In logistic regression analysis, incobotulinumtoxinA-treated patients were 2.6 times more likely to achieve this endpoint than placebo-treated patients. A significant difference between incobotulinumtoxinA and placebo was observed regardless of baseline pain severity. Additionally, 27.1% of incobotulinumtoxinA- versus 12.4% of placebo-treated patients reported complete pain relief at Week 4 (p = 0.0006). Pain relief increased with multiple injection cycles. To achieve patient-centred care, pain relief may be considered a treatment goal in adults with spasticity-associated pain regardless of pain severity. This study contributes to understanding the benefits of incobotulinumtoxinA in treating limb spasticity-associated pain.Some studies have shown that incobotulinumtoxinA reduces spasticity-associated pain, but further evidence is needed. This exploratory analysis pooled pain-relief data from six Phase 2 or 3 studies of incobotulinumtoxinA (four placebo-controlled studies) for treating upper limb spasticity in adults. Spasticity-associated pain was assessed at baseline and 4 weeks post incobotulinumtoxinA injection using the disability assessment scale (DAS) for pain. Only data for patients with pain at baseline were analysed. Overall, 544  of 937 patients (58.1%) experienced pain at baseline. At Week 4, a significantly greater proportion of incobotulinumtoxinA- (52.1%) than placebo-treated patients (28.7%; Chi-square  Spasticity of the upper and lower limbs following a stroke or as a consequence of other aetiologies  can be a painful condition that limits patient mobility and quality of life, and impacts psychosocial well-being ,2,3. PhaThe advantages of BoNT-A over systemic antispastics include local application and a selective action in the targeted spastic muscles, with better tolerability . Three BThe prevalence of pain among patients with limb spasticity varies widely from 46% to 74% depending on the patient population studied ,20,21. TThis exploratory analysis pooled data explicitly on pain relief from six studies of incobotulinumtoxinA for the treatment of limb muscle spasticity in adults.A total of 937 patients participated in the six studies, of whom 544 (58.1%) experienced spasticity-associated pain (DAS pain score ≥1) at baseline and form the basis for this pooled analysis. Of the 544 patients, 83.8% (456/544) had mild or moderate pain, while 16.2% (88/544) had severe pain . Of thesA higher percentage of incobotulinumtoxinA-treated patients showed an improvement in DAS pain score of 1, 2 or 3 points at Week 4 compared to those treated with placebo. Additionally, patients treated with incobotulinumtoxinA were less likely to show no change in DAS pain score at Week 4 than placebo-treated patients  .p < 0.0001). In logistic regression analysis, the OR for the difference in pain response rate between the two treatment groups was 2.62 , reflecting that incobotulinumtoxinA-treated patients were 2.6 times more likely to show a ≥1-point improvement in DAS pain score at Week 4 than placebo-treated patients. In the sensitivity analysis of patients not taking concomitant pain-relief medication, the difference in pain response rate between incobotulinumtoxinA and placebo was still significantly in favour of incobotulinumtoxinA  (Treatment with incobotulinumtoxinA produced a higher response rate (≥1-point improvement in DAS pain score) at Week 4 than treatment with placebo . The difference in overall pain response rate between the incobotulinum-toxinA and placebo groups  was statistically significant (Chi-square  0.0001) .A similar pattern of greater pain response rates with incobotulinumtoxinA versus placebo at Week 4 was seen across all completed individual studies, with incobotulinumtoxinA response rates generally ranging from 50% to 60%. The exception was the prematurely terminated study MRZ_60201_0307, in which two patients in each treatment group showed a response, resulting in a higher response rate in the placebo group .p = 0.0007) for those with mild pain, 19.9%  for those with moderate pain and 27.7%  for those with severe pain.Patients treated with incobotulinumtoxinA showed a significant improvement in overall pain response rate compared to placebo-treated patients, for those with mild, moderate or severe pain at baseline . The difIncobotulinumtoxinA-treated patients were more likely than placebo-treated patients to report a lower level of pain severity at Week 4 compared with baseline, regardless of baseline pain severity . In addip = 0.0006).Patients treated with incobotulinumtoxinA were significantly more likely to achieve complete pain relief than patients treated with placebo: at Week 4, 27.1% of incobotulinumtoxinA-treated patients  versus 12.4% of placebo-treated patients  experienced complete pain relief. The difference between the two treatment groups amounted to 14.6% , which was statistically significant  of a single injection of BoNT-A (specific formulation not specified but studies published between 1989 and 2012 were reviewed) in upper or lower limb spasticity found that the quality of evidence for pain was low/very low . In addIn this pooled analysis, the DAS pain response rate improved with each incobotulinumtoxinA treatment cycle. Interestingly, the re-emergence of pain between injection visits also diminished over time, possibly indicating a cumulative pain relief effect, which may translate into maintained pain control with long-term use. A post-hoc analysis of two studies of patients with upper limb spasticity who received injections of abobotulinumtoxin A into the shoulder muscles also found slightly greater improvements in DAS-rated pain with each injection cycle .At the time when the studies included in this analysis were conducted, there was a lack of instruments specifically for measuring spasticity-associated pain. Most studies used non-specific pain scales, including numeric rating scales ,32,39,40Often, studies using DAS assessments before and after BoNT-A treatment have focused on individual goal attainment, where patients—together with their physician—select one of the four DAS domains  as their individual principal therapeutic target. For example, in the study by Kanovsky et al. , which iPost-stroke pain is complex and heterogenous, with multiple contributory mechanisms . PatientProviding pain relief is an important consideration for the holistic treatment of any disease to improve patient quality of life and avoid behavioural changes that may occur because of pain ,54,55. IStrengths of our analyses include the fact that they were performed in the largest patient cohort to date from mainly controlled studies; other studies of pain relief with BoNT-A in patients with upper and/or lower limb spasticity have involved population sizes of fewer than 500 patients ,30,31,32Limitations of our analyses include potential bias due to different patient numbers from the different studies used in the pooled analyses. For example, the PURE study  contribuThis analysis provides additional evidence to support the use of incobotulinumtoxinA for reducing limb spasticity-associated pain in adults, which was seen by 4 weeks post injection, and warrants further controlled studies to confirm the pain-relieving benefits of BoNT-As in post-stroke spasticity and to investigate potential earlier onset of effects. The results of this analysis are relevant for clinicians treating this patient population by highlighting the benefits of incobotulinumtoxinA as an option for pain relief at all levels of pain severity.This pooled analysis showed that incobotulinumtoxinA is significantly more effective than placebo in reducing limb spasticity-associated pain at 4 weeks post injection in adults. This is the largest patient cohort analysed to date in this setting, providing additional evidence to support the use of incobotulinumtoxinA for pain relief. Almost 60% of adults in this analysis experienced limb spasticity-associated pain at baseline, and approximately 20% of these patients experienced severe pain. The pain-relieving effects of incobotulinumtoxinA increased as the number of treatment cycles increased and were observed regardless of pain severity. This suggests that pain relief may be considered an important treatment goal in all patients with spasticity-associated pain to provide patient-centred care. IncobotulinumtoxinA may represent an important local treatment option to achieve better outcomes for patients with limb spasticity by significantly reducing associated pain.®; Merz Pharmaceuticals GmbH, Frankfurt, Germany) in the treatment of upper (five studies: MRZ_60201_0307); ), and were performed using Statistical Analysis Software (SAS) 9.4 . A p-value of ≤0.05 was considered statistically significant.This pooled analysis evaluated data only for patients with spasticity-associated pain at baseline based on a DAS pain score of ≥1. For the analyses involving a comparison with placebo, only data from the first injection cycle were analysed; further treatment cycles were not placebo controlled. Data analysed at Week 4 following an incobotulinumtoxinA injection included the frequency of change in DAS pain score for incobotulinumtoxinA- and placebo-treated patients, and the percentage of incobotulinumtoxinA- and placebo-treated patients who responded to treatment, where a response was defined as a ≥1-point improvement in DAS pain score from baseline (Injection Visit 1), as used in other studies ,60. The


Acute low back pain (LBP) is one of the most prevalent diseases worldwide. Since there is evidence of excessive prescriptions of analgesics, i.e., opioids, the aim of this study was to describe the use of pain medications in patients with LBP in the Swiss primary care setting. A retrospective, observational study was performed using medical prescriptions of 180 general practitioners (GP) during years 2009–2020. Patterns of pain medications , paracetamol, and opioids) as well as co-medications were analyzed in patients with a LBP diagnosis. Univariable and multivariable regression analyses assessed GP and patient characteristics associated with the prescription of pain medication. Patients included were 10,331 ; 6449 (62.4%) received at least one pain medication and of these 86% receive NSAIDs and 22% opioids. GP characteristics  and patient characteristics  were associated with significantly higher odds of receiving any pain medication in multivariable analysis. 3719 patients (36%) received co-medications. Proton-pump-inhibitors and muscle relaxants were the most commonly used co-medications. In conclusion, two-thirds of LBP patients were treated with pain medications. Prescribing patterns were conservative, with little use of strong opioids and co-medications. Low back pain (LBP) is one of the most prevalent diseases worldwide . The lifDespite the often self-limiting and benign character of LBP ,8, the iThe focus of this study was the prescription of pain medications for the treatment of LBP in the Swiss primary care sector. In particular, we aimed to determine the number of patients with LBP treated with at least one pain medication and to examine the patterns of prescriptions. We sought to determine prescriber and patient characteristics associated with higher odds of receiving pain medication. Finally, we aimed to determine frequencies and patterns of prescribed co-medications in the treatment of acute LBP.This observational study was retrospective. Data were extracted from the FIRE  database. The database, since 2009, collects routine medical data from around 500 General practitioners (GPs), around 10% of all GPs in the German-speaking area of Switzerland. Currently it holds records of >780,000 patients and >9.4 million consultations.The study period was 2009–2020. According to the current International Classification of Primary Care 2 (ICPC-2) diagnosis code system LBP was defined as: (1) L86-Back syndrome with radiating pain; (2) L84-Back syndrome without radiating pain; (3) L03-Low back symptom/complaint. All patients ≥ 18 years with a LBP diagnosis and at least one consultation within the twelve months (baseline period) prior to the LBP diagnosis  were incPain medications of interest were nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and opioids. Prescription patterns were described in terms of percentages of patients with one or more prescriptions. Time of prescriptions was defined as a continuous variable (in month unit) or categorized in two ways, as necessary: (1) before diagnosis, at diagnosis, within week 1 after diagnosis, within week 2–4 after diagnosis, later than four weeks after diagnosis; (2) before diagnosis, at diagnosis, 0–2 months after the diagnosis, 2–6 months after the diagnosis.To determine patient and prescriber characteristics associated with prescriptions, we used the following characteristics: patient related  and GP related . Type of practice was defined as: single, double or group practice. Type of employment categories were: self-employed or employee. Level of employment was defined as: <50%, between 50 and 79%, between 80 and 99% and 100%. Drug dispensing was considered as a possible factor that might influence prescriptions at GP level. In fact in some regions of Switzerland, GPs are allowed to dispense drugs, but not in others, therefore the variable drug dispensing was defined as yes or no.Co-medications of interest were: proton-pump-inhibitors (PPI), antidepressants, sleeping pills, and muscle relaxants. All medications were analyzed using the Anatomical Therapeutic Chemical Classification System (ATC) codes. All ATC codes are provided in p-values, as appropriate. Patients with code combinations (for example patients with simultaneous codes for “Low back symptom/complaint” and “Back syndrome without radiating pain”) were excluded for group comparisons. Analogously, co-medications use was also compared between these groups.Summary statistics were reported as means  and range (min–max), median  or number  as appropriate. In descriptive tables prescription patterns were compared between the LBP syndrome groups using one-way ANOVA test and chi-square test, with/without simulated Prescription rates of pain medications were represented graphically with the density  and cumulative (cumulative frequency of prescribed pain medications) functions. Counts of prescriptions per patient, overall and stratified by LBP groups, were modelled through Poisson regression models corrected for repeated measurements within patients. Results were presented as risk ratio (RR) ).p ≤ 0.2 in univariable analysis and then implementing a stepwise backward elimination to include all relevant factors which better fit the models. Missing observations were removed from the analysis. Results of regression analyses were presented as odds ratio (OR) (95% CI) with indication of the number of non-missing observations, in terms of patients and GP. Intra-class correlation (ICC) was also reported in multivariable analysis. For all tests, p ≤ 0.05 was considered statistically significant. All analyses were carried out using statistical package R version 3.6.1. .Univariable and multivariable mixed-effects logistic regression analyses were performed to assess the association of GP and patient determinants with any pain medication prescription and, as separate analyses, any NSAIDs, opioids and Paracetamol prescriptions. A stratified analysis by LBP groups was also performed. Mixed models were used to account for the correlation of patients within GP and were performed for any and specific prescriptions. In univariable analysis, every effect was considered separately in a single model. In multivariable analysis, relevant characteristics were considered together. Multivariable models were developed starting from variables with Research using the FIRE database did not need ethical approval, as the project did not fall under the scope of the Federal Act on Research involving Human Beings (Human Research Act) (BASEC-Nr: Req-2017-0079).We included 10,331 patients . 5289 5.p < 0.001) (Patterns of prescribed pain medications were presented in < 0.001) . Among p< 0.001) .During the baseline period, we observed a consistent rate of prescriptions, and nearly 50% of NSAIDs were prescribed before diagnosis . In patip = 0.017). Moreover, after correcting for time of prescriptions, in all LBP subgroups Opioids and Paracetamol have a lower incidence rate compared to NSAIDS.The models of the number of prescriptions per patient, overall and by LBP diagnosis groups were reported in p < 0.001), but decreased odds of prescribing opioids  or paracetamol .Associations between patient and GP characteristics on pain medication prescription (any pain medication and by pain medication subgroup) are shown in p < 0.001). Of all patients, the co-medications prescribed were: 12.7% (muscle relaxants), 7% (antidepressants), 6.4% (sleeping pills), and 22.4% (PPI), respectively, with pantoprazole and tizanidine the most commonly used drugs. Only one-third (31.7%) of patients with a NSAID therapy had a co-medication with a PPI.3719 patients  received one or more co-medications of interest and had no other ICPC-2 diagnosis codes, which would qualify for one of the co-medications . PatientIn this study, we determined frequencies and patterns of pain medication prescriptions in patients with LBP in Swiss primary care. Only two-thirds of all patients with an ICPC-2 diagnosis code of LBP were managed with any kind of pain medication therapy and if a pain medication was prescribed, in 86% of these cases at least a NSAID was prescribed. However, opioids were prescribed in one-fifth of all patients.Nearly two-thirds of all patients in our cohort received at least one pain medication, with diclofenac, ibuprofen, and paracetamol being the most commonly used drugs. This proportion is similar to pain medication prescription rates from studies conducted in the US or The Netherlands ,17. HoweIn real life, however, there is a difference between pain medication prescribed and pain medication taken by the patients. Back pain is one of the most common reasons for taking over the counter (OTC) pain medication . Due to Pain medications are recommended in acute LBP  and in aWe identified both patient and GP characteristics associated with increased odds of pain medication prescriptions. To our knowledge, there are no studies analyzing specific patient or GP characteristics associated with prescribing patterns for acute LBP in the outpatient setting. However, pain in general is a strong predictor for the use of healthcare services . For patOne third of the patients, 36%, received co-medications: proton-pump-inhibitors and muscle relaxants were the most commonly used. Co-medication use, especially the use of muscle relaxants or antidepressants, is common among patients with LBP and their use is mentioned in many guidelines ,26. In cThe study has some limitations. First, we cannot exclude specific pain medication prescriptions for a reason other than an acute LBP episode . This is because ATC codes do not depend on ICPC-2 code in FIRE database. Therefore, our approach was conservative and all patients with ICPC-2 diagnosis codes, qualifying for a pain medication beside the LBP diagnosis,  were excluded. Moreover, a long baseline period of twelve months minimized the chance of missing a diagnosis qualifying for a pain medication. Second, we could only analyze the first LBP episode for each patient. Due to the different structures of medical software used by conducting GPs, we could not definitely exclude cases where diagnosis codes were reported along the subsequent patient consultations, even if the reason of encounter was for other complaints. Finally, we could not exclude the possibility that patients take additional OTC pain medications, which are not prescribed by the GP. Therefore, there is a possibility that we overestimate the number of patients without any pain medication and underestimate the number of pain medication taken.On the other hand, the main strength of this study is the large sample size of patients. The validity of our data and consequently of our results, is supported by the fact that the distribution of age, gender as well as the mean of the number of consultations and the number of patients receiving any kind of pain medication, are in line with the numbers reported in similar health care settings ,38,39 anThe study described patterns of pain medication therapy in a large cohort in Swiss primary care. More than one-third of the patients had no pain medication and 86% of the pain medications was at least a NSAID, in line with current guidelines. However, the still substantial use of opioids suggests that GPs have to be aware of handling of opioids in non-cancer pain.


Low back pain is the most common type of global disability and annually costs the United States over two billion dollars. Opioids have been used to reduce low back pain, although current evidence concerning efficacy is lacking. Sacroiliac joint dysfunction (SIJD) is estimated to be a primary pain source of low back pain in between 10 and 25% of affected patients. The primary objective of this study was to evaluate the rate of SIJD identified through osteopathic techniques in a convenience sample of patients seeking low back pain treatment. The secondary objective was to assess prevalence of low back pain and SIJD among different age groups, and genders.Retrospective chart reviews were completed the adult patients who had received osteopathic manipulative treatment for low back pain at Family Health and Wellness Center in Essexville, MI from January 2018 through June 2019. The prevalence of patients with SIJD was identified during reviews of osteopathic procedural documentation for patients seeking low back pain treatment. Data regarding patients’ age, sex, and treatment modalities were also extracted. Descriptive statistics consisting of frequencies and percentages were calculated.A total of 84 patient records were reviewed. A total of 51 (60.7%) patients seeking low back pain treatment were diagnosed with SIJD identified by osteopathic providers. This included patients with both lumbar and sacral diagnoses simultaneously. SIJD alone accounted for 26 (31%) of patients seeking treatment. Female patients were more likely to have SIJD involvement than males. Forty one (48.8%) treated patients were between 45-64 years old. Muscle Energy Technique was documented to be the most used for 68 (81%) patients. In addition, techniques tended to move from direct to indirect for older patients.Our study demonstrated that SIJD appeared to contribute to low back pain in 51 (60.7%) of low back pain cases identified using osteopathic techniques. This is much greater than the previously reported percentages of 10 to 25%. One possible confounding influence included varied resident screening and reporting of sacral dysfunction. Since multiple areas of the body can be treated at one time, our current procedure notes did not allow for distinguishing between which types of modalities were used on each region or capture residents’ preferred treatments.Although further studies are needed, our results suggest that knowledge of SIJD’s impact on low back pain could lead to improved patient outcomes such as decreased medical costs and opioid use. Low back pain is the fifth most common chief complaint in the primary care setting, affecting more than 26 million Americans.In addition to the physical toll of low back pain in the US, this high rate of this condition results in a substantial financial impact.In contrast, surgical patients in this same study comprised 29.3%, spending $784 million .Although evidence appears to be lacking in regard to opioids providing short-term low back pain relief, adherence to an opioid regimen has been shown to provide some functional improvement.One modality with the potential to mitigate opioid use by decreasing low back pain is osteopathic manipulative treatment (OMT). Manipulation is known for its noninvasive, low-risk benefits, and has been demonstrated as a first-line treatment for chronic low back pain.Osteopathic physicians are trained to look at structure and function as a whole; they connect somatic dysfunctions to patients' symptoms.When SIJ is included in the differential diagnosis for chronic low back pain, there is a decrease in not only pain, but in health care expenditures.Research is currently lacking in osteopathic manipulative diagnosis of low back pain, and SIJD. Recent studies have shown that manipulative treatments have a positive effect on decreasing patients' pain with some improvement on functional status.The primary purpose of this retrospective descriptive correlational study was to evaluate the relationship between low back pain and sacroiliac joint dysfunction as identified using OMT within the primary care population. Secondarily, this study sought to assess the prevalence of low back pain and sacroiliac dysfunction by age and gender. Before the study, the authors hypothesized that sacroiliac joint dysfunction would be more common than previously found.The authors’ institutional review board approved the study protocol prior to any data collection. This study was conducted at an outpatient family medicine residency clinic in Essexville, Michigan. Charts were identified and evaluated of patients who were: 18 years and older and had received OMT for low back pain between January 1, 2018 and June 30, 2019.The McLaren Medical Group’s Business Info Specialist and Physician Biller generated a report based on office billing codes of patients who had a diagnosis of low back pain along with OMT procedure codes. This report listed the patient's name, date of birth and date of service, identifying which charts would be utilized. A report of eligible charts was shredded after use, and all necessary research data was kept on a spreadsheet containing only a unique patient identifier with all study information.All data were solely recorded on the encrypted McLaren Cloud information system. Specifically, charts were evaluated for the percentage rates of patients with sacroiliac joint dysfunction, as documented note for patients who had received OMT for low back pain. As part of routine OMT procedures for the treatment of low back pain, providers had completed notes of any sacroiliac joint dysfunction diagnosed as based on Osteopathic Manipulative Medicine (OMM) principles.Patients’ charts were excluded if they were found to be non-English speaking without an interpreter present during treatments, pregnant, or have known mental and/or physical disabilities. There were no vulnerable populations identified for recruitment in this retrospective chart review.Before proceeding with statistical analyses, data were examined for data outliers, out of range values, and the need for data cleaning and editing before performing a series of frequencies, proportions, descriptive statistics  and figures . After this process was performed, any needed data editing for simplification and clarity was conducted. Descriptive statistics such as percentages were presented from this study. The last author CFR-B performed all statistical analysis using the Stata statistical software package .A total of 84 unique patients were identified and reviewed during this study, including 58 (69.0%) females and 26 (31.0%) males. Forty one (48.8%) sample patients who received treatment were between the ages of 45-64 years old.  A total The prevalence of somatic dysfunctions were identified overall for patients with a chief complaint of back pain. Lumbar somatic dysfunction alone was most common at 33 (39.3%), followed by only sacral somatic dysfunction 26 (31.0%), then combined sacral and lumbar somatic dysfunction 25 (29.7%). Our secondary objective was to examine the prevalence of low back pain by gender and explore different treatment modalities used for low back pain. Generally, females were more likely to have SIJD involvement than males. Females had 39 (67.2%) of overall sacral involvement, with 20 (34.5%) females accounting for SIJD alone. While males accounted for 12 (46.2%) sacral or sacral and lumbar involvement and six (23.1%) of sacral alone. Although multiple modalities can be individually or simultaneously used to treat low back pain, Muscle Energy Technique (MET) was found to be the most commonly used 68 (81.0%) treatment. Following MET, High Velocity Low Amplitude (HVLA) and Myofascial Release (MFR) were both next at 40 (47.6%). Counterstrain (CS) was used least frequently at 17 (20.2%). When examining which modalities were most commonly used for each gender, MET was still the most common for in both female 50 (86.2%) and male 18 (69.2%) patients. Overall, females were more likely to receive treatment multiple modalities. Specifically, females were more likely to receive all types of treatment except for HVLA. For females, MET was most used for 50 (86.2%), followed by MFR 32 (55.2%), HVLA 23 (39.7%), and finally CS 15 (25.9%). For males, MET was most used for 18 (69.2%), followed by HVLA 17 (65.4%), MFR eight (30.8%), and CS two (7.7%). When examining modalities by age subgroup, techniques were seen to change from direct to indirect for older patients. For patients under 24 years old, HVLA and MET were equally used, both being used in five (71.4%) patients in this age subgroup. For ages 25-44, MET was most common (n = 23 (69.7%) with HVLA being second most common at 17 (51.5%). For ages 45-64, MET was again most common (n = 38 (92.7%) with MFR being second most likely at 24 (58.5%) respectively. For patients aged 65 and older, MET and MFR were seen to be equally as common, with both being used in two (66.7%) patients in this age range. It is evident from these results that SIJD involvement in low back pain is possibly being overlooked. Our study demonstrated more than double the rate of SIJD than was found in previous studies.First, our sample size was a small section of the overall low back pain population. Rates of SIJD could potentially be different in a larger sample. Also, many sample patients may have come in for routine treatments of their chronic ailments and may have not always received the same OMT diagnoses during each visit. Incorporating data from each visit may have increased our total sample size. Another explanation for this finding is that osteopathic physicians are trained to seek out other diagnoses which cause low back pain. This could have potentially led to surveillance bias.There were several confounding influences that may have affected our final results, the largest involving screening and documentation. As our data collection used chart reviews, there was no standardized process for screening patients’ somatic dysfunctions or documentation. Although osteopathic providers are taught systematic ways to screen and document osteopathic findings, these practice patterns are always utilized in practice.Physicians may not screen for dysfunctions outside of the immediate area, such as in the sacrum, when they are examining a patient for low back pain.In 2016, the American Osteopathic Association provided guidelines for OMT to assist osteopaths with regards to low back pain in the proper utilization of OMT rather than guidelines for screening.For example, our documentation system only enables osteopaths to denote that MET, HVLA, MFR and CS were used and that lumbar, sacral, and cervical regions were treated. As a result, we were unable to tell which treatments were used on each region of the body and to what affect. This is likely a nationwide issue and has major room for growth in the osteopathic community.Unlike our retrospective chart review project, larger-sample prospective studies comparing groups given SIJ injections to those receiving osteopathic manipulation, a less invasive technique, could contribute a new gold standard for diagnosing sacroiliac joint dysfunction. Additionally, longitudinal studies could examine how osteopathic treatments over time impact the severity of low back pain, concurrent analgesic and/or opioid use frequency, and subsequent surgical procedure rates. Another prospective study design would be to record pain scales prior to, and following, treatment of patients’ SIJD to further identify how dysfunctions might impact low back pain.Finally, it will be important to consider the holistic osteopathic tenants when developing projects in this area of research. Non-invasive osteopathic medicine treatment style improve patients’ quality of life from improved structural and functional self-regulating and self-healing has a significant potential to become a mainstay treatment for SIJD.Previous research indicates that 10 to 25% of chronic low back pain has a SIJ pain source.The overall results of this study were presented as a poster presentation at the Statewide Campus System Poster Day, May 2020.The authors declare no conflict of interest.


The occurrence of extracranial pain and allodynia was higher in the CM-MOH than in the EM and in the TTH groups but was not related to the co-occurrence of vitD deficiency . Our findings show that 25(OH)D deficit is also related to chronic headache, probably because of vitD anti-inflammatory and tolerogenic properties, reinforcing the idea of a neuroinflammatory mechanism underpinning migraine chronification.Several studies focused on the role of vitamin D (vitD) in pain chronification. This study focused on vitD level and pain chronification and extension in headache disorders. Eighty patients with primary headache underwent neurological examination, laboratory exams, including serum calcifediol 25(OH)D, and headache features assessment along with three questionnaires investigating depression, anxiety, and allodynia. The 86.8% of the population had migraine (48% episodic and 52% chronic). The 44.1% of patients had extracranial pain, and 47.6% suffered from allodynia. A vitD deficit, namely a serum 25(OH)D level <20 ng/ml, was detectable in 46.1% of the patients, and it occurred more frequently ( Migraine and tension-type headache (TTH) are common disorders, affecting up to 22 and 78% of the population, respectively , 2. AlthRecently, several studies focused on the possible role of micronutrients and especially of vitamin D (vitD) in chronic pain development.In vitro and animal experimental studies could demonstrate that vitD promoted anti-inflammatory and tolerogenic behaviors in both innate and adaptive immune cells, at the expense of proinflammatory subsets (Circulating vitD mostly derives from the activation of its endogen precursor (7-dehydrocholesterol) in the epidermis by ultraviolet B radiation, followed by two consecutive hydroxylations , 9. In t subsets , 13. Sev subsets –27.The aim of our study was to explore the level of vitD in different kinds of headaches and, more specifically, in relation to pain chronification and the occurrence of chronic extracranial pain and allodynia.Our observational retrospective study aimed at investigating the potential implications of vitD status on headache characteristics and extracranial pain extension.2, normal if between 18.5 and 24.99 kg/m2, overweight if between 25 and 29.99 kg/m2, and obese if ≥30 kg/m2 D] concentration is widely considered the most reliable indicator of vitD reserve, reflecting both dietary intake and exposure to UV radiation. Serum [25(OH)D] levels can be assessed by different analytical methods ; we usedp = 0.05.Demographic and clinical characteristics have been summarized as mean values (±standard deviation) or proportions. The continuous variables were also categorized as normal or abnormal depending on whether the specific value for a given subject fell inside or outside the normal limits. Depending on the type of variable, the analyses were based on either parametric (ANOVA) or non-parametric (chi-square test) methods. The significance value was set at The 86.8% of the sample was diagnosed with migraine, episodic (with or without aura) in 48% of the cases and chronic in the remaining 52%. Since CM was complicated by medication overuse (MOH) in 91% of the cases, the CM and MOH groups were lumped together in the CM-MOH group. The remaining 13.2% of the patients suffered from episodic TTH. Thus, a three-category study variable  was taken into consideration for headache diagnosis.F = 4.87, p = 0.01) larger than those of the EM  and of the TTH  groups, and this was reflected by the higher occurrence of menopause in the CM-MOH than in the two other diagnostic groups.The mean age of the CM-MOH group  was slightly but significantly (p = 0.006) in the CM-MOH (64.7%) than in the EM (26.9%) and in the TTH (12.5%) groups. The 47.6% of the patients suffered from allodynia, and again, the occurrence in the CM-MOH group was significantly larger  (66.7%) in the CM-MOH than in the other groups . On the other hand, the number of subjects with extracranial pain and allodynia was not related to the co-occurrence of vitD deficit as shown in The 44.1% of the cephalalgic patients also had extracranial pain and significantly more .The season of enrolment  did not F = 0.98; p = 0.38). According to the results of the HADS-A questionnaire, the three groups suffered from a mild state of anxiety , again not statistically significant .Regarding the analyses of questionnaires, the mean FFS scale final score in the whole sample was 36 points. The subgroups suffering from EM and CM-MOH got higher scores at FFS  compared to the TTH group (29.3 ± 14.4), but these differences were not statistically significant  nor on the diagnostic group . The level of vitD and BMI were not significantly correlated .The BMI group that the subjects belonged to was independent from the diagnostic group; moreover, if BMI was considered as a continuous variable, the BMI mean values did not depend on the occurrence of vitD deficit  was not different depending on the headache diagnostic group and on the occurrence of vitD deficit.The main result of our study was that the occurrence of vitD deficiency was more frequent in the CM-MOH than in the EM and TTH groups. A similar results was detectable both for monthly migraine days and the migraine symptomatic intake that were larger in the vitD-deficit group, but these results are explicable because the patients with a high frequency of attack and of symptomatic intake belong to the CM-MOH group; moreover, pain killers are not listed among the causes for vitD deficit.This result, neither influenced by the season of evaluation nor by the patient lifestyle or headache treatment, supported the hypothesis of a relationship between vitD status and the diagnosis of CM-MOH. The vitD deficiency was not significantly associated with any of the other variables that we considered, not to clinical features such as extracranial pain, allodynia, and prophylactic treatment, nor to biological parameters. None of the other micronutrients tested proved to be different in the three diagnostic groups.Our findings are in keeping with recent data that showed that poor vitD status was correlated to chronic pain  and withVitD mitigates inflammation by the reduction in proinflammatory mediators , favoring expansion of anti-inflammatory molecules  . NotablyAn intervention study demonstrated that the reduction in proinflammatory cytokines by vitD supplementation was correlated to the improvement of musculoskeletal pain .The regulation of oxidative balance is another potential mechanism of vitD anti-inflammatory action , 49, 50.Obesity is a proinflammatory condition and bears the potential to intensify neurovascular inflammation. Previous reports observed that high BMI was correlated to severity and frequency of migraine episodes . In our Our study has two main limitations. It is a retrospective not interventional study, and the sample size is not so large. The availability of many parameters for each patient partly compensate for the first limitation, but, on the other hand, their usability is still statistically limited by the sample size.Although, preliminary, our results show an association between CM-MOH and vitD deficit, probably reflecting the vitD anti-inflammatory and tolerogenic properties, we did not find the same relationship between vitD deficit and extracranial pain and allodynia, thus suggesting that their pathophysiological mechanism is not exactly the same of pain chronification in CM-MOH.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.VR, LP, DG, and PT collected the data and performed the neurological and endocrinological assessment. MM and MV did the statistical analyses. All authors contributed in interpreting the data and writing the manuscript, read and approved the final manuscript, and have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved, and the resolution documented in the literature.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.


Effective perioperative pain management is essential for optimal patient recovery after surgery and reduces the risk of chronification. However, in clinical practice, perioperative analgesic treatment still needs to be improved and data availability for evidence-based procedure specific analgesic recommendations is insufficient. We aimed to identify procedures related with high pain scores, to evaluate the effect of higher pain intensity on patients and to define patient and intervention related risk factors for increased pain after standard gynaecological and obstetrical surgery. Therefore, we performed a prospective cross-sectional study based on the German registry for quality in postoperative pain (QUIPS). A cohort of 2508 patients receiving surgery between January 2011 and February 2016 in our tertiary referral centre  answered a validated pain questionnaire on the first postoperative day. Maximal pain intensity was measured by means of a 11-point numeric rating scale (NRS) and related to procedure, perioperative care as well as patient characteristics. The interventions with the highest reported pain scores were laparoscopic removal of ovarian cysts (NRS of 6.41 ± 2.12) and caesarean section (NRS of 6.98 ± 2.08). Factors associated with higher pain intensity were younger age , chronic pain  and surgery performed outside the regular day shift . Shorter duration of surgery, peridural or local analgesic and preoperative sedation reduced postoperative pain. Patients reporting high pain scores (NRS ≥ 5) showed relevant impairment of daily activities and reduced satisfaction. Caesarean section and minimal invasive procedures were associated with the highest pain scores in the present ranking. Pain management of these procedures has to be reconsidered. Younger age, receiving surgery outside of the regular shifts, chronic pain and the surgical approach itself have a relevant influence on postoperative pain intensity. When reporting pain scores of 5 or more, patients were more likely to have perioperative complications like nausea or vomiting and to be impaired in mobilisation. Registry-based data are useful to identify patients, procedures and critical situations in daily clinical routine, which increase the risk for elevated post-intervention pain. Furthermore, it provides a database for evaluation of new pain management strategies. Furthermore, pain management in female patients may be more complex compared to male patients. Female patients reported higher scores for acute pain2, had a higher risk of developing chronic pain4 and sometimes did not benefit from standard analgesic medication the same way as male patients did7. High pain intensity scores after surgery are associated with negative consequences such as decreased patient satisfaction, delayed rehabilitation, chronification of pain and increased morbidity and mortality10. Although procedure-specific strategies for reduction of postoperative pain have been established for surgeries such as laparoscopy for pelvic disease or caesarean section, gynaecological and obstetrical surgeries belong to the interventions with highest postoperative pain scores13. Therefore, surgical techniques as well as demographic factors increasing risk of significant postoperative pain need to be investigated in more detail in order to develop specific strategies for preventing and managing postoperative pain. Particularly, improvement of perioperative pain management with regard to reduction of opioid consumption is a contemporary issue15.Standard surgical procedures performed in gynaecology and obstetrics can be associated with severe postoperative painThis study aimed to identify procedures associated with higher pain scores as well as perioperative and demographic risk factors for increased post-operative pain in women undergoing surgical procedures in gynaecology and obstetrics. Secondary aims were (1) Assessment of the relationship between increased pain scores and postoperative patient impairment, satisfaction and side effects of therapy. (2) Evaluation of the effect of healthcare management aspects on pain intensity, including timing of surgery and use of new analgesic treatment options.This is a cross-sectional register-based study performed at the department of gynaecology and obstetrics in the Jena University Hospital, Germany, a tertiary referral centre for gynaecological surgery and obstetric medicine. All methods used in this study were performed in accordance with the relevant guidelines and regulations. Study approval was obtained from the responsible ethics committee. Before entering the study, all patients gave their written informed consent.www.pain-out.eu) is a multicentre initiative to evaluate intern quality of acute postoperative analgesic management in all surgical disciplines and to compare pain outcome parameters among participating hospitals through a benchmarking tool16. As defined for this project, data collection in an open registry is standardized and all participants receive a specific training and instruction before taking part in the project. With more than 639,000 records, the German QUIPS represents the most comprehensive database for acute pain worldwide.For this study, data from our centre collected for the “Quality Improvement in Postoperative Pain Treatment” project (German: QUIPS) between January 2011 and February 2016 were used. QUIPS . If a patient was unable to fill out the questionnaire by herself, the research assistant interviewed the patient. The questionnaire was developed and validated18 by the pain-unit of the Jena University Hospital and is divided into different domains addressing pain intensity, functional impairment, side effects of pain treatment, and global assessment of postoperative pain management by the patient  after surgery to collect demographic, clinical and outcome data. Patients were instructed to anonymously fill in a validated pain questionnaire assessing patient-reported outcomes  of the department without changes within the study period, as described in detail in the supplemental material. Also, surgical procedures were developed following specific internal SOPs. Rationale for special surgical approaches is given in the supplemental information.21 value defines moderate to severe pain, and is known to correlate with the negative impact of pain in physical and emotional aspects of patient care24. Only variables which showed a significant relationship with increased pain in the chi-squared test were included in that multivariate analysis. After identifying relevant factors influencing pain scores in the multivariate model, pain intensity scores were recalculated adjusting for those factors using the regression equation. Specifically, adjustment was performed for the variables age, surgical approach, use of innovative pain strategies, chronic pain patient and timepoint of beginning of surgery. These adjusted values were used for the comparative ranking of pain intensity.In order not to lose statistical accuracy, procedures performed in less than 10 patients during the study period were excluded from the analysis. Categorical variables were analysed using chi-squared or Fischer’s exact test as appropriate. For the analysis of risk factors for increased pain, a multivariate model was created and analysed using a binary logistic regression. For this regression, increased pain was defined if maximal pain intensity score was 5 or more. This cut-pointp values were < 0.05. Statistical analysis was performed using SPSS version 20.0 .To asses relationship between duration of surgery and maximal pain intensity Spearman’s correlation was used since both variables are linear. For the variable timepoint of beginn of surgery, a binary value was defined by using the cut-off time of 4:30 PM, because this was the time scheduled surgery ends in our centre. Statistical significance was considered if This research was covered by the study approval for the German registry for Quality of management on postoperative pain (QUIPS) of the Ethics Commission of the Jena University Hospital, Germany. Registry-Number 2722-12/09 from the 8th of December 2009.Study outline presented by Ingo B. Runnebaum at the 22nd Annual Congress of the European Society of Gynaecological Endoscopy, 16–19 October 2013, Berlin. Concept and preliminary data of the study were orally presented at the 61st Congress of the German Society for Gynaecology and Obstetrics (DGGG), Oct. 19.-22., 2016, Stuttgart, Germany.Between January 2011 and February 2016, 2975 patients were eligible to be included in the study sample. 232 patients refused the questionnaire, 201 patients did not complete it  were more likely to report higher pain scores .Surgeries were classified into seven groups depending on surgical area and surgical approach Table : laparosComparison of elective and intra-partum caesarean section showed no significant difference (Mann–Whitney-U-Test) regarding pain on ambulation/stress (p = 0.888), maximum pain intensity (p = 0.557), minimum pain intensity (p = 0.394) and satisfaction with pain treatment (p = 0.672), respectively.Performing subgroup analysis, we found no increased risk for elevated pain associated with laparoscopic endometriosis surgery compared to laparoscopic interventions in total . Compared to the standard laparoscopy/laparotomy, need for adhesiolysis  or need for uretherolysis  did not increase the risk for higher postoperative pain.Regarding the duration of surgery, we found a significant correlation between longer surgeries and higher pain intensities. Spearman´s correlation index demonstrated a weak correlation . Interventions on patients who reported elevated pain levels lasted longer than those on patients with lower pain: 127.8 min (SD ± 3.3) vs 104.4 min (SD ± 3.6) (p < 0.001).Surgery started during late shifts (after 4:30 p.m. in our centre) was also associated with higher postoperative pain after adjustment for age, kind of surgery and chronic pain , laparoscopies in 16 cases (15.8%), 50 caesarean sections (49.5%), 7 surgeries of the vulva (6.9%) and 5 breast surgeries (5%). Use of epidural catheters for postoperative analgesia were related with lower pain intensity . Also premedication showed to have a significant influence on reporting higher pain levels (53.2% vs 60.8% p < 0.001).As described above, two novel strategies were implemented during the study period for reducing postoperative pain: Prophylactic use of Oxycodone 10 mg/Naloxone 5 mg and perioperative local infiltration of Ropivacaine at the surgical site. Within the study period 1705 (68%) patients received at least one of those interventions. Local infiltration alone was applied in 984 39.2%) patients, prophylactic oxycodone alone was used in 375 (15%) patients and the combination of both was implemented in 346 (13.8%) procedures. Compared with standard therapies, both strategies combined but also independently from each other were found to have a protective effect on increased pain after surgery. The OR for prophylactic oxycodone was 0.67  and for local anaesthetics was 0.66 , and the OR for the combined use of both strategies was 0.66 (p < 0.01)  reported maximal pain scores of five or more in the NRS (increased pain). As shown on Fig. To our knowledge, this is the largest prospective cross-sectional study to date comparing standardised pain intensity scores subsequent to a wide range of obstetric and gynaecologic surgeries, in search of risk factors for postoperative pain. This approach aimed to demonstrate the painfulness of routine interventions and provides a relation between painfulness, the treatment provided and patient characteristics.1. Concerns about pharmaceutical analgesic therapy with respect to breast feeding and anxiety in the early postoperative time with respect to baby care have been discussed as factors contributing to high pain intensity25.Results of this study show that some minimally invasive laparoscopic procedures and caesarean section were associated with patients reporting higher pain scores. The results are consistent with the literature for caesarean sections29. The results of our study do not show this benefit with regard to pain for the first 24 h after surgery for our centre. This difference may be explained by different standards of care for these surgeries as well as patient characteristics. Patients after radical surgeries such as lymphadenectomy including radical hysterectomy or other surgeries with extensive tissue trauma received postoperative regional analgesia and routine visits by the acute pain service (APS), regularly optimising pain therapy. Patients with minor and less invasive procedures were expected to experience less pain, and often were excluded from advanced pain management by APS. Furthermore, patients undergoing laparoscopic surgeries for ovarian cysts or endometriosis frequently were younger than patients treated with hysterectomy or pelvic organ prolapse surgery. As a result of our study, younger age was an independent risk factor for developing higher pain intensity. This is consistent with evidence from other studies and other surgeries33.Advantages of laparoscopic surgery related to postoperative pain and postoperative recovery have been confirmed by well-designed large randomised studies34.In this study, patients with chronic pain reported significantly higher pain scores. This has been a well-defined risk factor in previous studiesAn additional risk factor for higher pain was time of day when starting surgery. Further exploring the influence of time of day, we analysed patients operated in late-shifts. They reported lower scores of satisfaction with pain management and would have desired more analgesics after surgery. Routine documentation of pain scores by nursing team may have played a relevant role here, since documentation rate was more than 30% lower in the night shift. This seems relevant since patients with reduced pain documentation showed less opioid consumption. An explanation here may be the reduced nurse-patient ratio at night resulting on a less attentive patient care. Furthermore, kind of surgery, as well as pre- and postoperative medication could be less accurate at this time. Surgeries on night shift were mainly caesarean sections, laparoscopic cyst extirpations or extra uterine pregnancies. We observed a significant amount of surgeries not receiving hypnotics for premedication, also after excluding caesarean sections. Therefore, the whole process of analgesic management on night shifts needs to be reviewed.Our results demonstrate the efficacy of new opioid-sparing analgesic treatment strategies such as prophylactic oxycodone and intraoperative wound infiltration with long-acting local anaesthetics.38. Patients with high pain intensity (NRS ≥ 5) reported increased side effects such as nausea and impairment of daily activities and were less satisfied with pain management.  and its international version PAIN OUT (www.pain-out.eu) are simple to use tools open to any institution to monitor quality of care in pain management, particularly during the first 24 h, using well defined standardised patient related outcomes and combining this information with data coming from routine daily patient care and demographical data42. More than 200 hospitals already participate in this benchmark program. Patients and hospitals can benefit from such a benchmark registry visualizing one’s own improvements of routine postsurgical pain management.Small-scale randomised studies or studies performed under controlled conditions were often unsuccessful to create practice-changing evidence to daily hospital environmentAfter evaluating the findings of our study, the entire staff of our surgery unit has been informed. The surgeons of our unit were convinced of the benefit of the studied protocol and voted for a strict adherence to the tested pain management protocols. In daily routine the here published protocol has consistently been practiced since. This comprises situations, in which deviation from standard practice had been more likely .Furthermore, local wound infiltration with Ropivacaine was implemented in the standard anaesthetic protocol for all surgical interventions. In perineal repair surgery, local anaesthetics with short duration of action (Lidocain) was replaced with Ropivacain with longer action.As to limitations of this study, data have been collected in a single centre making it difficult to exclude bias due to centre related singularities. Data were collected discontinuously over 5 years between 2011 and 2016. Changes in perioperative pain management in our centre within this time period have been evaluated in the present study, so influence of other factors appears unlikely but cannot be excluded. Data were not presented directly following data acquisition, but after stable implementation into all clinical routine situations.In order to reduce selection bias, a high number of patients were enrolled. The study centre is a high-volume reference centre for gynaecological benign and oncological surgery (by German standards), so no significant fluctuations on reference population were expected. Authors tried to reduce potential performance and measurement bias by excluding any member of the surgical or ward team from data collection or data management. External assessors were especially trained in a defined program for this task. Influence of other factors, which could act as confounders, such as grade of anxiety, level of education or social background, were not aim of this study and have not been evaluated.Minimally invasive surgeries reported unexpected higher pain intensity compared with other gynaecologic procedures. As an internal control, Caesarean section was expectedly associated with highest postoperative pain scores of the spectrum of surgeries analysed. Younger patients, patients with the diagnosis of chronic pain and patients being operated outside of regular day shifts were at risk of developing increased pain. These patient groups were more likely to be handicapped due to pain and should be identified prior to surgery. The benchmark registry QUIPS/PAIN OUT enabled us to define risk criteria for postsurgical pain in order to improve analgesic management in gynaecologic patients. Specific types of surgery will need specific techniques to further tailor postoperative opioid-sparing pain-preventive measures, which should be evaluated in another prospective benchmark analysis or a randomized-controlled study.Supplementary Information.


Background: Peritoneal carcinomatosis often results in alterations in intestinal peristalsis and recurrent abdominal pain. Pain management in these patients is often unsatisfactory. This study aimed to investigate whether endothelin-1 (EDN1) was involved in pain mediation in peritoneal carcinomatosis, and thus whether the EDN1 pathway could be a new therapeutic target for peritoneal carcinomatosis-associated pain.Methods: EDN1 plasma levels and abdominal pain severity were assessed in patients with abdominal tumors, with or without peritoneal carcinomatosis, and in healthy donors. The effects of EDN1 on the visceromotor response to colorectal distension, and on colonic contractions were then examined in mice, and the mechanism of action of EDN1 was then investigated by measuring the impact of EDN1 exposure on calcium mobilization in cultured neurons. Inhibition studies were also performed to determine if the effects of EDN1 exposure could be reversed by EDN1-specific receptor antagonists.Results: A positive correlation between EDN1 plasma levels and abdominal pain was identified in patients with peritoneal carcinomatosis. EDN1 exposure increased visceral sensitivity and the amplitude of colonic contractions in mice and induced calcium mobilization by direct binding to its receptors on sensory neurons. The effects of EDN1 were inhibited by antagonists of the EDN1 receptors.Conclusions: This preliminary study, using data from patients with peritoneal carcinomatosis combined with data from experiments performed in mice, suggests that EDN1 may play a key role mediating pain in peritoneal carcinomatosis. Our findings suggest that antagonists of the EDN1 receptors might be beneficial in the management of pain in patients with peritoneal carcinomatosis. Peritoneal carcinomatosis (PC) is frequently observed in patients with ovarian or digestive tract tumors. Most patients with PC develop symptoms including intestinal colic, continuous and diffuse abdominal pain, and present abnormal peristalsis associated with nausea and vomiting. Management of the abdominal pain in patients with PC has improved over recent years with the use of combined treatments involving analgesics (opioids), antiemetics, and antisecretory agents . HoweverEndothelin-1 (EDN1), a peptide secreted by endothelial cells , has beeThe aim of this study was to investigate whether EDN1 plays a pro-nociceptive role in the mediation of visceral pain in PC, and therefore determine if inhibition of the EDN1 signaling pathway could provide a potential new therapeutic target for the treatment of visceral pain in patients with digestive tract tumors associated with PC. Thus, we first conducted a preliminary study to assess whether there was a correlation between plasma levels of EDN1 and the intensity of abdominal pain in patients with PC. We then evaluated the effects of EDN1 on visceral sensitivity and colonic peristalsis in mice, and investigated the mechanism of activation of EDNRs in dorsal root ganglia (DRG) neurons. We also studied whether the effects of EDN1 in mice could be reversed by exposure to EDNRs antagonists.Synthetic EDN1 peptide was purchased from the American Peptide Company . Atrasentan hydrochloride , an EDNRA antagonist, and bosentan (BOS), an antagonist of both EDNRA and EDNRB, were purchased from MedChem Express  and Selleckchem , respectively.Blood samples (5 mL) were obtained from patients mainly with abdominal primary tumors , with or without PC, and from healthy donors. Samples were collected in tubes containing EDTA and immediately centrifuged at 2,000 g for 15 min at 4°C. Plasma samples were then recovered, aliquoted, and frozen at −20°C until use. EDN1 levels in the plasma were quantified using the QuantiGlo chemiluminescent sandwich ELISA kit .Abdominal pain was monitored at the time of the blood collection using the Numeric Pain Rating Scale (NPRS): patients rated their current level of pain on a scale of 0–10, with a score of 0 indicating “no pain” and a score of 10 indicating “the worst pain imaginable.”Written informed consent was obtained from each patient and healthy donor prior to inclusion in the study. Quantification EDN1 levels in the plasma samples was approved by the local ethics committee of the Sud-Seine et Marne Hospital (05/12/2015). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and its subsequent amendments, as reflected by its a priori approval by the institution's human research committee.−1). The electromyographic activity of the abdominal muscles was recorded 30 min after the injection by connecting the electrodes to an electromyogram acquisition system , via a high performance differential amplifier . Visceromotor responses were analyzed using the Chart 5 software (ADInstruments). Colorectal distension was achieved by inserting a balloon catheter  into the colon, 5 mm from the anus. The balloon catheter was then progressively inflated in stepwise increments of 15 mm Hg: 10-s distensions were performed with pressures of 15, 30, 45, and 60 mm Hg and 5-min rest intervals between each distention. The same procedure was then used to analyze colorectal distension in the presence of EDNR antagonists: 30 min before the injection with EDN1, the mice received intraperitoneal injections of 10 mg.kg−1 of either ATRA or BOS. All procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the European Council and were approved by the US006/CREFE Animal Care and Ethics Committee .Colorectal distension was performed as already described , 14 to mProximal colon segments (10 mm in length) were obtained from C57Bl/6 mice treated with EDN1 and/or BOS as described above. The segments were incubated in an oxygenated Krebs-Ringer bicarbonate/glucose buffer (pH 7.4) for 30 min prior to being attached to an isotonic transducer  and immersed in tubes containing 25 mL of Krebs-Ringer buffer at 37°C. The load applied to the lever was 2 g (20 mN). Isotonic contractions were then recorded for 10 min using the basic data acquisition software . Average colonic contraction amplitudes were calculated from recordings taken over 10-s intervals and the data collected were then normalized to obtain the average amplitude of the basal contractions, as described previously .−1 papain  and L-Cysteine  for 10 min at 37°C. The DRG were then rinsed in Leibovitz's L-15 Medium  containing 1% penicillin/streptomycin and 10% Fetal Bovine Serum (FBS)  and digested twice with 4 mg.mL−1 dispase II (Sigma) and 1 mg.mL−1 collagenase type I (Sigma) for 5 min at 37°C. Enzyme activity was then neutralized by adding L-15 buffer and the neurons were mechanically dissociated. After centrifugation at 600 g for 5 min, neurons were plated into an 8-well Nunc™ Lab-Tek™ II CC2™ Chamber Slide System  and cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 2.5% FBS, 1% penicillin/streptomycin and 10 μM of a cocktail of mitosis inhibitors including cytosine-B-arabinofuranoside, F-uridine, and uridine (Sigma) for 3 days before being used for calcium imaging assays.DRG were collected from C57Bl/6 mice, washed with Hanks Balanced Salt Solution , and incubated in HBSS containing 27 μg.mL2. Neurons were then incubated with either 10 μM BOS in 0.001% DMSO HBSS or a vehicle for 5 min before adding increasing amounts of EDN1. Neurons were imaged using an inverted microscope (Zeiss) and a 10x 0.5 NA objective. Images were acquired using a CCD camera (Zeiss) and Zen software (Zeiss). Acquisition parameters were kept constant during each experiment. Kinetic analysis was performed using 80 recordings (one per second). Baseline fluorescence was determined for 0–5 s, and then fluorescence was measured from the 6 to 60 s after the neurons were incubated with the drugs or control. At 60 s 50 mM KCl was added to the cells in order to allow discrimination between neurons and glial cells. Variations in fluorescence intensity measured in each neuron were identified using Image J software. The percentage of responding neurons was calculated as the number of DRG neurons in which EDN1 induced calcium mobilization, relative to the total number of neurons identified by their ability to respond to 50 mM KCl. A neuron was defined as responding when the ratio between the highest fluorescence measured between 6 and 60 s and the baseline measured between 0 and 5 s was higher than 1.Before calcium imaging, the neurons were incubated with HBSS containing 20 mM Hepes, 1 mM fluo-4 acetoxymethyl (AM) ester (Thermo Fisher) and 0.02% pluronic F-17 for 30 min at 37°C, followed by an additional incubation for 30 min at room temperature. The medium was then discarded and replaced by HBSS containing 1.26 mM CaClpost-hoc Dunn's multiple comparison test using the Prism 5.0 software . A two-way repeated-measures analysis of variance (ANOVA) was used to compare two independent treatments over a range of concentrations. The strength of the correlation between abdominal pain intensity and EDN1 plasma concentration was evaluated by using the nonparametric Spearman's correlation coefficient.Results are expressed as the mean ± the standard error of the mean (SEM). Statistical analyses of intergroup comparisons were performed using the nonparametric Kruskal-Wallis test combined with a A total of 24 patients (nine men and 15 women) and five healthy donors were included in the study. The median age of the patients was 71.5 years (range: 46–90 years). The abdominal tumors in these patients were located in the colon (14 patients), kidney (one patient), ovary (three patients), pancreas (two patients), or stomach (two patients). One patient with esophageal cancer and PC, and one patient with melanoma and PC were also included in the study. Overall, 11 of the patients had PC and five of these patients had undergone nasogastric suction for bowel obstruction. The other 13 patients had local abdominal tumors without PC .n = 10/11) of the patients with PC suffered from abdominal pain. In contrast, 77% (n = 10/13) of the patients without PC presented with no pain (Ninety-one percent ( no pain . None of−1 were rarely associated with significant pain (NPRS > 4). All the patients with EDN1 plasma levels higher than 4 pg mL−1, including solely patients suffering from PC, experienced severe (4 < NPRS < 6) to very severe (NPRS > 6) abdominal pain . The correlation coefficient increased to 0.7 when only patients with PC were included in the analysis . This observation led us to examine the effect of EDN1 on intestinal motility. Our ractions . This EDractions .in vivo, ex vivo, and in vitro experimental data from mice on the effects and mode of action of this peptide, our study suggests that EDN1 could mediate pain in PC by triggering visceral hypersensitivity and alterations in intestinal motility via direct activation of the EDNRs to induce calcium ion mobilization and activation of the pain signaling pathway in nociceptive fibers.Our study provided evidence that EDN1 could be a key mediator of pain in PC. Using data obtained from assessments of EDN1 plasma levels and pain severity scores in PC patients, combined with The results of our exploratory study involving patients with PC revealed that EDN1 was more abundant in patients suffering from advanced abdominal tumors with PC than in healthy donors or patients with digestive tract tumors without PC. In addition, the concentration of EDN1 in plasma samples correlated with the intensity of abdominal pain, thus indicating that EDN1 could play a key role in the mediation of visceral pain in patients with PC. Indeed, although EDN1 was first described as an endogenous vasoactive peptide , it has The interesting findings in patients with PC led us to investigate the effect of END1 on abdominal muscle contractions and intestinal motility in mice. In agreement with our findings suggesting that EDN1 plays a role in visceral pain in PC, we showed that EDN1 induced visceral hypersensitivity and increased colonic peristalsis in mice.As intestinal spasms associated with increased peristaltic activity may induce painful sensations, we investigated whether EDN1 could directly activate the pain signaling pathway by investigating the ability of this peptide to induce calcium mobilization in primary cultures of sensory neurons. Our results showed that exposure to EDN1 led to a dose-dependent induction of calcium mobilization, suggesting that EDN1 directly activates the EDNRs in sensory neurons. This is a potentially important finding as these receptors are expressed all along the pain signaling pathway, including in both C-type and Aδ-type nociceptive fibers , 23–27.We also showed that the effects of EDN1 on abdominal muscle contractions, intestinal motility and calcium ion mobilization observed in our study could be inhibited by EDNR antagonists. Indeed, BOS has already been shown to have an analgesic effect on pain in preclinical animal models of carcinoma . Our inhAlthough more extensive studies are required, our results provide strong evidence for a major role for EDN1 in the mediation of pain in patients with abdominal tumors and PC. These findings may form the basis for larger therapeutic trials investigating the clinical use of EDNR antagonists to alleviate refractory visceral pain in patients with PC.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 Ethic Committee of the Sud-Seine et Marne Hospital (05/12/2015). The patients/participants provided their written informed consent to participate in this study. This animal study was reviewed and approved by the Animal Care and Ethics Committee of US006/CREFE .CG, BD, SC, and AL enrolled patients. LB, CD, AF, CK, and NC designed and conducted experiments and acquired and analyzed the data. LL and Y-YZ acquired data. CG, CB, and GD supervised the study, designed experiments, analyzed data, and wrote the manuscript. All authors contributed to the article and approved the submitted version.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.


The incidence of mild to moderate AEs was 1.83  per 100,000 treatment sessions, and that of severe AEs was 0.04 (95% CI 0.00–0.16) per 100,000 treatment sessions. Thus, AEs of any level of severity were very rare after CMT. Moreover, there were no instances of carotid artery dissection or spinal cord injury, which are the most severe AEs associated with manual therapy in other countries.Studies have reported that mild adverse events (AEs) are common after manual therapy and that there is a risk of serious injury. We aimed to assess the safety of Chuna manipulation therapy (CMT), a traditional manual Korean therapy, by analysing AEs in patients who underwent this treatment. Patients who received at least one session of CMT between December 2009 and March 2019 at 14 Korean medicine hospitals were included. Electronic patient charts and internal audit data obtained from situation report logs were retrospectively analysed. All data were reviewed by two researchers. The inter-rater agreement was assessed using the Cohen’s kappa coefficient, and reliability analysis among hospitals was assessed using Cronbach’s Alpha coefficient. In total, 2,682,258 CMT procedures were performed in 289,953 patients during the study period. There were 50 AEs, including worsened pain ( Chuna manipulation treatment (CMT) is a form of manual therapy used by Korean medicine doctors (KMDs) to treat structural or functional pathologies by applying effective stimuli to a patient’s body using hands or an assistive device. It was developed by employing and advancing various manual therapy strategies from other countries on the basis of traditional Chuna therapy, which is rooted in Korean medicine theories that emphasise a balance between function and structure. The techniques employed in CMT are divided into two broad types: bonesetting Chuna therapy that is performed on the joints in the body, and fascia Chuna therapy that is performed on the soft tissues. Bonesetting Chuna therapy was advanced from chiropractic therapy and encompasses techniques such as manipulation; high-velocity, low-amplitude technique; and thrust. Fascia Chuna therapy was advanced from Chinese tui na and encompasses joint mobilisation, joint distraction, and soft tissue technique . CMT hasManual therapy is performed in various forms by chiropractors, osteopaths, and physical therapists across the world, including the United States, Europe, and Australia. The use of spinal manipulation has increased in recent decades in Western countries , as has The reported incidence of AEs associated with manual therapy varies from 0.00005% to 83% depending on the research methodology used and the severity of the AEs . To dateThis study is a retrospective analysis of electronic patient records and internal hospital audit data drawn from event report logs at 14 Korean medicine hospitals located in major cities of the Republic of Korea.Our institution has been designated as a “spine specialty Korean medicine hospital” by the Korean Ministry of Health and Welfare and has 20 branches in main centres nationwide. For this study, we excluded centres with an incomplete AE reporting system, and collected data from 14 Jaseng hospitals located in Gangnam, Bucheon, Jamsil, Gwanghwamun, Nowon, Ansan, Suwon, Incheon, Daejeon, Cheongju, Gwangju, Daegu, Haewundae, and Ulsan. The target study population comprised inpatients and outpatients with musculoskeletal disorders who received at least one session of CMT between December 2009 and March 2019. Inpatient treatment was performed if the patient was in severe pain that interfered with daily life or if outpatient treatment was not possible. The data collected from the electronic records included patient age and sex, district, disease or injury, number of CMT sessions received, length of hospital stay, and number of hospitalisations. AEs were identified in situational report logs; when an AE was confirmed to be associated with CMT, additional data were obtained from relevant records . The patients’ ID was anonymised for privacy of the data. All documents were encrypted, and only authorised researchers had accessed to the documents.Nurses are trained to record and report all AEs, complaints, and other noteworthy issues on a daily basis. These records are collated weekly and submitted to the head nurse and KMDs. Nurses perform at least five daily rounds for inpatients and attend outpatients at least twice per visit. Therefore, any untoward event is easily detected and well documented. Events occurring outside the hospital can be reported by the patient or caregiver to the on-call KMD via a hospital landline that is functional for 24 h a day and are recorded in the nursing department. Furthermore, nurses routinely contact patients who stop treatment prematurely by telephone as part of the clinical follow-up to ensure the quality of care. Further, the patients are instructed to notify the hospital via the 24-h nurse line in case of relapse of pain or in the event of any other AEs even after the discontinuation of treatment.Nursing situation reports from the 14 Korean medicine hospitals were integrated into our data. Reports containing inadequate data were excluded. Ten KMDs with at least 3 years of clinical experience received offline education about the definition, criteria, and screening for AEs. Additional educational materials were provided as needed during the screening phase.The screening was performed in two stages. First, the 10 KMD researchers were allocated to screen the nursing situation reports and identify AEs associated with CMT in such a way that all data were double-checked by two researchers. If one researcher in a pair determined an AE to be associated with CMT, the screening proceeded to the second stage, in which the two researchers reviewed pertinent comorbidities, results of AE-related investigations, and medical records to determine causality and the severity of the AE, referencing the criteria proposed by the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality scale and National Cancer Institute ,14. Any An AE was defined as any unfavourable sign, symptom, or disorder temporally associated with the treatment, irrespective of whether the relationship was deemed causal , in accoThe severity of each AE was classified according to the National Cancer Institute guideline as mild, moderate, severe, life-threatening, or fatal  , and an unpleasant sensation , with additional reports of cervical pain (n = 2), knee-related symptoms (n = 2), worsening hip pain (n = 1), and the onset of temporomandibular joint pain (n = 1). There were 15 cases under the age group of 40 years and younger, 10 in the age group of 4059, and 4 in the age group of 60 years and older. The mean number of CMT sessions was 9.3. Twenty-one of the 23 patients with worsening of radiating lumbar or lower limb pain had pre-CMT magnetic resonance imaging (MRI) scan results available, the findings of which were abnormal in all cases. Twelve of these patients showed disc extrusion and seven showed disc protrusion. Pre-procedural MRI showed disc herniation in the two patients with worsened neck pain. Nine patients in whom the worsened lumbar pain did not improve were referred for a nerve block with or without continuation of their existing treatment. Eight patients continued with their Korean medicine regimen even after the worsening of their lumbar pain. Nine patients had a mild increase in musculoskeletal pain, which did not require additional treatment. Further measures, such as nerve block or analgesics, were required in 19 moderate cases, and one patient with severe worsening pain was referred to the surgeons upon diagnosis of avascular necrosis (AVN) of the femoral head. Causality was considered possible in 28 cases and probable in one.Most cases of worsening pain involved radiation of pain in the lumbar region and lower limbs . Six of the 11 women had also been using medicinal herbs at the time of the fracture.The minimum age of patients who experienced a fall was 54 years, and the median age was 63.5 years. The falls occurred during climbing onto the Chuna bed, changing position on the bed, or leaving the bed. Four patients sustained a contusion as a result of their fall but had no symptoms. Pre-emptive radiographs were obtained in 50% of patients, none of whom required additional treatment; the contusions were rated as mild in these cases.Other AEs included one case each of an unpleasant sensation and headache with vertigo and two of chest pain. The patient who reported an unpleasant sensation was a 26-year-old woman who received CMT in the supine position while wearing a skirt. The 38-year-old patient who complained of headache and vertigo immediately after CMT had no abnormal brain MRI or MR angiography findings, and the symptoms improved after using herbal medicine and anti-inflammatory drugs for five days. Two patients who had chest pain were in their 70s and had no abnormal radiographic or ultrasound findings, and the pain had improved 1 month later.Although manual therapy is effective for musculoskeletal disorders , there hAlthough exacerbation and progression of disc herniation following manual therapy have been reported , a studyn = 129/227). They also found that 66% of patients who developed an AE had been treated by a chiropractor. In the present study, there were two cases of worsened neck pain; however, no life-threatening or severe AEs were observed that would support previous concerns [Kranenburg et al.  analysedconcerns . Furtherconcerns ; this maThere were clear sex- and age-specific characteristics in the 11 cases of rib fractures. Female sex hormones play a crucial role in maintaining bone mineral density ; therefoAll six cases of falls resulted in mild contusions that did not require additional treatment. The median age of the patients who experienced falls was 63.5 years, which is expected given that falls are more common in older patients. Approximately 35–40% of individuals aged ≥65 years fall at least once a year . All ourOne patient had headache and vertigo that persisted for 5 days after CMT, but mild and transient discomfort following CMT, such as systemic pain and headache, may be interpreted as a normal response to mobilisation or stimulation of periarticular soft tissue . One patWe identified 49 cases of mild to moderate AEs, with an incidence rate of 1.83 per 100,000 treatments, which was lower than that (2.5) reported by a study that retrospectively examined chiropractic safety . There wThis study is of value in that it included a markedly greater number of cases than those examined in past studies investigating AEs. Nielsen et al. targeted the largest study population of 34,605 in their overview of 125 studies to examine the safety of the spinal manual therapy . In thisOne limitation of this study is its retrospective design, which means that mild AEs may have been missed and the incidence rate underestimated. However, AEs that require additional treatment or were abnormal would have been detected by KMDs; hence, it is highly unlikely that significant AEs were overlooked. Moreover, the retrospective design made it difficult to examine the incidence of AE according to each type of manual therapy technique. Another limitation is the association between AEs and CMT, given that treatments other than CMT, which had been administered in most patients, may have caused increased musculoskeletal pain. Acupuncture (100%), pharmacotherapy and herbal therapy (93%), and cupping therapy (83%) were performed concurrently with CMT in the patients who complained of increased pain; hence, it was impossible to attribute causality to CMT alone. We adopted a conservative approach in this study by including AEs with unclear causality. In addition, although standardised CMT was conducted through education and qualification tests, there may be differences in the level of each operator due to the nature of manual therapy.This study found that severe AEs after CMT were very rare. In particular, there were no reports of carotid artery dissection or spinal cord injury, which are reportedly the most dangerous AEs associated with manual therapy as found by studies conducted in other countries. In our study, although inclusion/exclusion criteria or outcome did not include the pre-treatment imaging results, they were used for diagnosis and treatment planning by clinicians. Moreover, the researchers used the imaging results to determine a causal relationship in the event of an adverse reaction to CMT. Although recent evidence suggests that imaging should not be routinely used for most musculoskeletal disorders , to ensuOur analysis of 289,953 patients and 2,682,258 cases of CMT indicates that both mild–moderate and severe AEs are rare after CMT. A total of 29 cases of increased musculoskeletal pain, 11 cases of rib fracture, 6 cases of falls, 2 cases of chest pain, 1 case of vertigo, and 1 case of mild discomfort were identified. The overall AE incidence was 1.86 per 100,000 treatment sessions. Serious AEs were identified in 1 out of 50 cases, with a frequency of 0.04 per 100,000 procedures. CMT performed by an expert can be considered relatively safe. Well-designed prospective studies are needed to examine CMT-related AEs in more detail.