain response for patients with spinal metastases. We built a highly accurate model using radiomic and clinical features for predicting pain relief after radiotherapy for painful spinal metastases. Our models provide proof-of-concept for predictive tools for pain response and, with further refinement, will become an essential clinical tool for patients with bone metastases.This retrospective study was approved by our institutional review board , with waivers for patients’ informed consents. We confirmed that all methods were performed in accordance with the relevant guidelines and regulations. Patients with painful spine metastases who received palliative radiation therapy were enrolled at the Aichi Cancer Center from 2018 to 2019. Eligible patients met the following criteria: (1) pathological diagnosis of cancer, (2) received palliative radiotherapy  for pain) for painful spine metastasis and (3) no prior radiation to the site. Exclusion criteria were: (1) metal artifacts close to target spine, (2) palliative surgery before radiotherapy, (3) other extraspinal metastases in the radiation field and (4) no pain assessment more than 1 month after radiotherapy.The methodological workflow is described in Fig. Three models including the radiomic model (radiomic feature-based model), clinical model  and combined model  were constructed with a selected feature subset and validated using the AUC.2. Pain response was categorized as ‘pain reduction’ if there was at least a 2-point reduction in NRS at the irradiated site from the initial worst pain  or an analgesic decrease of at least 25% without an increase in NRS. Patients were categorized as responders if they met the criteria for pain response at an evaluation at least 1 month after radiotherapy. Patients who did not show pain response were categorized as non-responders.We defined complete response or partial response based on the International Consensus Criteria for pain responseNon-contrast enhanced CT scans for radiotherapy were used in this study. An Aquilion LB CT system  was used with the following conditions: tube voltage = 120 kV, tube current = automatic exposure control, matrix size = 512 × 512 pixels, field of view = 550 mm, and slice thickness = 3 mm.We made three regions of interest (ROI) including the spinal canal, the spine, the spine and surrounding tissues Fig. . The ROIIn all ROIs, regions outside the treatment field were eliminated. All manual adjustments were done by one radio-oncologist with more than 2 years of experience.9. 107 quantitative radiomic features were extracted from all three ROIs including: 18 first-order statistics, 14 Gy level difference matrices, 24 Gy level co-occurrence matrix features, 16 grey-level run length matrix features, 16 Gy level size zone matrix features, 5 neighborhood gray-tone difference matrix features, and 14 shape features.The PyRadiomics Python package (version 2.2.0) was used for the extraction of radiomic featuresThe following clinical features were derived from medical records: NRS (continuous), primary tumor sites , PS (0–1 or 2–4), gender, age (continuous), biologically effective dose (BED10) (continuous), short versions of the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) (0–11 or 12–24) and the spine instability neoplastic score (SINS) (0–6 or 7–12). To compare baseline categorical and continuous variables, chi-square and Mann–Whitney tests were used between the responder and non-responder groups.N is the total number of features which RFE was applied to). Then, N feature subsets could be obtained by selecting a different number of features. Each feature subset was fed into the RF and validated by LOOCV. Training and validation were repeated ten times and its performance could be evaluated using the score of the area under the curve (AUC). Finally, the feature subset with the highest AUC was selected as the optimal subset for the discrimination task.Features with a Pearson correlation coefficient of > 0.7 were considered dependent factors and the feature with the larger mean absolute correlation with all remaining features was eliminated. We used RF-RFE to optimize the number of features. RFE calculates the importance of the feature to determine the best subset. N features were ranked from the most to the least important  curve analysis was performed to calculate the AUC and its corresponding 95% confidence interval.Statistical analysis was performed using R version 3.5.2 . The level of confidence was kept at 95% and To better understand pain response following radiotherapy for spinal metastasis, we performed a retrospective analysis using patient clinical features and radiology-based images. 69 patients were enrolled, and their clinical features are listed in Table p = 0.599) and the radiomic model was not significantly better than the clinical model (p = 0.208), however; it was significantly greater than the clinical model (p = 0.044). To this end, we have developed a predictive model which will aid in the determination of patient outcome when treating spinal metastases with radiotherapy.Based upon the feature subset, random forests and recursive feature elimination (RF-RFE) was performed. The feature selection process is depicted in Fig. Incomplete patient response to radiotherapy for painful spinal metastases greatly hinders quality of life. Using a combination of clinical features and radiomics, we sought to establish a predictive model for patient pain response to radiotherapy treatment. Our study found that a model combining pre-treatment CT based radiomic features and clinical features showed good predictive scores for pain relief after palliative radiation in patients with painful spinal metastases compared to a clinical feature-based model.11. Other features which have been reported as affecting pain response after radiotherapy are gender, performance status, primary tumor site, neuropathic pain, Bilsky grade, prior radiation at the site of interest, and sleep disturbance14. In this study, we evaluated NRS and S-LANSS as pain indices because they are widely used, and were recorded in all patients. SINS, which we also evaluated, is an indicator of spinal instability and we referred it to when consulting with the spine surgery department or at multidisciplinary conferences. The AUC in previous studies that modeled pain response from clinical features was 0.633. All of the models created in our study yielded better AUCs than previous reports, suggesting our refined methods were more successful in generating accurate models.In our study, age, NRS, and BED10 were determined as important features using our combined model. Previous studies have reported that pain response is associated with age and NRSRadiomics is a non-invasive way to obtain high-dimensional, mineable and quantitative data from medical images such as CT scans. CT scans are routinely taken for diagnostic purposes. CT scan are also taken during and after treatment to check for changes in lesion size, shape, and characterization. Compared to blood tests and biopsies, radiomics does not require specialized equipment, making it an accessible diagnostic option. The goal of radiomics is to improve diagnosis and prediction in clinical practice.18. In contrast, radiomics is able to extract more information from the ROI, such as intensity and shape, which can be combined to create a model with high predictive and diagnostic capabilities21. There have been several studies examining bone metastases utilizing radiomics25. To the best of our knowledge, we are the first to examine pain response using pre-treatment CT radiomic features.Previous studies that did not use radiomic features have investigated medical images to assess the response of bone metastases after therapy26. Radiotherapy is an important treatment for pain relief from bone metastases, however; the inability to move for several minutes can cause pain. If the patient moves, there is a risk of injury. In the case of palliative irradiation of bone metastases, the radiation dose is low, but it is not without the potential for adverse events. Considering these aforementioned risks associated with therapy, it is important to identify patients who have a higher likelihood to respond to treatment. If the study can identify patients who are not expected to respond, it will be possible to choose alternative treatments such as higher-dose radiotherapy, early surgical intervention, switching opioid regimens or systemic therapy.Pain from bone metastases is a common symptom with many patients exhibiting debilitating painSome limitations from our study should be noted. The number of cases was small. 52 patients were excluded from our initial population owing to our exclusion criteria. The anthropogenic changes in spinal structures and metal artifacts due to surgery, which were included in the exclusion criteria, were thought to influence some radiomic features and this was expected to lead to a decrease in prediction accuracy. In addition, we excluded re-irradiated cases. The exclusion of re-irradiated cases was done to create an accurate model with a more homogeneous group of cases.Due to the limited sample size, the evaluation of our model was measured based on the training cohort, and not the test cohort. Only examining the training cohort caused overfitting in feature selection and training on RF. We avoided overfitting by using LOOCV and not using hyperparameter optimization. Second, segmentation may also need to be investigated. In the present study, we used a semi-automatic segmentation approach for the spine and surrounding structures using CT number. This allows us to reduce the differences in manual segmentation between images. In some cases, it is possible that most of the volume of the ROI may have been normal structures. It is preferable to evaluate the radiomic features of the actual bone lesion, but some patients did not have an MRI which is required to accurately delineate bone lesions. We decided to include patients who did not have an MRI in order not to reduce the number of enrolled patients and abandoned the evaluation of the ROI based on segmentation of the actual bone lesion. We also abandoned the analysis of MRI radiomic features which were used to analyze bone metastatic lesions.In the future to address the limitations of our study, we will conduct a multicenter observational study, which will expand the sample size and prepare the external validation set to test the prediction performance and generalization capacity of our model. Future studies will be needed to consider re-evaluating segmentation settings and usage of MRI images.In conclusion, we created a model combining clinical and radiomic features to predict patients who respond to radiotherapy for spinal metastases. We hope that our model, and subsequent refinements, will inform on clinical decisions for patients with bone metastases and improve their quality of life.


Bone loss leading to fragility fracture is a highly prevalent late effect in hematopoietic stem-cell transplant patients, who are affected 8–9 times more than the general population, particularly for vertebral compression fractures. Spinal interventions such as lumbar epidural steroid injections and vertebral augmentation may be helpful for providing pain relief and improved function, quality of life and return to ambulation. However, interventional procedures should be approached with caution in these patients. Our study found that there is a paucity of scientific studies addressing the risks of spinal injections in these patients and there is no absolute recommendation specific to spinal injections in patients receiving immunosuppressive agents or who have a history of solid organ or hematopoietic stem cell transplant. It is imperative to consider proper timing of the intervention to minimize risks while optimizing the benefits of the intervention combined with a well-defined post-transplant rehabilitation plan. Moreover, the decision to proceed with spinal interventions should be done case by case and with caution. Therefore, this article reports the case of a multidisciplinary treatment for a vertebral compression fracture in a patient with a hematopoietic stem-cell transplant, in particular discussing safety appropriateness in interventional pain management and rehabilitation considerations for this condition in this patient population. Bone loss leading to fragility fracture is a highly prevalent late effect in hematopoietic stem-cell transplant (HSCT) patients, who are 8–9 times more likely than the general population to be affected, primarily within 6 to 12 months post-transplant ,4. VerteHSCT can be very stressful on the body’s physiology and can leave patients with significant debility; therefore, supportive care measurements to improve QoL and overall survival are key components in post-transplant care. Physical rehabilitation aims to improve post-transplant musculoskeletal sequelae, such as pain, fatigue, and inflammation ,8,9,10. A spinal injection, such as a lumbar epidural steroid injection (ESI), can provide short-term relief from back pain and an improvement in function. However, an ESI may also exacerbate bone mineral density (BMD) loss . VertebrTherefore, this case report discusses the multidisciplinary treatment of a vertebral fracture in an HSCT patient, particularly emphasizing safety appropriateness in interventional pain management and rehabilitation treatment considerations.A case report.A 58-year-old female with a medical history of acute myeloid leukemia post-HSCT, pancytopenia, steroid-induced myopathy, GVHD, chronic immunosuppression, and treatment with glucocorticosteroids, was transferred to the inpatient rehabilitation unit on day 90 post-transplant. Her hospital course was complicated by recurrent Gram negative and enterobacter cloacae complex bacteremia and atypical pneumonia. She made significant progress while in rehabilitation, until two-weeks into her course, when she developed acute onset low back pain (LBP) without radicular symptoms. Symptoms started after taking a shower during a supervised occupational therapy session. Specifically, no fall, trauma, or accident was reported by the patient or staff. The day after reaching forward in the shower, she reported a gradual onset of back pain localized in the thoracolumbar region and lumbar spine. In addition to her previous Tylenol and opioid analgesic therapy, she was prescribed ice, heat, cyclobenzaprine and a lidocaine patch. A physical examination revealed a limited spinal range of motion, bilateral paravertebral muscle tenderness to palpation without focal spinous process tenderness, no erythema, and no ecchymosis. There were no neurological deficits: the seated straight-leg raise test was negative, manual motor testing did not reveal any focal weakness, deep tendon reflexes were symmetrically equal, and the sensation was grossly intact. The pain persisted for a few days, without significant response to increased dosages of analgesic and adjunctive pain relief medications as one would expect with mechanical musculoskeletal back pain. Furthermore, the patient had a slight decline in function, and had more difficulty participating in therapies, and performing activities with the physical and occupational therapists, which prompted further evaluation with advanced diagnostic imaging. A lumbar spine magnetic resonance (MRI) scan was performed, which revealed superior endplate compression of L1, L2, and L4 vertebral bodies, with prominent bone marrow edema at the L4 level, which was consistent with an acute L4 VF, and old L1 and L2 VFs . There wMultidisciplinary rehabilitation in HSCT can be divided into pre-rehabilitation, post-rehabilitation, and survivorship. In particular, pre-transplant rehabilitation is important because it facilitates the maintenance of a minimum level of function focusing on cardiopulmonary function and improving muscle conditioning. This level of function can be assessed in pre-transplant patients using the baseline functional assessment tests: the 6 min walk, 50 foot fast walk, timed repeated sit-to-stand, forward reach, and grip/pinch strength ,8. This Post-transplant inpatient rehabilitation emphasizes reducing the symptomatic burden of the patient, as well as pain management and minimizing the risks of secondary complications such as pneumonia, pressure injury, and bowel/bladder dysfunction. Inpatient rehabilitation, particularly supervised exercise components, has also been shown to reduce fatigue in cancer survivors ,8,9. AddIt is important to note that glucocorticosteroids are often used in post-transplant treatment, which is known to increase the risk of bone loss in a dose-dependent manner ,8,20. ThIn the ambulatory patient in the inpatient rehabilitation phase, at least 30 min of daily weight-bearing exercises is recommended to help maintain proximal muscle strength and function and to prevent steroid-induced myopathy. It also serves to decrease the risk of falls and secondary complications of immobility, such as pneumonia and thrombus venous embolism. Thoracolumbar bracing may be an option for reducing pain and preventing excessive forward flexion, particularly if there is an acute VF. Multi-modal exercise and nutritional programs after a fragility fracture of the spine have been shown to improve function and QoL and have been shown to offer improved morbidity and mortality ,9,10,25.Interventional spinal procedures should be approached with caution in HSCT and immunocompromised patients  because In our case report, the decision to withhold VA and proceed with a single lumbar transforaminal epidural steroid (TFESI) injection bilaterally at the L4–5 level was made with several critical clinical considerations in mind. The patient was severely thrombocytopenic  two days prior to the procedure. Thrombocytopenia is a significant risk with potentially catastrophic effects when located nearby the spinal cord; therefore, we decided to minimize this risk by performing a low-risk intervention, in contrast to a significantly higher-risk intervention, such as vertebral augmentation. Furthermore, the goal of the intervention was to reduce pain and facilitate an early return to mobilization and rehabilitation therapies; therefore, the patient and the medical team opted for the TFESI, in contrast to the VA, which is a longer procedure entailing more tissue and instrument manipulation, more pain, and with the perceived increased risk of adverse events and complications. Caution should be taken when performing spinal procedures with a platelet count less than 80,000, including greater attention while performing the intervention and monitoring for catastrophic complications, such as epidural hematoma and nerve paralysis. Post-procedure vital signs and repetitive neurological examination, as well as written information to the patient on monitoring for complications should be given. Spinal procedures are usually contra-indicated when the platelet count is less than 50,000 . In addiOur review did not find any studies published comparing the use of lumbar TFESI versus VA for the management of VF. This is not a surprise as the use of VA has been widely documented as both safe and effective in the management of VF in the general population, while the use of lumbar TFESIs has been well-documented in providing relief in patients suffering from persistent back pain and radiculopathy ,19,34. AThere is a well-documented increased risk of bone loss and VF fracture in patients post-HSCT. Multimodal exercise and nutritional programs have been shown to improve function, QoL and reduce morbidity and mortality from VF fractures. Interventional pain procedures for these patients should be approached with caution, as commonly performed procedures in the general public, such as VA, may carry significant risks in this population due to an immunocompromised state often combined with pancytopenia. Appropriate platelet level and function must be accessed and confirmed since impairment may lead to potentially catastrophic consequences, such as spinal hematoma. Infection risks associated with a high-risk procedure, such as VA, could be significantly more dangerous for an immunocompromised patient; as such, other minimally invasive options may be a safer alternative for providing short-term pain relief and a faster return to mobilization and function, but there is limited data discussing safety considerations of interventional pain management options in this population. While there are no clear recommendations, it is essential to consider proper intervention timing to minimize risks while optimizing the intervention benefits. The decision to proceed with treatment should be made with caution on a case-by-case basis. In this case, we decided to proceed with a lumbar ESI to facilitate return to early mobilization with improved pain control, and the patient was readmitted the same day to the inpatient rehabilitation unit and continued her rehabilitation course uneventfully until being discharged home with improved mobility and function, similar to baseline before the fragility fracture.


Opioid-induced hyperalgesia (OIH) is characterized by a heightened sensitivity to pain that occurs in patients following opioid use. Prescription of opioids is currently the standard form of pain management for both neuropathic and nociceptive pain, due to the relief that patients typically report following their use. Opioids, which aim to provide analgesic effects, can paradoxically cause increasing degrees of pain among the users. The increased nociception can be either due to the underlying pain for which the opioid was initially prescribed, or other unrelated pain. As a result, those who are initially prescribed opioids for chronic pain relief may instead be left with no overall relief, and experience additional algesia. While OIH can be treated through the reduction of opioid use, antagonistic treatment can also be utilized. In an attempt to reduce OIH in patients, low doses of the opioid antagonist naltrexone can be given concurrently. This review will analyze the current role and effectiveness of the use of naltrexone in managing OIH in opioid users as described in clinical and non-clinical studies. Additionally, it seeks to characterize the underlying mechanisms that enable opioid antagonist naltrexone to reduce OIH while still allowing opioids to act as an analgesic. The authors find that OIH is a prevalent condition, and in order to effectively combat it, clinicians and patients can benefit from an extended study on how naltrexone can be utilized as a treatment alongside opioids prescribed for pain management. With over 153 million written prescriptions a year, opioids are the predominant treatment for chronic pain and postoperative pain in the United States. As opioids are considered the most effective analgesics, they are often used for moderate to severe nociceptive and neuropathic pain that is not cured by weaker medications .Currently, there is no definitive treatment for patients experiencing OIH; however, there have been numerous trials to attempt to understand the effect of the concurrent use of opioid antagonists to prevent or treat OIH. One treatment that has shown significant efficacy in trials to treat OIH is the use of naltrexone, an opioid antagonist typically used to treat substance abuse. While naltrexone was not originally designed to treat OIH, it has been shown to improve symptoms in low doses through its mechanism as a pure opioid receptor antagonist -2. HowevOIH is characterized as a paradoxical phenomenon whereby treatment of both acute and chronic pain with opioids results in increased nociceptive sensitivity. As such, patients will experience heightened levels of pain to certain stimuli from even a single morphine administration . Althougi/o to the hyperalgesic excitatory Gs. The data referenced in Table i or Go proteins are recruited to the G-protein-coupled receptors (GPCRs) and activated. Subsequent signaling results in diminished levels of cyclic adenosine monophosphate and hyperpolarization due to heightened potassium efflux and reduced calcium influx, leading to reduced pain transmission [i to excitatory Gs proteins, further amplifying pain propagation and the development of OIH. In fact, a controlled study analyzing nociceptive neurons in mice demonstrated that morphine and similar opioids can elicit MOR G-protein-mediated hyperalgesic effects at doses 1,000-fold less than the dose necessary to elicit an analgesic effect, as measured by tail-flick assay [s regulatory protein by intrathecal injection of antisense oligonucleotides in mice and similarly observed reductions in low-dose morphine-induced hyperalgesia [i/o to Gs transition along with reductions in analgesic tolerance, withdrawal symptoms, and dependence induced by opioid usage [Recent research has demonstrated that in the presence of abundant exogenous opioids, there occurs a shift in (MOR)-G-protein coupling from the default inhibitory subtype Gsmission . Currentck assay -8. Theseid usage . In addis-coupled opioid receptors, no side effects or adverse events are likely to occur with co-treatment of opioid agonists [In addition to mitigating unwanted changes or internalization of the MOR and other similar opioid receptors, several studies have reported significant increases in the analgesic potency of opioids when co-treated or pre-treated with ultra-low-dose 10 ng/kg) naltrexone  ng/kg na. Moderatagonists .Despite all the progress that has been made in the efforts to understand OIH so far, further research is still required in order to develop a more permanent treatment for those who suffer from this condition and are far beyond the threshold for naltrexone co-treatment. Perhaps other medications that break down the production of beta-lipoproteins, such as the metal-chelator ethylenediaminetetraacetic acid (EDTA), could be used in stabilizing and analyzing nociceptive and μ-opioid receptors for more novel treatment options . AdditioDue to the exacerbation of the opioid epidemic, it is becoming increasingly crucial to develop preventative measures around opioid abuse and addiction at a healthcare level. It is necessary for healthcare providers to reiterate the detrimental side effects of opioid use, including tolerance and OIH, which counteract opioid analgesia and drive dose escalation . As suchBased on the studies mentioned above in this review, it is clear that naltrexone, naloxone, and other related opioid antagonists show great promise as a treatment for OIH due to their properties as selective substrates of the MORs when combined in low doses with opioid prescriptions. This is especially important due to the scope and enormity of the ongoing opioid epidemic in the United States. The review shows the potential of naltrexone, when administered in doses as low as 0.3 mg twice a day, as a co-treatment with opioids, in preventing OIH and reducing the dosage of opioids overall. Additionally, naltrexone co-treatment reduces the necessary dosage for analgesia when prescribing opioids, thereby helping to mitigate the risks of over-prescription and abuse. Future studies should be conducted to further understand the effect of naltrexone as a treatment for OIH when taking prescription opioids. Future studies should also aim to gain a deeper understanding of the mechanisms by which OIH arises in patients. Practitioners should give more attention to naltrexone and other opioid antagonists as a potentially viable treatment for OIH.


Emergency Centres (ECs) have a prominent trauma burden requiring effective pain management. This study aimed to review analgesia-prescribing habits in minor trauma, reviewing the patient demographics and diagnoses, analgesia-prescribing habits of health care professionals (HCPs) managing these cases, and differences in prescribing noted by patients’ age group, gender and triage code.A prospective, cross-sectional, descriptive study was conducted in a regional EC in KwaZulu-Natal. HCPs managing minor trauma patients completed a closed-ended questionnaire which indicated the patients’ demographics, diagnosis and analgesia prescribed.The study comprised of 314 cases of which the demographic most represented were male patients aged between 20–30 years with soft tissue injuries. Simple analgesics and weak opioids  accounted for 87.9% of prescriptions. Referral clinics prescribed less analgesics than that provided in the EC. There were mostly no significant differences in prescription habits by patients’ age group, gender and triage code.Presenting complaints in our study were varied and likely to result in mild to moderate pain. Only a minority of patients received analgesics at initial contact. Standardised protocols providing treatment guidance for nurse-initiated pain management at initial contact is thus important. There were no significant differences in analgesics prescribed for adults and the elderly, which is worrisome given the potential negative side effects of analgesics in the elderly. Similar concerns in our paediatric population were not noted. Ensuring adequate analgesia with cognisance for safety at the extremes of age is of paramount importance. Trauma-related injuries contribute around 25% of the workload in most state hospital ECs in KZN.3 Pain, initiated by inflammatory mediators, accompanies most tissue injury. Hence, whilst not all trauma is necessarily painful, given that trauma has the potential to cause pain, effective pain management is an essential skill for any healthcare professional (HCP) working in an EC.Emergency Centres (ECs) in African regions such as KwaZulu-Natal (KZN) face many challenges, including the high burden of trauma cases that are seen on a daily basis. The World Health Organisation (WHO) estimates that the global mortality rate from injuries is around 5 million per annum.4 Initial analgesia prescribing habits amongst HCPs working in ECs have been found to be notoriously poor for pain management, potentially because of under assessing patients’ pain.5 Prescribing habits can be substantially improved with pain management seminars and nurse-driven triage protocols for pain assessment and management.8 The concept of oligo-analgesia (single drug administration in the treatment of pain) is a concern in ECs as this may result in inadequate analgesia and hence, protocols for stepwise increments of pain management should be implemented.9 A standardised pain management protocol can greatly improve a patient’s hospital experience and overall satisfaction.10Analgesia-prescribing habits vary amongst HCPs in ECs around the world.The aim of this study was to review analgesia prescribing habits for minor trauma in the EC. To achieve this, the study reviewed the demographics of patients presenting with minor trauma; assessed the types of minor trauma presentations to the EC; assessed what analgesics were prescribed when HCPs faced minor trauma cases in a state hospital’s EC; described the contact point within the healthcare system when the analgesia was prescribed as well as the route of administration, and described any differences in types of analgesics or dosages noted by patients’ age group, gender and triage code.13 The SATS uses physiological parameters, symptoms and certain modifiers, to categorise patients into triage categories: green, yellow, orange, red and blue. Patients categorised as green or yellow codes were considered to be minor trauma patients for this study.A prospective, cross-sectional, descriptive study was conducted in the EC of Edendale Hospital, a 900-bed regional state hospital in KZN which serves a mix of rural and urban patients. The study was conducted over a period of 6 months from 01 May 2019 to 31 October 2019. It included all minor trauma patients – coded green or yellow, according to the South African Triage Scale (SATS).The following HCPs were based in the EC at the study site during the study period: four emergency medicine specialists (consultants), five emergency medicine registrars, seventeen medical officers, three clinical associates and five medical students. The medical students’ prescriptions were subsequently supervised and co-signed by a doctor. Thus, the EC is staffed by a varied range of HCPs with differing levels of expertise and experience. Written consent was completed by each HCP prior to participation. All HCPs working in the EC were asked to complete data collection sheets voluntarily and anonymously in the form of a survey with a closed-ended questionnaire for patients that they treated during their shift that had presented with minor trauma, over the study period. All ranks of HCPs working in the department were represented in the data collection sheets that were completed. It was anticipated that not all HCPs would complete data collection sheets, and data collection sheets would not be completed for all patients seen. Thus, a time frame of 6 months was chosen in order to collect data collection sheets from a wide variety of HCPs for a wide range of presenting pathologies in order to gain a representative, albeit convenience sample.Demographic data collected included the patients’ age, gender, diagnosis and triage code. A list of commonly prescribed analgesics was listed in the survey with a tick box of both which analgesic the patient received and when the patient received the medication from the registered or professional nurse at the referring clinic (if applicable), on arrival at the EC as part of a triage-initiated analgesia programme (on presentation), during treatment in the EC, or dispensed on discharge. Space was available to add other medications given that were not listed on the data collection tool. The study neither addressed non-pharmacological strategies for pain management, nor did it address pain management by means of nerve blocks.For each data collection sheet completed, space was provided for the HCP in the EC to document analgesia prescribed and administered at a clinic level. Referral letters from surrounding clinics were assessed by the attending HCP after completing the data collection sheet to determine if analgesia was administered by the HCP  working in the referral clinics. Thus, analgesia given at that point in the continuum of care was captured.Data collection sheets were placed in a sealed box in the EC upon completion by the HCPs. These data collection sheets were collected periodically, and the data collected was entered by the author onto a password protected Microsoft Excel  document. The data was cross-checked by the corresponding author by single person double entry.The information collected was analysed using Stata  to create descriptive statistics such as frequencies and percentages to summarise patient demographics, triage codes and to classify types of minor trauma presentations. The patients’ age distribution did not follow a normal distribution; it was analysed using a visual evidence histogram and the Shapiro-Wilk test, and therefore the median (with interquartile range) was reported to analyse the distribution.Frequency tables were constructed to summarise and analyse medication prescribed by referral clinics, to analyse which medications were prescribed at each point within the continuum of care and to analyse medications prescribed, both by type of analgesia and dosages for age groups of patients , patients’ gender and SATS code.The Pearson chi-squared test was used to analyse if significance existed between the type of medication prescribed by age group, gender and SATS code. The Kruskal Wallis test was used to assess if a significant difference existed between dosages prescribed between age groups. The Mann-Whitney U test was used to describe if any significant differences existed between dosages prescribed and patients’ gender and SATS code.Ethical approval was granted by the University of KwaZulu-Natal Biostatistics Research Ethics Committee (BREC reference: BE664/18) and KwaZulu-Natal Department of Health (KZ_201902_028).The study focused on the analgesics prescribed in patients presenting with minor trauma within the EC of a regional state hospital in KZN. All HCPs working in the EC at the study site were invited to complete data collection sheets for all patients attended to with minor trauma over the study period. A total of 316 data collection sheets were collected over the 6-month study period of which 314 were included in our study. Completed data collection sheets were represented by all ranks of HCPs .n = 192; 61.1%). The age distribution of patients presenting with minor trauma-related injuries was mostly patients 40-years old or younger  making up close to 80% of the study population . Their median age was 26.5 years (interquartile range of 14–37). The minimum and maximum ages were 1 and 93, respectively.Most patients included in the study were male patients . However in our study, the data collection sheets reflected that a large portion of fractures were triaged green  were triaged green and 64 (20.4%) were triaged yellow. Eighty-five (27.1%) were children and 229 (72.9%) were adults. According to SATSed green . This man = 121; 38.5%). The term soft tissue injury is used to describe injuries to the soft tissues in the body, rather than the harder bones: for example bruises, sprains and muscle contusions.14The most diagnosed minor trauma-related injury  was softAnalgesia was prescribed by the HCPs  working in referral clinics prior to arrival in the EC in 45 cases, making up a total of 59 medications prescribed  out of tThe most prescribed analgesics were paracetamol , ibuprofen  and tramadol  and this was representative throughout all the contact points within the continuum of care within the EC . ParacetLignocaine was prescribed during the treatment stage in the continuum of care only when suturing or wound closure was undertaken. Ketamine was prescribed as an intramuscular injection a total of nine times during the treatment stage in the continuum of care – all to paediatric patients – for procedural sedation for either wound closure or burns management. Pethidine, naproxen and indomethacin were prescribed on discharge, each for a single patient only, all for soft tissue injuries. Ethyl chloride spray was prescribed and used once during treatment for management of a soft tissue injury to a finger, with delayed presentation resulting in a paronychia.There were no statistically significant differences when comparing which analgesic medications were prescribed by age group . Of note, non-steroidal anti-inflammatory drugs (NSAIDs) were prescribed with equal frequency in the elderly as in other age groups. Sixty-five per cent of elderly patients received ibuprofen orally, 10% of elderly patients received diclofenac IMI and 5% of elderly patients received naproxen orally. There were no statistically significant differences between dosages prescribed for the adult age group and the elderly across all medications, inclusive of potent opioid analgesics.There were no statistically significant differences between either type of analgesic medication prescribed or the dosage of analgesic medication prescribed by gender.p = 0.00), as was ketamine IMI (8% vs. 2% p = 0.02). There were no statistically significant differences for any other type of analgesic medications or dosages by triage code.Morphine IVI was prescribed more commonly for patients triaged yellow versus green by SATS triage code , and even fewer were treated with a strong opioid such as morphine and fentanyl (4.2% and 0.3% respectively). More potent analgesics such as morphine IVI tended to be prescribed for patients with a higher triage code which could be considered appropriate, as these patients are likely to have more severe injuries and thus potentially more severe pain. However, to regard this as appropriate with certainty, regular assessment of the patients’ response to pain would be necessary. The WHO describes a stepwise approach to pain management.28 Ketamine IMI was administered on four occasions as procedural sedation, all to paediatric patients in situations where lignocaine was not used.Underreporting could have occurred within the study for certain analgesics. Forty-eight patients had a diagnosis of laceration, but subcutaneous lignocaine use was only documented on 41 occasions. Alternatively, it is possible that lignocaine may not have been used in the management/suturing of lacerations as they were superficial and did not require closure or because of the practice of procedural sedation, which is growing in popularity within ECs in Africa.29 it is imperative that adequate analgesia is provided for patients at the clinic level. Our study assessed what analgesics were prescribed at the clinic level by registered and staff nurses. Of the 45 patients that did receive analgesia at the clinic level an average prescription rate of 1.3 medications per patient was prescribed. Without an assessment of patients’ satisfaction with regard to treatment of pain, it is impossible to ascertain whether this relative oligo-analgesia resulted in inadequate pain relief, or whether analgesia requirements were adequately met. It is important that there is a focus on strengthening the district platform within South Africa with regards to training on assessment of pain and early provision of adequate analgesia, as this will inevitably result in better patient management at the clinic level.8Given that there has been an increase in the volume of patients making use of primary healthcare facilities within the public sector in South Africa, particularly amongst those living in rural areas,13 The SATS provides guidance on the time frame within which patients should be seen by an attending doctor in ECs by triage code. It is recommended that patients triaged ‘yellow’ be seen within 1 h and patient’s triaged ‘green’ be seen within 4 h. Despite these recommendations it is our anecdotal experience that because of patient overcrowding, which is a frequent problem in our ECs, patients may wait in excess of these time frames to be seen.31 Thus, there has been much discussion in the literature of the advantages of nurse-driven analgesia at triage.8 Our study has demonstrated that of a total of 976 individual medications prescribed for patients with minor trauma, only 145 (14.9%) were prescribed at presentation (at triage). Given that the next point in the continuum of care that the patient may be assessed may be several hours post triage, it is possible that analgesia requirements are not being met timeously. The introduction and/or augmentation of nurse-initiated triage of pain and protocol-driven management of pain upon presentation of the patient to the EC could potentially improve both the patient’s experience within the EC and wound healing itself. Inflammatory mediators released in response to tissue injury typically contribute to healing through their vasodilatory and pro-angiogenic stimulation of healing. However, pain that is poorly controlled, especially chronic pain, may be associated with an imbalance of mediators that result in protracted inflammation and delayed wound healing with neuropathic pain.32 The majority of analgesics were prescribed by HCPs during treatment or upon discharge.On arrival at the EC, patients are triaged according to the SATS.34 There are a number of challenges that affect the HCPs assessment of pain in children, including language barriers  and cultural differences.33 Again, a previous study comparing adults and paediatric patients noted that analgesics were prescribed less commonly in paediatric patients and at lower relative dosages.34 It is thought that this may be because of HCPs being less comfortable both, in assessing pain and providing pain relief – with particular concern about the safety aspects of prescribing certain analgesics such as narcotic analgesics.34 It is possible that this concern for inadequate pain management in paediatric patients is not seen in our study because of the Hawthorne effect,35 in that HCPs were aware that their prescribing habits were being monitored and therefore they were more vigilant in terms of what analgesia they prescribed. It may also be possible that as a result of previous educational drives, paediatric analgesic needs are appropriately assessed and attended to.It is interesting to note that there is no statistically significant difference in the types of analgesics prescribed across different age groups  in our study. Previous studies have suggested that pain management in paediatric patients is not prioritised by HCPs, mainly because of a lack of both knowledge and expertise amongst HCPs.36 Typically, this is as HCPs are cautious of treating pain in elderly patients as the elderly often do not tolerate common pain treatment advocated for adults well , are sensitive to drug-drug interactions and have multiple co-morbidities which may impact on the pharmacology of analgesic medications prescribed.36 It has been noted that polypharmacy and the indiscriminate use of NSAIDs is a major problem in the elderly.36 It is of possible concern that the elderly patients in our study received NSAIDs and opioids at similar rates and dosages as the adult population group. Potentially this could have resulted in unwanted side effects – an aspect that was not specifically addressed in our study – and warrants further investigation. A limitation of our study may be that because of both the low number of elderly patients represented in our study sample as well as the low number of opioids prescribed, especially potent opioids, this may have diluted the possible statistical effect.In our study there were also no statistically significant differences in both the types of analgesics prescribed and the dosages of these analgesics in the elderly patient population. Previous studies have indicated that elderly patients are at high risk of having their pain inadequately managed.37 It is thought that female patients reported more pain than their male counterparts and are perceived to experience more pain by the attending HCP. The reasoning for this was postulated to be social – it is more socially acceptable for female patients to express pain and, when pain is expressed by a patient, it is more likely that HCPs will respond to a female patient.38 However, more recent studies seem to have contradicted this, showing no particular bias based on patients’ gender.39 Certainly, in our study, there was no statistically-significant difference in either the types of analgesics prescribed, or the dosages of these analgesics by gender.Previous studies have shown conflicting results in terms of prescriptions of analgesics by gender. Earlier studies did appear to suggest that female patients were prescribed more analgesics and more potent analgesics than male patients.35 may have made HCPs more aware of the need to prescribe adequate analgesia during the study. Data may have been affected if patients were transferred out of the EC for ongoing care elsewhere, in which case analgesics prescribed on discharge would not have been captured in our data.There are several limitations to our study. Referral letters from clinics were used to assess what analgesics were prescribed at a clinic level. It is possible that analgesia may have been prescribed and administered at the clinic level, but not documented in the referral letter and thus analgesia prescribed at this point in the continuum of care would not have been correctly captured in our data collection. Although all HCPs working in the EC were invited to participate in the study and complete data collection sheets, it is possible that not all HCPs participated. Furthermore, data collection sheets were not completed for every case of minor trauma attended to. This convenience sampling model therefore has the potential to introduce bias into the study. In order to mitigate this, a longer sampling time frame of 6 months was chosen in an attempt to ensure that a wide range of minor trauma cases were represented and all ranks of HCPs were represented in the data collection. Consideration of the possible negative effects of the use of analgesics, such as side effects and cost analysis, were not included in this study. Furthermore, several confounding factors have been identified in this study. There is limited availability and accessibility of analgesics in both the state regional hospital’s EC and the surrounding referral clinics. Allergies of patients to medications were not accounted for. The Hawthorne effect40 Pain control is of paramount importance in managing both the trauma patients’ experiences through an EC and, by managing pain early and appropriately, the risk of chronic pain with an imbalance of inflammatory mediators potentially resulting in delayed wound healing is mitigated.Patients presenting with minor trauma in our study were predominantly male patients aged between 20 and 30 years of age. The minor trauma prompting presentation for patients in our study was varies, with soft tissue injuries predominating. Given that tissue injury results in release of inflammatory mediators that often result in pain, the minor trauma presentations noted in our study are likely to have resulted in mild to moderate pain. Trauma-related pain has been shown to be best managed timeously and in a multimodal fashion.Only a small number of patients in our study received analgesia prescribed by an HCP at clinic level. The analgesia prescribed tended to be predominantly simple analgesia such as paracetamol and ibuprofen. There is a role for nurse-initiated assessment and management of pain at the clinic level. Oligo-analgesia (which has been demonstrated in our study at the clinic level) may be inappropriate unless the patients present with mild pain that is well controlled with oligo-analgesia.Analgesics prescribed in the EC tended to be simple analgesics and less potent opioid analgesics, which may suggest a stepwise approach to analgesia as suggested by the WHO. It is noted that only a minority of patients received analgesia at triage and thus again, there is a role for nurse-initiated assessment and management of pain on presentation to the hospitals’ ECs (at triage).Our study has demonstrated that analgesia prescribed at extremes of age (paediatric and elderly patients) should always be given special consideration. This is to ensure that both, adequate analgesia for the patient is prescribed timeously and that the safety aspects at these extremes of age are well thought-out.It is a major limitation of the study that patients’ experience of pain was not assessed and that likewise, response to analgesia was not assessed.Further research taking into account patients’ assessment of pain and perceived effect of analgesia could be undertaken and could incorporate other ECs within Southern Africa to compare with the findings suggested in this study.


Materials and Method. In this clinical trial, thirty-four adults with painful primary knee osteoarthritis for at least three months were randomized to two groups: ozone plus hypertonic saline 5% and hypertonic saline 5% alone. Prolotherapy and thrice follow-up with two-week intervals were done. The outcome measures included Oxford Knee Scale (OKS), Western Ontario McMaster University Osteoarthritis Index (WOMAC), and Visual Analog Scale (VAS), which were obtained from the patients before the injection and after the 2nd and 4th weeks after the start of the study.  Knee osteoarthritis is a common disease that is associated with chronic pain and disability in patients. Prolotherapy is a complementary therapeutic approach for improving pain and function in patients with osteoarthritis. We aimed to compare the effect of hypertonic saline with ozone plus hypertonic saline in improving the symptoms of osteoarthritis in the patients. p > 0.05). The results showed that VAS and OKS values decreased over time (p < 0.001) in each group, but there was no significant difference in the reduction of those between the two treatment groups . Both interventions improved the mean values of WOMAC pain, WOMAC stiffness, WOMAC act, and WOMAC total. However, there was no significant difference in WOMAC pain reduction rate (p = 0.465), WOMAC stiffness rate (p = 0.656), WOMAC act rate (p = 0.376), and WOMAC total rate between the two methods (p = 0.528).  The mean age of the participants was 60.12 ± 7.54 years. There were no statistically significant differences between demographic characteristics before the injection between the two groups ( The results showed that intra-articular prolozone therapy and hypertonic saline injection can lead to improvement of pain and function in patients with knee osteoarthritis at the same status without any significant difference. Osteoarthritis, the most common form of arthritis, is the leading cause of musculoskeletal pain and disability worldwide . OsteoarIn industrialized societies, OA is the leading cause of physical disability, increases in healthcare usage, and impaired quality of life . The socConservative treatment usually includes lifestyle modification, strengthening exercises and physical therapy, simple analgesics , topical treatments , 8, diffBased on the multifactorial etiology of osteoarthritis and the pressing need to find new therapeutic options, recent evidence suggests that prolotherapy has a role in the routine care of osteoarthritis , 14. SevProlotherapy  is an injection-based therapy for chronic musculoskeletal pain conditions including osteoarthritis and overuse tendinopathy . It has 2–O3) is an allotropic form of oxygen which has anti-inflammatory, analgesic, trophic, and immunomodulatory properties [Ozone , trauma, any intra-articular injection in the past 3 months, or prolotherapy in the past year; lower extremities deformity, any kind of disease disturbing the symptoms of knee pain such as active lumbar radiculopathy and neuropathy; and diabetes or rheumatic diseases such as rheumatoid arthritis, lupus, Ritter's disease, gout, and Brucella were excluded from our study. Moreover, during the study period, if patients had severe allergic reaction to the specified drug or had inability to cooperate in filling out forms (cognitive impairments or language problems), they were excluded.Patients who had evidence of 3In order to deal with possible side effects, the research team offers a solution for patients. In order to achieve this goal, in case of emergency, it is possible for the patient to go to the clinic in person. It also explains how people access the doctor and the research team by providing a landline number and cellphone to the patient.The sample size was determined by considering a significance level of 0.5, power of 0.80, and probable dropout rate of 20%. The sample size was approximated to be 21 patients in each group . We usedThe patients in group A received 4 ml saline 5% + 4 ml lidocaine 2% + 7 ml ozone at a concentration of 20 micrograms per liter in separate syringes, with intra-articular injection. The treatment in group B consisted of intra-articular injection of 4 ml saline 5% + 4 ml lidocaine 2%. Both groups were educated and recommended to follow the correct lifestyle and practice the proper exercises to reduce the knee pain, as explained in the clinic. For each of the two groups, three times of injection were performed at 2 weeks' interval. The patient was placed in a supine position, with knee flexion measuring 10 to 15°, and the landmark of injection area on the lateral side of knee was specified. Then, injection was done using needle G22 after aspiration and ensuring correct needle placement in the joint performed.Both groups completed the standard questionnaire including Western Ontario and McMaster Universities Arthritis Index (WOMAC) , Oxford Pain severity was measured by a ten-point pain Visual Analog Scale (VAS).This questionnaire is a measure of performance that examines three categories of functional characteristics including pain (5 questions) and physical function (17 questions). Each question is rated as none (0), mild (1), moderate (2), severe (3), or very severe (4). If the patient scores less in this questionnaire, it means that she/he is in a better condition.The OKS provides a single summed score, which reflects the severity of problems that the respondent has with his/her knee. The questionnaire consists of 12 questions, each rated as none (4), mild (3), moderate (2), severe (1), or very severe (0). If the patient scores higher in this questionnaire, it means that she/he is in a better condition.t-test, repeated measures analysis of variance, and chi-square), using SPSS version 19 software.The results of the present study were analyzed by descriptive (mean and standard deviation) and analytical tests ; participation in the study was voluntary and the patients were free to leave the study at any time. Methods and design were not changed after we commenced the trial. If any complication occurred during the study, the researcher followed up and treated the patients completely. We tried to prevent any problem for the patients; we recommended exercise and lifestyle modification and prescribed acetaminophen if there was severe pain.The study method was approved by the Medial Ethics Committee of Shiraz University of Medical Sciences (SUMS) with the reference number “15497.” The aim of the study was to explain orally to all participants before they participated in the study. Also, the researcher obtained written informed consent. The enrollment of the patients initiated. The study protocol was registered as a clinical trial under registration ID: p > 0.05) and evaluation of VAS, OKS, and WOMAC  questionnaires before injection  and 19 patients in the hypertonic saline group . The mean age of the participants was 60.12 ± 7.54 years. There was no statistically significant difference between the saline + ozone and saline groups considering demographic data (njection .p < 0.001) in each group independently, but comparison of the two groups showed no significant difference (p = = 0.57).According to p = 0.42). This means that the pattern of OKS changes over time does not differ significantly between the two groups.Indeed, the results showed that there was not any significant difference in the increase in the OKS value between the two intervention groups (p < 0.001). In the hypertonic saline + ozone and hypertonic saline groups, from the beginning until two weeks after the injection, WOMAC pain values increased slightly; then, it decreased from two weeks to four weeks after the intervention. However, in general, there was not any significant difference in WOMAC pain reduction between the two treatment methods (p = 0.46). Also, the test results showed that the effect of time was significant and changed the average WOMAC stiffness values (p < 0.001). There was not any significant difference in WOMAC stiffness reduction between the two treatment methods (p = 0.65).As demonstrated in p < 0.001) in each group. There was not any significant difference in WOMAC function reduction between the two intervention methods (p = 0.37). In the last three subscales, the results showed that the effect of time was significant and changed the average WOMAC total values (p < 0.001), but finally there was not any significant difference in WOMAC total reduction between the two intervention methods (p = 0.52).About the results of the WOMAC function test revealed that the effect of time was also significant and changed the average WOMAC function values (Osteoarthritis (OA) has a marked impact on the patients' quality of life and comorbid conditions as well as a dramatic economic cost around the world . TherefoIntra-articular ozone-oxygen injections, particularly for the knee and shoulder joints, have shown themselves to be effective and relevant in acute and chronic painful diseases of the joints , 22. Howμg/mL was injected into the affected knee joint of patients in the ozone group and HA (20 mg/2 mL solution) could be effectively used for improving the function and reducing pain in selected knee OA patients, but neither of the two showed any superiority at 6-month follow-up. Ozone dosage for injection was more than that in our study in this survey. Also in another similar study, Momenzadeh et al. assessed the effect of two medical treatments using oxygen-ozone mixture (15 μg/mL) and HA on pain and disability of patients with KOA. They concluded that the use of two interventions to relieve pain and disability is effective without any significant difference. Considering the mean dose of ozone use in Momenzadeh et al.'s study, we declare that ozone therapy in lesser amounts than in our study could be effective. [Based on our results, we found that the mean pain score in terms of VAS in the ozone + hypertonic saline group did not make a significant difference in any of the intervention times compared to the hypersaline group. In the same line with our findings, Raeissadat et al.  comparedfective. .Hashemi et al.  comparedOur results also showed that in the study groups, the mean OKS score increased significantly during the follow-up in each group separately although the difference in this increase in the two groups was not significant.2-O3 group and HA group reduced in the first and second months after the last injection. It can be concluded that the use of pharmacological treatments is effective in reducing pain and disability caused by KOA, but the two treatments for oxygen-ozone mixture and HA worked similarly [Indeed, our findings showed that the mean amounts of all four WOMAC subscales increased from the beginning to two weeks after the intervention slightly and then decreased from two weeks to four weeks after the intervention. In Raeissadat et al.'s study, the total WOMAC score decreased significantly in the ozone group and in the HA group. A similar trend was observed in pain improvement according to WOMAC pain, stiffness, and function significantly improved in each groups independently, but no difference was found between the groups . Similarimilarly . In lineimilarly . Also, iimilarly . Howeverimilarly . Dosage In the present study, the results showed that hypertonic saline injection alone has an effective impact on VAS, OKS, and WOMAC scores of KOA patients. However, there are few studies which have indicated the effectiveness of hypertonic saline , 31.Regarding the differences between our results and those of other studies, we can mention its limitations such as low sample size and short-term follow-up, while long-term follow-up seems necessary. It was also stated that there was no significant relationship between the patients' satisfaction and treatment groups, so the type of intervention did not affect the patients' satisfaction and no considerable adverse effect was seen in the participants; mild local pain was just observed in some patients in both groups who were relieved by nonsteroidal anti-inflammatory drugs. Indeed, using higher authorized doses of ozone, even 35, to reach the probable efficacy in OA patients is suggested.The results of the present study showed that prolotherapy could improve pain and function in patients with osteoarthritis, but no significant difference in effectiveness was seen between the two types of treatment methods used in the present study. Given the fact that our study has been associated with limitations such as short-time follow-up, different results may be observed in other conditions. In addition, the same statistically significant results of the two methods would be due to the selected dose. Therefore, it is recommended that future studies should be done with a higher sample size and with more tracking times as well as an increase in ozone concentration and longer follow-up.


Objective: New technologies to measure pain responses, such as heart rate variability and skin conductance hold promise in the development of tools that can be reliable and quantifiable of detecting pain. The main objective of this study was to assess the capability of two monitors i.e., Newborn Infant Parasympathetic Evaluation (NIPE) and Skin Conductance Algesimeter for detecting procedural pain in non-anesthetized infants.Materials and Methods: Thirty-three non-anesthetized infants were enrolled to the study. To detect pain caused by heel stick, NIPE, and Skin Conductance monitors and behavioral pain scales were used. Three minutes before and just after heel stick, pain was evaluated by behavioral scales, and simultaneously over the whole period by NIPE and SCA.Results: A statistically significant decrease of NIPE Index and an increase of SCA values were found after the HS procedure. There were no statistically significant differences between the decrease in NIPEi values and the increase in PPS values between subgroups based on pain assessment by behavioral-scale scores.Conclusion: Both NIPE and SCA can be useful for detection of procedural pain and may constitue an additional valuable tool for better handling of pain among patients treated in NICUs. More studies on larger groups of patients are needed. Infants in neonatal intensive care units are exposed to numerous painful procedures each day as a part of routine care. Although there are some basic differences in the physiology of pain perception in infants, even preterm babies can perceive pain comparable to older children and adults. There is strong evidence that untreated or undertreated pain may impair their brain and cognitive function development –5. RepeaThe main objective of this prospective, observational study was to assess the capability of these two devices i.e., NIPE monitor and Skin Conductance Algesimeter for detecting procedural pain in non-anesthetized infants. The second objective was to evaluate the influence of gestational age, type of breathing (spontaneous or non-invasive ventilatory support), birth weight and weight at the time of evaluation on obtained NIPE and SCA values.To the best of our knowledge, this is the first study that compares NIPE and SCA in the clinical setting of NICUs.This multicenter prospective observational pilot study was performed at six distinct N/PICUs in Poland between 15 October and 31 December 2018. For this pilot study, 33 newborns and infants admitted to N/PICUs were enrolled. They all were breathing spontaneously or receiving only non-invasive respiratory support and did not require analgesia and/or sedation. Inclusion criteria were gestational age >26 weeks and postnatal age <3 months. Exclusion criteria included bradycardia <80/min., tachycardia >200/min., except for transient episode (<15 s) of sinus bradycardia or tachycardia, cardiac rhythm different from sinus rhythm, the use of catecholamines or other drugs influencing the autonomous nervous system  during a period of seven days before the study, intraventricular hemorrhage - grade IV, inborn brain malformations, severe birth asphyxia treated with therapeutic hypothermia, neuromuscular disorders, and seizures in the seven days preceding the study. All guardians were given information forms, gave their approval for the study, and written informed consent was obtained from the parents of all participating patients. This was a prospective, observational study which did not require any changes regarding the standard treatment of patients included. The acceptance of the local Ethical Committee was granted (270: 11.10.2018).The characteristic of the studied group is presented in To prevent pain oral sucrose was used as a non-pharmacological measure before heel lancing in all patients. Fifteen minutes before a due standard heel stick (HS) for capillary blood sampling, continuous monitoring of HRV by means of NIPE monitor  and continuous SC monitoring by means of Skin Conductance Algesimeter  were started. Patients stayed calm over the 15-min period before HS. A comprehensive description of the NIPE methodology has been published by De Jonckheere et al. . The NIPDescription of the SC methodology has been published by Storm , 16. Ourp < 0.05 as significant. The influence on the decrease of NIPEi and elevation of PPS by the gestational age, postnatal age, type of breathing (spontaneous or non-invasive ventilatory support), birth weight and weight on the study day, as well as that of postmenstrual age, was evaluated using multivariable linear regression analysis.The statistical analysis was performed using SAS software version 9.4  and R version 3.5.1 . Normality assumption was checked using the Shapiro-Wilk test. In subgroups, depending on the assessment of pain in the behavioral scale, comparison of NIPEi values 1 min before HS was performed using the Mann-Whitney U test. Comparisons of NIPEi values 1 min before, as well as the lowest values within 3 min after HS, the comparison of PPS values 1 min before, and the highest values 3 min after HS, was performed for the whole group and for subgroups, using a Wilcoxon signed rank test. For multiple comparisons, the Holm-Bonferroni method was used. We considered a In four patients enrolled to the study (12%), the NIPE and SCA signals (PPS) were distorted by artifacts due to movements and could not be interpreted. In the final analysis, 29 babies were included, in whom 36 HS procedures were analyzed. One minute before HS, no pain was detected in any patients according to the behavioral-scale scoring. The assessment of acute pain should be an essential component of infants' care in NICUs and should lead to improved pain control. However, assessment of pain is complicated and mainly based on behavioral scales which are still the gold standard in evaluating severity of pain in this age group of patients, they are not free from bias and have some limitations. New technologies to measure pain responses, such as heart rate variability and skin conductance, seem to be promising in the development of tools that can be reliable, and capable of detecting pain. The main objective of our study was to evaluate the ability of the Newborn Infant Parasympathetic Evaluation monitor and Skin Conductance Algesimeter to detect procedural pain sensation in infants. To our knowledge, this is one of the first studies evaluating concurrently the capability of these two methods for assessing procedural pain in non-anesthetized infants. In our study we have observed the statistically significant decrease of NIPEi values and increase of PPS values after a painful procedure. It may indicate the ability of both devices to detect pain in infants. Similar results regarding SCA have been obtained by Munsters et al. They have shown that a stress response to heel stick can be detected with skin conductance measurements from 22 weeks GA . Also, TBoth NIPE and SCA are useful for detection of procedural pain and may constitute an important tool for better handling of pain among patients treated in NICUs. Further studies are needed to assess the ability of these devices to measure the intensity of pain. In our study, such factors as sex, gestational age, postmenstrual and postnatal age, birth weight and weight at study, type of breathing (spontaneous or non-invasive ventilatory support) had no influence on the ability to detect pain after a procedural intervention.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee of Regional Medical Chamber in Opole, Poland. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.WW, ZH, TS, and JL-G was involved in the study conception and design, requested the data sets, and drafted the manuscript. IM, EM, MR, AK, and MW requested the data sets and drafted the manuscript. MS, JD, and MJ-N was involved in the study conception and design and provided statistical support. AP was involved in the study conception and design and critically reviewed the draft manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.MJ-N was employed by MDoloris Medical Systems. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Structural brain alterations in chronic pain conditions remain incompletely understood, especially in chronic visceral pain. Patients with chronic-inflammatory or functional bowel disorders experience recurring abdominal pain in concert with other gastrointestinal symptoms, such as altered bowel habits, which are often exacerbated by stress. Despite growing interest in the gut-brain axis and its underlying neural mechanisms in health and disease, abnormal brain morphology and possible associations with visceral symptom severity and chronic stress remain unclear. We accomplished parallelized whole-brain voxel-based morphometry analyses in two patient cohorts with chronic visceral pain, i.e., ulcerative colitis in remission and irritable bowel syndrome, and healthy individuals. In addition to analyzing changes in gray matter volume (GMV) in each patient cohort vs. age-matched healthy controls using analysis of covariance (ANCOVA), multiple regression analyses were conducted to assess correlations between GMV and symptom severity and chronic stress, respectively. ANCOVA revealed reduced GMV in frontal cortex and anterior insula in ulcerative colitis compared to healthy controls, suggesting alterations in the central autonomic and salience networks, which could however not be confirmed in supplemental analyses which rigorously accounted for group differences in the distribution of sex. In irritable bowel syndrome, more widespread differences from healthy controls were observed, comprising both decreased and increased GMV within the sensorimotor, central executive and default mode networks. Associations between visceral symptoms and GMV within frontal regions were altered in both patient groups, supporting a role of the central executive network across visceral pain conditions. Correlations with chronic stress, on the other hand, were only found for irritable bowel syndrome, encompassing numerous brain regions and networks. Together, these findings complement and expand existing brain imaging evidence in chronic visceral pain, supporting partly distinct alterations in brain morphology in patients with chronic-inflammatory and functional bowel disorders despite considerable overlap in symptoms and comorbidities. First evidence pointing to correlations with chronic stress in irritable bowel syndrome inspires future translational studies to elucidate the mechanisms underlying the interconnections of stress, visceral pain and neural mechanisms of the gut-brain axis. Despite substantial individual and societal burden, chronic pain is often overlooked and remains incompletely understood, especially with respect to brain mechanisms relevant to pathophysiology, disease course, and treatment. Clinical conditions characterized by chronic visceral or pelvic pain are particularly understudied using brain imaging techniques. Dedicated visceral pain research is warranted not only given the unique clinical presentation of chronic visceral pain. Many afflicted patients do not experience pain arising from the viscera  in isolation, but rather suffer from recurring episodes of abdominal pain or discomfort in concert with other gastrointestinal (GI) symptoms, such as bowel disturbances. Work in visceral pain is also called for in light of increasing knowledge about the specificity of visceral pain both in terms of psychological as well as central mechanisms. In contrast to somatic pain, visceral pain is perceived as more diffuse and more unpleasant, provokes more pain-related fear, may be more sensitive to stress –4, and, Numerous GI conditions are characterized by visceral pain and pain-related symptoms arising from the GI tract, together contributing to substantial psychological distress, functional disability, and healthcare costs . The mosThe role of psychological factors in acute and chronic visceral pain has inspired translational research elucidating the complex signaling pathways between the GI system and the brain, both in health and disease. There exist multiple connections between the gut and the central nervous system involving microbial, immunological, metabolic, hormonal, and neural processes . ChronicFurthermore, efforts to elucidate correlations between structural brain abnormalities and relevant pain-related GI symptoms, as well as with chronic stress as a major psychological factor relevant to the pathophysiology, disease course, and treatment in both IBS and IBD , 32, havTo close research gaps in structural neuroimaging studies focused on patients with chronic visceral pain, we herein present results of parallelized voxel-based morphometry analyses accomplished in patients with UC and patients with IBS, compared to matched healthy control groups. In order to minimize effects of acute inflammation and severe symptoms characterizing phases of active disease, we only included patients in full remission or with very mild and stable disease activity, at the same time minimizing possible effects of medical treatments routinely necessary in these patients, especially during exacerbations. As a first step in the analysis strategy, voxel-based morphometry was accomplished to determine changes in GMV in each patient group compared to healthy controls, using whole-brain analyses given variability of findings and the widespread structural alterations observed in previous studies. Although alterations in GMV compared to controls were expected in both disorders, differences were hypothesized to be more pronounced and widespread in IBS than in UC given differences in the etiology and pathophysiology, especially regarding the presumably more prominent role of central mechanisms along the gut-brain axis in IBS. As a second step, we performed analyses aiming to address associations with symptom severity and chronic stress in each patient cohort compared to controls using multiple regression analyses. Given overlap in symptoms experienced by patients with UC and IBS and evidence for the role of stress in both disorders , it was N = 96 adult volunteers , acquired within two comprehensive visceral pain studies conducted by our group between the years 2015 and 2020 at the University Hospital Essen, Germany. Primary studies involved different emotional learning/memory tasks (data will be presented elsewhere), all accomplished subsequent to the acquisition of data analyzed herein. Importantly, all participants underwent sociodemographic, psychological and clinical characterization and structural magnetic resonance imaging (MRI) prior to other experimental manipulations. Highly standardized and parallelized procedures were implemented for recruitment, screening and all other assessments that are part of this report, all accomplished within the same biomedical research setting using the same MR scanner. Work was conducted in accordance with The Declaration of Helsinki, and studies were approved by the local Ethics Committee of the University Hospital Essen . All volunteers gave written informed consent and received monetary compensation for participation.For the purposes of the present analyses, we used data from a total of The screening process consisted of a standardized telephone screening, followed by an on-site visit with study staff, and completion of questionnaires . General exclusion criteria for all participants included age <18 or >65 years, body mass index <18 or >30, MRI-specific criteria like claustrophobia, pregnancy or ferromagnetic implants, and any evidence of structural brain abnormalities, verified by a neuroradiologist (author NT). Pregnancy was ruled out using a commercially available pregnancy test on the day of the MRI . For healthy controls, additional exclusion criteria included any known somatic or mental health condition, clinically-relevant anxiety or depression symptoms based on Hospital Anxiety and Depression Scale (HADS), or regular use of medications . For the UC group, only patients in clinical remission or with very low ongoing disease activity were included to avoid interference of active disease with study-related procedures, and to minimize putative effects of acute inflammation  on study-related measures of interest acquired herein. Clinical disease activity was assessed based on symptom reports, initially evaluated in a structured screening interview, and then quantified with the Clinical Colitis Activity Index . In addN = 13 patients), which is why we provide CAI average scores computed based on 6 items for all patients for consistency. In results, we refer to this measure as symptom-based CAI for clarity.In all participants, GI symptoms were quantified with a standardized questionnaire that we routinely use in our group as it is applicable across visceral pain conditions as well as in healthy volunteers . A rangChronic stress was assessed by the 12-item screening scale of the Trier Inventory of Chronic Stress . The scIn addition, the Hospital Anxiety and Depression Scale  was uset-tests, and data are reported as mean ± standard deviation, unless indicated otherwise.All questionnaire data and other self-report variables were analyzed using IBM SPSS Statistics 27 . Group comparisons were accomplished using independent-samples 2, voxel size 0.9 × 0.9 × 0.9 mm3]; sequence 2 . All group analyses were accomplished after a matching of healthy controls (based on the entire sample of N = 44) to each individual patient group, providing dedicated control groups for UC and IBS, respectively, referred to subsequently as HCUC and HCIBS. The matching procedure was based on MR scanning sequence and age, accounting for the slightly different acquisition parameters of the two sequences. Note that the data included for analyses of IBS vs. HCIBS were all acquired with sequence 1; analyses of UC vs. HCUC had equal number of patients and healthy controls measured with sequence 1  and 2 . The acquired images were pre-processed and analyzed with the CAT12 toolbox  and SPM12  implemented in Matlab R2020a . The analysis followed the standard protocol for this toolbox  using default settings and parameters, unless otherwise specified. The main processing steps included the segmentation of voxels into gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF), and normalization using optimized shooting registration. After pre-processing, the homogeneity of the sample was checked by inspecting the correlation between all volumes to ensure data quality. As all images showed high correlation values (>0.86), no images were excluded from further analysis. Modulated normalized GM maps were smoothed with a Gaussian kernel of 8 mm (FWHM). The smoothed images were used for further analysis to test for regional GMV differences between groups. Atlas labeling was based on MRI scans originating from the Open Access Series of Imaging Studies (OASIS) project. The labeled data were provided by Neuromorphometrics under academic subscription . The total intracranial volume was determined for each subject, as it is an important confounding variable in voxel-based morphometry.Structural images were acquired on a 3 Tesla MR scanner using a 32-channel head coil . All data were acquired on the identical scanner, and used one of two 3D-MPRage T1-weighted sequences with very similar yet not identical acquisition parameters: sequence 1 .All whole-brain statistical analyses were performed within the CAT12 environment. To increase sensitivity and to avoid the arbitrary choice of an initial cluster-forming threshold, the Threshold Free Cluster Enhancement TFCE; , 54] too too54)] p < 0.001. For each cluster identified by multiple regression analysis, the estimated GMV of its peak brain region was extracted and transferred to SPSS. As exploratory analysis, we examined correlations of GMV within brain regions identified by multiple regression analyses and GI symptoms and chronic stress, respectively, within each group using partial correlation analyses. To this end, the extracted tissue volumes within anatomical regions and GI symptoms and chronic stress were regressed based on total intracranial volume, age, and sequence (where appropriate). Correlational analyses were then accomplished and plotted using RStudio .In a second step, four multiple regressions were calculated  to test for group interactions in the correlation of GMV with GI symptoms and chronic stress, respectively, controlling for total intracranial volume, age (and sequence where appropriate) as covariates of no interest. For these analyses, we report FWE-corrected results as well as results without correction applying an alpha level of UC, all analyses were re-computed in a subsample comprising only women, i.e., after exclusion of 5 male patients and their 5 age-matched female controls. Secondly, to indirectly address whether patterns of GMV alterations in patients with UC and IBS are disease-specific, further data and results are provided . As intended by matching and consistent with stringent screening for abnormal BMI, no differences between the patient and control groups were evident in age or BMI (SD = 1.99), and a median fecal calprotectin concentration of 41.88 μg (IQR = 83.74 μg). IBD-related medications continued as prescribed by the treating physician included aminosalicylates (N = 20), local corticosteroids (N = 2), TNF-α blocker (N = 2), and azathioprine (N = 2). Few patients reported additional extraintestinal pain symptoms . Patients with IBS reported different bowel habit disturbances, as is typical for this condition, with diarrhea-predominant (N = 9), constipation-predominant (N = 4), mixed IBS (N = 9), or unspecified (N = 1). IBS-related medications included selective serotonin reuptake inhibitors (N = 1), muscarine receptor antagonists (N = 2), and loop diuretics (N = 1). Extraintestinal pain symptoms were reported by some patients . Regarding psychological variables, significantly higher levels of psychological distress based on HADS total score were observed in both patient groups, while only patients with IBS reported significantly more chronic stress when compared to controls , comprising additional frontal and occipital regions , comprising additional frontal and temporal regions as well as the left posterior cingulate gyrus . Conversely, the same analysis in patients with IBS and controls revealed a significant interaction effect between group and chronic stress in a total of 10 clusters, encompassing the bilateral angular gyrus, bilateral temporal pole, left superior frontal gyrus , right middle frontal gyrus, right inferior frontal gyrus (triangular part), right postcentral gyrus, right thalamus, and right inferior occipital gyrus . Supplem caudate , Table 4 caudate .For details on methods and results, see Structural brain alterations in chronic pain conditions remain incompletely understood, especially in chronic visceral pain. We herein included UC as a chronic-inflammatory bowel disease and IBS as a disorder of gut-brain interactions as two distinct and clinically-relevant patient cohorts, together comprising the most prominent clinical conditions associated with chronic visceral pain and other burdening GI symptoms of the gut-brain axis. To elucidate structural brain alterations, we accomplished parallelized whole-brain voxel-based morphometry analyses in UC and IBS, each compared to an age-matched healthy control group. In addition to assessing altered GMV using analysis of covariance, multiple regression analyses were accomplished testing associations with symptom severity and chronic stress as a crucial psychological factor relevant to the pathophysiology and treatment of both conditions.N = 18) without any disease activity for at least 6 months, and with no more than one inflammatory flare since diagnosis (N = 31) were not as restrictive, allowing recruitment of a sample with disease ranging from full remission to low and well-managed disease activity, without restrictions with respect to number of previous flares or medication history. Consistent with this strategy, UC patients in our study reported significantly more GI symptoms, including lower abdominal pain, as well as greater psychological distress, when compared to healthy controls. This clinical presentation is arguable more representative of the typical patient population with UC outside of acute exacerbations, consistent with evidence that patients with IBD often report GI symptoms and a psychological disease impact during remission.In our UC patient cohort, we observed decreased GMV in the anterior insula and middle frontal cortex when compared to age-matched healthy controls, in line with findings reported for patients with Crohn's disease , 25 and iagnosis . While wBearing the critical considerations described above in mind, it is nevertheless interesting to discuss our findings suggesting possibly reduced GMV in the anterior insula and the middle frontal cortex in UC. The anterior insula is part of the salience network, which is highly relevant to pain anticipation and pain modulation in acute and chronic visceral pain e.g., , 20, 23], 2320, 2Our parallelized analyses in a patient cohort with IBS, which we consider an interesting disease control group for UC, revealed largely distinct and much more widespread structural brain alterations when compared to healthy controls. Brain alterations comprised both decreases as well as increases in GMV in multiple regions of the sensorimotor, central executive, and default mode networks, all demonstrably relevant to different facets of chronic visceral pain  and largFor a better understanding of GMV alterations, elucidating their relation with clinical as well as psychological factors is an important step. Associations of GMV changes with symptom severity have previously been demonstrated in patients with IBS and patients with Crohn's disease in terms of disease duration , 27, 68,In addition, the present study is the first to investigate whether structural brain measures are related to chronic stress in patients with chronic visceral pain. This question arises given the broad role of stress and stress mediators in normal visceroception , visceraper se exclude an impact but rather a disease-specific differential association compared to controls. Clearly, our data do not provide conclusive answers, and hopefully inspire further study, possibly in selected patient groups presenting with higher stress levels or other impairment in psychological health, as recently accomplished by our group in a treatment trial .The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: Neurovault . The funding organization was not involved in study design; in collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.