Although patients with diabetes reportedly have more back pain and worse patient-reported outcomes than those without diabetes after lumbar spine surgery, the impact of diabetes on postoperative recovery in pain or numbness in other regions is not well characterized. In this study, the authors aimed to elucidate the impact of diabetes on postoperative recovery in pain/numbness in four areas  after lumbar spine surgery. The authors retrospectively reviewed 993 patients (152 with diabetes and 841 without) who underwent decompression and/or fixation within three levels of the lumbar spine at eight hospitals during April 2017–June 2018. Preoperative Numerical Rating Scale (NRS) scores in all four areas, Oswestry Disability Index (ODI), and Euro quality of life 5-dimension (EQ-5D) were comparable between the groups. The diabetic group showed worse ODI/EQ-5D and greater NRS scores for leg pain 1 year after surgery than the non-diabetic group. Although other postoperative NRS scores tended to be higher in the diabetic group, the between-group differences were not significant. Diabetic neuropathy caused by microvascular changes may induce irreversible nerve damage especially in leg area. Providers can use this information when counseling patients with diabetes about the expected outcomes of spine surgery. The reported prevalence of painful diabetic peripheral neuropathy shows wide variability  owing to differences in study design, diagnostic criteria, and sampling methods9. In addition, diabetic neuropathy can profoundly impair the quality of life10. Compromised vascularity and secondary peripheral neuropathy may affect the recovery of nerve roots after surgical decompression11. Therefore, patients with coexisting diabetes and lumbar spine disease may experience significant limitations in overall function11.Diabetic neuropathy can cause chronic peripheral pain due to microvascular changes and irreversible nerve damage11 assessed the outcomes of surgery for intervertebral disc herniation, spinal stenosis, and degenerative spondylolisthesis; the results showed that patients without diabetes experienced significantly greater improvement in low back pain-associated disability than patients with diabetes. Another large size prospective study12 assessed the outcomes of neck surgery and low back surgery; patients with diabetes showed worse pre- and postoperative PROs, which did not improve to the same extent as that in patients without diabetes. However, these studies did not analyze peripheral pain or numbness; in addition, the latter study assessed patients with both neck pain and low back pain. In another small scale retrospective study13, patients with diabetes exhibited a tendency for greater visual analog scale scores for low back pain and leg numbness after lumbar spine surgery. Hence, a larger size study based on prospectively collected data is required to evaluate the effect of diabetes on peripheral pain or numbness in back, buttock, leg, and sole areas after lumbar spine surgery.Two noteworthy studies investigated the effect of diabetes on outcomes of lumbar spine surgery, especially patient-reported outcomes (PROs) and disability associated with low back pain. A secondary analysis of a large prospective study (SPORT study)The primary purpose of this study was to evaluate whether the presence of diabetes is associated with worse peripheral pain or numbness and worse PROs at 1 year following lumbar spine surgery. The authors hypothesized that outcomes of decompression surgery in patients with diabetes will be worse than those in their non-diabetic counterparts owing to microvascular angiopathy and irreversible nerve damage caused by peripheral neuropathy.A prospective spine surgery registry was started at eight institutions in the greater Tokyo metropolitan area, after obtaining approval from the Clinical Research Support Center of the University of Tokyo Hospital (10335-(3)) and the institutional review boards of all participating hospitals i.e., The University of Tokyo Hospital, Japanese Red Cross Medical Center, Yokohama Rosai Hospital, Kanto Rosai Hospital, Japan Community Health-care Organization Tokyo Shinjuku Medical Center, Toranomon Hospital, Japanese Red Cross Saitama Hospital, and Japanese Red Cross Musashino Hospital. The present study was carried out in accordance with the relevant guidelines and regulations/ethical principles of the Declaration of Helsinki. The authors have obtained informed consent form with opt-out method from patients.11. The authors analyzed patients who underwent elective decompression or fixation surgery within three levels of lumbar spine. Fixation included posterior interbody fusion, transforaminal interbody fusion, and posterolateral fusion. The exclusion criteria were (1) age < 20 years; (2) including thoracic level; (3) emergency surgery; (4) revision surgery; (5) surgeries involving osteotomy; and (6) surgical site involving > 3 levels.The authors evaluated a consecutive cohort of patients with 1-year follow-up from April 2017 and June 2018. Patients in this cohort are divided into nine main disease categories, i.e., degenerative spine disease, intervertebral disc hernia, ossification of posterior longitudinal ligament or yellow ligament, spinal deformity, spinal cord tumor, vertebral tumor, spinal trauma, infectious disease, and others. The authors included only patients with degenerative spine disease and intervertebral disc hernia, as per a previous report12. Data pertaining to glycosylated hemoglobin (HbA1c) levels during the pre- and postoperative period were collected for patients with diabetes. Patients were divided into diabetic group and non-diabetic group. Data pertaining to demographic characteristics and operative parameters were obtained from the registry. The variables included age, sex, body mass index (BMI), smoking status (current or none), American Society of Anesthesiologists (ASA) classification, operative time, and estimated blood loss, as per the previous reports12. Use of interbody fusion or endoscopy was also analyzed. The authors recorded intra- and postoperative complications including nerve root damage, dural tear, deep venous thrombosis, surgical site infection, sepsis, and revision surgery within 30 days after surgery.Patients with diabetes were identified solely through the medical records (self-reported history of diabetes requiring medication)14, (2) Oswestry Disability Index (ODI) for assessment of pain-associated disability15, and (3) Euro quality of life 5-dimension (EQ-5D)-3L for assessment of health-related quality of life (QOL)17. The Japanese versions of ODI15 and EQ-5D16 have been validated previously. The NRS measures the intensity of pain and numbness over the preceding 4 weeks; the scores range from 0  to 10 (the worst pain imaginable). To evaluate the effect of lumbar spinal decompression both on back pain and radiculopathy, the authors analyzed six NRS domains: back pain, buttock pain, leg pain, leg numbness, sole pain, and sole numbness. The following “missing” rules were applied in the case of missing data: for ODI and EQ-5D: no missing data were allowed because these scales consist of only one item per domain. As for NRS, because the number of questions was more, one missing response per questionnaire was accepted. We assumed missing–at-random for missing data mechanism and performed no imputations for missing data.The authors used a booklet of questionnaires, including the Japanese version of (1) Numerical Rating Scale (NRS) used in a previous reportt-test for continuous variables. Student t-test was used to examine the between-group differences with respect to pre- and postoperative NRS, ODI, and EQ-5D scores. For further evaluation of the difference in each outcome score, the authors calculated the adjusted p values by inverse probability weighting method after calculating propensity scores based on seven variables  as per a previous report12.Baseline demographic and clinical characteristics in diabetic group and non-diabetic group were compared using the chi-square test for categorical variables and Student 19; therefore, the authors defined pain or numbness relief as decrease in NRS score by 50%. Patients who did not have preoperative pain or numbness (preoperative NRS = 0) were judged to have achieved pain or numbness relief if there was no pain 1 year after surgery (postoperative NRS = 0). The rates of achievement of pain or numbness relief were analyzed by chi-square test.In addition to comparing the mean values of NRS, the authors tried to assess the effect of diabetes on the relief in pain or numbness. A 50% reduction was shown to be substantially important for patients treated for pain20, a total sample size of at least 800 patients was required. The level of significance was set at p < 0.05. All data analyses were performed using SPSS version 21.0 statistical software .The sample size for this study was calculated based on multiple linear regressions controlling for eight independent variables (diabetes plus seven variables used for propensity score), which required ten cases per variable. Estimating 10–20% of diabetes prevalence as per previous prospectively collected database2, P < 0.001), and included a higher percentage of ASA class ≥ 3  than the non-diabetic group. There were no significant between-group differences with respect to smoking status, disease category, or surgical invasiveness   used to measure the effect of clinical treatments. Importantly, patients with diabetes showed an approximately 24-point improvement in ODI scores and a 0.2-point improvement in EQ-5D scores. Taken together, surgical intervention for degenerative disease and disc herniation is an appropriate treatment plan for patients with diabetes, resulting in clinically important differences from the baseline to 1-year follow-up, although they showed significantly greater leg pain and poorer PROs compared with patients without diabetes. Poor improvement in leg pain in the diabetic group may have contributed to worse postoperative PROs in our relatively old cohort. Leg strength and proprioception are associated with physical function; poor leg strength and proprioception may predispose patients with diabetes to greater risk of falls and slower walking speed27.The authors observed worse postoperative PROs in the diabetic group, similar to that in previous studies28. Our data revealed that diabetic neuropathy had a minor-to-moderate effect on the improvement in NRS score for leg pain; the difference between the diabetic and non-diabetic groups in this respect was approximately 0.6. In a study by Takahashi et al.13 the final leg pain in patients with diabetes was greater than that in their non-diabetic counterparts ; however, the difference was not statistically significant. In light of these findings, the estimated negative effect of diabetes on NRS leg pain score is in the range of 0.5–0.6. The present study indicated that the rate in achievement of 50% relief in pain/numbness was associated with diabetes. Although the p value for leg pain relief was over 0.05 in the analyses excluding patients with 0 pain at baseline, postoperative leg pain was significantly worse in the diabetic group compared to the non-diabetic group in the chi-square test and inverse probability weighting method , without preoperative differences. These results supported that the effect of diabetes on leg pain relief was not negligible.Diabetic microvascular changes can induce variable degrees of peripheral neuropathy and irreversible nerve damage29. Theoretically, the occurrence of nerve fiber degeneration is proportional to the nerve length and the blood supply. The length from ganglion to leg is longer than that to the buttock area. The difference between the relief of buttock pain and leg pain may be influenced by the length of the nerve. Subjective symptoms of diabetic neuropathy start bilaterally from distal lower limbs6, and the effect of diabetic neuropathy on buttock area may be relatively minor compared with leg area.Chronic symmetrical length-dependent sensorimotor polyneuropathy is the most common form of diabetic neuropathy5, our study showed no significant between-group difference with respect to postoperative sole pain and numbness. This can be explained by statistical reasons. Mean pre- and postoperative NRS scores for sole pain and numbness were < 4, which reflects minor pain30. It is difficult to demonstrate difference of changes from small baseline values in the 11-point pain intensity NRS system31; therefore, the negligible effect of diabetes on postoperative improvement is likely due to the small baseline values. Use of other scoring system  may have demonstrated a significant between-group difference in this respect.Contrary to the theory that diabetic neuropathy affects peripheral area32. However, the between-group difference was not significant in 5 out of 12 quoted papers32. Higher BMI is also an established risk factor of surgical site infection, and the typical cut-off value is 30 or 3533. The average BMI of the patients in the present study was lower than the average BMI reported in previous studies in the US12. Type 2 diabetes can develop in East Asian patients with a lower mean BMI compared with that in those of European descent34. Collectively, the effect of diabetes on surgical site infection or revision surgery can differ according to the population due to the differences in BMI. The effect of ASA classification should be mentioned. The present study included 25.7% of participants with an ASA classification ≥ 3 in diabetic group compared to 7.4% in the non-diabetic group. The relatively high-age cohort may mask the effects of unknown comorbidities and optimal medical care provided by the physician, not quantified in this study, can minimize the clinical differences of PRO at the 1-year follow-up between groups. More importantly, the effect of ASA was adjusted by inverse probability weighting method.Interestingly, no difference in complication rate was observed between the diabetic and the non-diabetic groups in the present study. Surgical site infection is an important cause of revision surgery, and diabetes is known to be one of the risk factors of surgical site infection as shown in a recent meta-analysis11. The degree of vascular calcification and other vascular diseases, including peripheral arterial diseases, were not evaluated in the current study. The authors used inverse probability weighting method calculated by propensity score, and the effect of confounding factors such as ASA classification ≥ 3 can be reduced. Second, the follow-up duration was 1 year, which was shorter than that in the two previous studies12; however, PROs assessed at 12 months adequately predict the long-term (24-month) outcomes after lumbar spine surgery35. Third, we did not approach a response shift in these results. PROs can be influenced by changes in values during study period, and such effects can be evaluated by the “then-test”36. Fourth, the authors were not able to analyze detailed information about pain-relief medication because this study was not an interventional study. A previous study only examined the use of opioids12, but smaller amount of opioid use was reported in Japan than in the US, especially for acute pain37, which may minimize the effect of long-term use of opioid. Another large sample-size study did not evaluate the effect of oral medication between the two groups11. Pain control was performed at each outpatient clinic to optimize patients in the two groups, and hence, the confounding factor of the oral medication can be considered negligible for this result.The authors believe that this study adds to contemporary knowledge about the effect of diabetes on patients undergoing elective spine surgery. However, some limitations of our study should be considered while interpreting our results. First, the authors were not able to collect detailed information pertaining to diabetes type and baseline glycemic control in patients with diabetes except for the HbA1c values. The type and chronicity of diabetes mellitus and the degree of glycemic control have an impact on neurologic and vascular sequelae of the diseaseDiabetes was associated with poor improvement in leg pain and worse PROs 1 year after spine surgery. Providers can use this information and pay attention to recovery in leg pain as well as back pain when counseling patients with diabetes about the expected outcomes of spine surgery.


Since the legalization of medical marijuana (MMJ) in Ohio in 2018, many chronic pain (CP) patients have become interested in it as an alternative or adjunct to prescription opioids. This has not only created a need for pain management specialists to learn about this potential indication for MMJ but also for them to have more detailed knowledge of patient attitudes and willingness to comply with providers’ recommendations regarding its safe use with other pain medications. For this purpose, we surveyed CP patients in a region severely affected by the opioid crisis in order to provide better education, formulate treatment plans, and develop clinical policies.We designed and administered the Medical Marijuana Interest Questionnaire (MMIQ) online to patients of the Western Reserve Hospital Center for Pain Medicine (CPM) with a diagnosis of CP who were not yet using MMJ. Questions addressed demographic and clinical characteristics, willingness to consider MMJ, and compliance with treatment plans and concerns. We then carried out a statistical analysis including Pearson chi-square, Spearman’s rho and Kendall’s tau tests to measure associations between variables to identify factors that may influence willingness to use MMJ.p = 0.023).After sending 1047 email invitations to complete the MMIQ, 242 (23.1%) completed questionnaires were returned. The average age range of all respondents was 51-60 years, 171 (70.7%) were female and 147 (60.7%) were current opioid users. The 204 (84.3%) respondents who were willing to consider using MMJ were given access to the entire questionnaire. Of these, 138 (67.6%) reported wanting to use less opioids after starting MMJ and 191 (93.6%) were amenable to following their pain specialists’ recommendations about using MMJ concurrently with opioids. Their greatest concern on a 0-5 scale was affordability (2.98) and there was a statistically significant negative correlation between older age and preference for inhaled forms (The MMIQ was successful in eliciting important data regarding patients’ attitudes about MMJ for opioid titration and potential compliance. Our study was limited by being administered online rather than in-person, which skewed the demographic makeup of the sample. The MMIQ can be used to study similar populations or adapted to patients already using MMJ. Similar surveys of MMJ-experienced patients could be combined with chart reviews to study the success of these products for pain control and opioid substitution. It has been estimated that chronic pain (CP) is one of the leading reasons for patients to seek medical care with 20% of Americans suffering from this group of conditions. Risk factors include female gender, low socioeconomic status, living in a rural area, and disability  who had not yet tried MMJ regarding their interest in it. Though some of our patients had already begun using MMJ and a study of this population could yield useful data, we chose to study MMJ-naïve patients for several reasons. First, they represented a sufficiently large sample from which to draw statistically significant conclusions, whereas only several dozen patients had experience with it. We decided that this much smaller group would be better studied retrospectively and presented with descriptive rather than statistical methods. Another factor that led to this decision was the implausibility of formulating the same questions for both MMJ-naïve and MMJ-experienced patients. Therefore, we decided to research both groups separately but to study the larger group first, as the need to address their educational and clinical needs was more relevant to our daily practice.The survey concerned three main lines of inquiry. The first was patients’ interest in MMJ for the purpose of reducing opioids, a class of drugs with significant adverse events, addiction potential, and long-term health risks  based on selected surveys from our search, patient questions, the approved indications for MMJ in Ohio, and our prior experience in survey research  followed by current opioid use and willingness to try MMJ. Patients responding negatively to this last question were not allowed to answer further questions, but their answers to this section were recorded. The second section (beginning with independent variables) started by asking what complaints they might seek MMJ treatment for. We divided these into primary pain complaints  and secondary psychosocial complaints . Since many of our patients suffer from multiple painful conditions, we gave them the option of selecting more than one complaint so that the results would more accurately reflect the prevalence of each in this population. The next questions were average Numeric Pain Rating Scale (NPRS) score over the previous week, expectation of percentage pain relief from MMJ , preferred forms , and acceptable monthly expenditure . Adherence was assessed by querying patients’ inclinations to: use the form and dosage suggested by their provider, attend monthly visits for safety monitoring, take less opioids and benzodiazepines while using MMJ, use MMJ even if that meant they could not take opioids, and participate in research on MMJ. For the final questions on concerns about MMJ use, we used a 0-5 point scale . Types of concerns included overdose, addiction, disapproval of friends and family, affordability, side effects/drug interactions, and driving safety.Prior to administering the survey, we obtained approval of the Western Reserve Hospital Research Committee and waiver of IRB review from the Lake Erie College of Osteopathic Medicine Institutional Review Board . This waOur initial protocol involved administering the MMIQ in-person by clinical staff on touchscreen devices, but a suspension of office visits due to the COVID-19 pandemic led us to distribute the survey via email instead. Using the eClinicalWorks® electronic medical record search engine of patients at CPM, we generated a list of 1047 patients based on the following criteria: > 18 years of age, diagnosis of chronic pain (ICD-10 code G89.4), and seen in the last 6 months. We emailed them a brief explanation of the survey with a link to the Google Forms page. This invitation directed them not to start the MMIQ if they had already tried MMJ or were currently using it. All responses were received between April 7, 2020, and May 20, 2020. We had determined previously that 200 responses were needed for statistical estimation of categorical percentages within a margin of error of +/− 7%. The data were then imported into a spreadsheet for analysis by a biostatistician.p < 0.05 considered statistically significant.Survey data were imported into SPSSv25.0 software . Cohort summaries were presented using frequencies and percentages for categorical data and mean, standard deviations, and minimum/maximum values for numeric data. Associations that were examined included (1) willingness to consider MMJ with demographics and opioid use, (2) opioid use with NPRS score, (3) opioid use with concerns, (4) age with concern of disapproval, (5) age with concern regarding driving safety, (6) age with preferred form, (7) NPRS score with type of pain, and (8) NPRS score with expected percentage relief. Pearson chi-square tests were performed to measure the association between nominally measured data. Kendall’s tau tests were performed to examine the relationship between dichotomous nominal data and ordinally scaled metrics. Spearman’s rho values were determined to measure the association between ordinally scaled data and tested for equivalence to zero. All statistical tests were two-sided with n = 171) of all responders identified as female, 90.5% (n = 219) as Caucasian/White and 29.7% (n = 72) reported at least some college education. The mean of the age ranges was 51-60 and 60.7% reported taking opioids as part of their current treatment regimen. Two hundred four (84.3%) reported they would consider trying MMJ (Table n = 1047), respondents (n = 242), and respondents willing to consider MMJ (n = 204), the latter group had less higher education and the group of all invitees skewed toward a higher average age (63.5 years) than respondents. Otherwise, there were no significant differences between groups  patients responded. In brief, 70.7% (n = 24) for 75-100% relief, 28.8% (n = 58) for 50-75%, 20.5% (n = 42) for 25-50% relief, 2.4% (n = 5) for 0-25%, and 36.6% (n = 75) reported being uncertain  preferred spending below $50, 38.7% (n = 76) were willing to spend $50-100, 20.2% (n = 40) to spend $100-200, 4.0% (n = 8) to spend $200-400 while no respondents wanted to spend more than $400 , sublingual drops , pills , inhaled , and topical . Figure The type and prevalence of primary and secondary complaints are shown in Figs. n = 191) agreed to follow recommended forms and dosages while the other 6.4% (n = 13) responded “maybe.” In total, 93.6% (n = 191) were ready to attend monthly visits for monitoring safety, 5.4% (n = 11) answered “maybe” and 1% (n = 2) reported unwillingness. In patients taking opioids, 68.1% (n = 139) were willing to take less with concomitant MMJ, 29.4% (n = 60) answered “maybe” and 2.5% (n = 5) answered “no.” Of those using benzodiazepines (n = 56), 75.0% (n = 42) were willing to wean off these after starting MMJ, 19.6% (n = 11) answered “maybe” and 5.4% (n = 3) answered “no.” Thus, a greater proportion of benzodiazepine users reported interest in decreasing these medications versus opioid users (75% vs. 67.8%). A total of 71.6% (n = 146) of respondents expressed interest in participating in research.A total of 93.6% (n = 31) rated this as a 5. Respondents were least concerned about the disapproval of family and friends, rating this on average as 0.57/5.The average level of each concern is shown in Fig. p = 0.053) and opioid users . There was no association between willingness and age (Table 3 in p = 0.023) with those over the age of 70 being much less likely to choose this route of administration (Table 4 in p = 0.069). There were no significant associations between the following: (1) Average NPRS score over the previous week and expected relief [Table 5 in Willingness to consider MMJ was marginally higher among men  and fibromyalgia  than average (6.79/10). A linear regression with pain modeled by fibromyalgia indication and female gender showed an insignificant contribution by the female gender factor . Headache sufferers reported slightly more pain as well, but this was only marginally significant .Though not relevant to the goals of this survey, we should note that statistical significance can be assigned to the slightly higher pain scores of those with arthritis  and having completed college (62.3%) than Summit County residents overall (78.2% Caucasian and 35.8% with college degrees) according to U.S. Census data  is consistent with the gender makeup of our clinic and does not, therefore, suggest an error with study design. Nonetheless, studies of other populations may demonstrate less of a disparity, since 22.1% of women in the general population have CP compared to 18.6% of men  for your pain?” might have contributed to the data on concerns. This could have been remedied by including the section on concerns earlier in the survey before these respondents were screened out of answering further questions.Finally, we would be remiss in not acknowledging a limitation inherent in all survey research: responses representing opinions and attitudes do not necessarily predict actual behavior.n = 21) reporting a 5  on the 0-5 scale was only 2.07 with 10% . For instance, there could be significant differences between chronic pain patients and those from other clinical settings who are less accustomed to complying with contracts, pill counts, drug screens, etc.In addition to these other uses of the MMIQ, more surveys of CP patients who have already tried MMJ will be useful in assessing effectiveness and safety given the lack of prospective studies to date. As stated above, it is our intention to perform a retrospective chart review of MMJ-experienced CP patients, perhaps in conjunction with a survey to assess their satisfaction with MMJ, costs, pain relief, possible legal or occupational problems, and side effects. Our anecdotal experience is that some patients often try MMJ but return to opioid therapy due to its higher cost and lack of effectiveness, so such a study could elucidate the actual prevalence and reasons for these patients’ decisions.While developing the MMIQ, we identified areas of inquiry that would be useful in evaluating patient attitudes toward using MMJ for opioid replacement. The survey was also designed to gather information that pain specialists need to create educational materials and assess compliance. Although the collected data showed a willingness to consider MMJ and comply with safety regulations, it also suggested that patient expectations of pain reduction and expenditure may not be realistic given current clinical evidence and MMJ prices in Ohio. Though there may not be a robust evidence base yet about MMJ as an opioid sparing tool, we feel that these results are the basis for providing more useful and patient-centered education to this population.


Paracetamol is recommended as a first-line treatment for pain and fever in paediatric patients. Intravenous (IV) infusions are recommended to be administered as a 15-min infusion to minimize local tissue trauma and related pain. The purpose of this study was to demonstrate that IV paracetamol could be administered during 5 min or less in paediatric patients without causing related adverse reactions.Prospective, observational safety study including children aged <18 years who received IV paracetamol. Pain scores before and after the paracetamol infusions were obtained using VAS, FLACC, COMFORT neo, or COMFORT behaviour scales with scores from 0 to 10 representing no pain to worst pain. Further, objective signs of inflammation at the infusion site were registered.P = 0.007), and no objective signs of inflammation were reported.We included 44 patients  who received paracetamol in a peripheral venous catheter (n = 22) or central venous catheter (n = 22). In total, the 93 paracetamol infusions had a median infusion time of 3:00 min, range 0:40 to 5:00 min. After infusions, pain scores were lower, compared to before infusions (mean change −0.26, 95% confidence interval −0.45 to −0.07, This safety study indicates that IV paracetamol can be administered in paediatric patients with a shorter infusion time than recommended without causing adverse reactions. The results may contribute to a more efficient workflow at paediatric departments.  •Paracetamol is widely used for treating pain and fever in paediatric patients.•The recommended infusion time of intravenous paracetamol is 15 min.•The infusion time can safely be reduced to ≤5 min in paediatric patients. With a Paracetamol is unstable in solutions and poorly soluble in water; therefore, propacetamol was introduced in the 1980s. Propacetamol is a water-soluble prodrug of paracetamol developed for parenteral administration, but the unphysiological osmolarity and pH value may induce pain during infusion. When prolonged from 2 to 15 min, this infusion-related pain could be reduced . In the 2This prospective, observational safety study was conducted at the Department of Paediatric Oncology, the Semi-intensive Paediatric Unit, and the Department of Neonatal and Paediatric Intensive Care at Copenhagen University Hospital Rigshospitalet in Denmark between October 29, 2020, and May 19, 2021. The study protocol was approved by the institutional review board, and approval for administering IV paracetamol with an infusion time of 5 min or less was obtained as a change in practice before the study began.2.1Children aged <18 years who received paracetamol as an IV infusion via a peripheral or central venous catheter  were eligible for inclusion. Nurses were instructed to administer paracetamol with a duration of infusion of 5 min or less. Patients were excluded if the duration of infusions were more than 5 min. The dosing schedule of paracetamol was three to four times daily using weight-based doses for paediatric patients and doses based on gestational age for neonatal patients. Paracetamol was administered using both unopened and reused vials. Paracetamol was administered manually via a syringe.2.2The treating nurses registered pain intensity scores before and during or immediately after the paracetamol infusion. Validated pain scales, corresponding to age and cognitive development of the child, were used: Visual Analogue Scale (VAS), Face, Legs, Activity, Cry, Consolability (FLACC), COMFORT neo, or COMFORT behaviour. For the VAS and FLACC scales, scores between 0 and 10 represented no pain to worst pain. For the COMFORT scales, scores between 6 and 30 represented levels of distress, while scores between 0 and 10 represented pain. Local pain was registered when infusions were administered via a PVC, and general pain was registered when infusions were administered via a CVC. Further, objective signs of inflammation  at the infusion site were registered for PVC administrations. Data were collected using a web-based survey developed in REDCap . For eacThe main outcome was a change in mean pain score before and after paracetamol infusion.We aimed to include 40 consecutive patients and allowed more than one data registration on individual patients.t tests were used to test for differences in mean pain score before and after paracetamol infusion with a P value < 0.05 considered statistically significant.Statistical analyses were performed using R version 3.6.1. Two-tailed paired 3We included 44 individual patients and data were registered during 93 paracetamol infusions. Two infusions were excluded because the duration of infusion exceeded 5 min. The primary diagnoses were acute lymphocytic leukaemia, acute obstructive laryngitis, anaemia, brain haemorrhage, brain tumour, craniosynostosis, gastroenteritis, headache, hydronephrosis, meningitis, osteomyelitis, pericardial disease, pneumothorax, preterm birth, post-surgery for gastrointestinal diseases related to preterm birth, skin infection or other malignancies. The indication for paracetamol prescription was pain in all patients. Patient and treatment characteristics are presented in 3.1P = 0.007, P = 0.11, P = 0.03). There were no signs of inflammation related to paracetamol infusions when administered via PVCs. In one patient, there was a report of pain when the infusion was aimed to be administered during less than 5 min, and the pain disappeared when the infusion time was changed to 10 min. The same patient had a previous infusion of less than 5 min with no report of pain.Across the 93 infusions, the mean pain score decreased, comparing pain scores before and after infusions  −0.45 to −0.07, 4With this safety study, we demonstrated that rapid paracetamol infusions were well-tolerated in patients below the age of 18 years. Paracetamol was successfully infused with a median infusion time of 3 min without inducing pain or objective signs of local inflammatory reactions, as previously shown in adults. Needleman et al. reviewed 100 medical charts of adult patients who received paracetamol with a median infusion time of 3:41 min, and they found only one patient who reported pain during the infusion . In our In general, IV infusions of solutions with unphysiological osmolarities generate a high incidence of pain, whereas solutions with physiochemical properties close to plasma can be infused without causing pain . AccordiNumerous and time-consuming infusions contribute to prolonged hours spent in inactive situations, especially for patients whose recovery depends on these infusions, e.g., in paediatric oncology. Further, health care professionals spend time with the patient during the longer infusions, which makes their work less flexible and efficient. A reduction in the duration of four daily paracetamol infusions from 1 h per day to 20 min per day may improve both the patient experience and quality of work for health care professionals.The strengths of this study are the prospective registration of pain intensity before and after paracetamol administration in a real-world setting. The patients represented a variety of diagnoses and ages, which make the results generalisable to patients at paediatric and neonatal departments. The study is limited by the relatively small sample size, the observational safety study design without a reference group, no assessment of vital parameters during the infusions, and no registration of concomitant medication or potential drug–drug interactions.5Paracetamol can be administered as a rapid IV infusion in paediatric patients without causing pain or signs of inflammation. The results may contribute to more cost-effective pain control by reducing the time of inactivity for patients and health care professionals.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in Current Research in Pharmacology and Drug Discovery.Astrid Eliasen: Conceptualization, Methodology, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization. Sigrid Otnes: Conceptualization, Methodology, Investigation, Resources, Writing – review & editing. Merete Matz: Conceptualization, Methodology, Investigation, Resources, Writing – review & editing. Lise Aunsholt: Conceptualization, Investigation, Resources, Writing – review & editing, Supervision. René Mathiasen: Conceptualization, Methodology, Writing – review & editing, Supervision.None.


Postural stability is a little-studied factor in non-specific chronic neck pain; the causes that can alter it are unknown. The relationship with chronic pain could be a determining factor for its deficit. The aim of this study was to investigate the relationship between sustained pain and a postural stability deficit. A randomized and blinded clinical trial  was conducted with a total of 69 subjects divided into three groups, two experimental  and a control treatment, and carried out over a treatment period of three weeks with a follow-up after 12 weeks. Their postural stability was assessed through the overall balance index (OBI). The postural stability of subjects with non-specific chronic neck pain improved in the experimental treatments. There were no statistically significant differences between the experimental groups. This trial found that manual therapy and therapeutic exercise significantly improved OBI compared to the control group. Trial registration: Brazilian Clinical Trial Registry, RBR-2vj7sw. Non-specific chronic neck pain (NCNP) is a severe condition in many patients whose functional capabilities are reduced and is a significant issue for healthcare systems globally ,2. The uA disturbance in the cervical proprioceptive system may trigger symptoms such as dizziness or vertigo because of connections between this system and the visual and vestibular systems ,9. That This phenomenon has been assessed previously, and it was found that patients with NCNP and post-traumatic neck pain suffer greater drunkenness and fainting sensations and a lack of proprioception than patients with benign paroxysmal vertigo . FurtherHowever, this is not the only theory developed to explain how this multifactorial system can be altered. Some studies indicate that there is a proprioceptive disturbance due to sustained exposure to pain that affects PS through the CNS; these changes may be due to changes in the cortical representation and the interaction between mechanical, central, and peripheral mechanisms ,21,22, aThe effectiveness of manual therapy and therapeutic exercise in patients with NCNP has been proven in numerous studies to improve pain, disability, and dizziness ,28,29,30Our study aims to analyze and compare the effects of two experimental treatments that help to reduce pain through different mechanisms of action, and to evaluate the evolution of cervical pain and its relationship with changes produced on postural stability. We hypothesize that both treatments will decrease neck pain intensity and that these changes will be related to improvements in postural stability.The randomized clinical trial was designed as a controlled, parallel, double-blinded, three-arm clinical treatment trial.Individuals with NCNP were recruited through a text message broadcast on Seville (Spain) social networks and were selected based on the eligibility criteria listed below. The study took place at the facilities of the physiotherapy department of the University of Seville.Patients between 18–50 years old with current neck pain, with pain having been experienced over the last three months.Exclusion criteria included: irradiated neck pain or pain associated with vertigo; diagnosed psychological disorders; radiological findings such as vertebral fractures, tumors, osteoporosis, or others; a history of neck surgery; red flags such as night pain, severe muscle spasm, loss of involuntary weight, symptom mismatch as unexplained symptoms outside of the clinical context; and other physiotherapeutic or pharmacological treatments continued in the previous twelve weeks.The manual therapy protocol was composed of three techniques based on scientific evidence for neck pain treatment ,33,34. THigh Thoracic Manipulation on T4. Patients are positioned supine with their arms crossed in a “V” shape over the chest. The therapist makes contact with the fist at the level of the spinous process of T4 and blocks the patient’s elbows with his chest; following this, he introduces flexion of the cervical spine until a slight tension is felt in the tissues the point of contact. Downward and cranial manipulation is applied. If cavitation is not achieved on the first attempt, the therapist repositions the patient and performs a second manipulation. A maximum of two attempts will be allowed in each patient .Cervical Articular Mobilization . The patient is placed on the stretcher prone, placing both hands under his forehead. The therapist makes contact with his two thumbs on the spinous process of the patient’s C2 vertebra and performs grade III posteroanterior impulses at a speed of 2 Hz and for two minutes. There are three mobilization intervals with a minute of rest between each one of them .Suboccipital Muscle Inhibition (3 min). With the patient lying supine, the therapist places both hands under the subject’s head by contacting their fingers on the lower edge of the occipital bone, exerts constant and painless pressure in the anterior and cranial direction for three minutes ,35.Therapeutic Exercise protocol: this protocol is based on a progression in load composed of different phases. At first, activation and recruitment of deep cervical flexors . SecondlWEEK 1: Exercises 1 and 2.Cranio-cervical flexion (CCF) in supine position with a towel in the posterior area of the neck. .CCF sitting. .WEEK 2: Exercises 1, 2, 3, and 4.3.Co-contraction of deep and superficial neck flexors in supine decubitus. .4.Co-contraction flexors, rotators, and inclines. Patients will perform cranial nerve flexion while the physiotherapist asks them to tilt, rotate and look towards the same side while he opposes a resistance with his hand. .WEEK 3: Exercises 1, 2, 3, 4, 5, and 6.5.Eccentric for extensors. The patient seated should perform cervical extension; then, they must complete a cranio-cervical flexion and finish doing a cervical flexion (10 repetitions).6.Eccentric for flexors. The patient will be in a quadrupedal and neutral neck position, should perform neck flexion. They must complete a cranio-cervical flexion and maintain that posture extending the neck and then finally losing the cranio-cervical flexion (10 repetitions).Control protocol: Patients were placed in the supine position, while the physiotherapist, sited at the head of the table, sets the palms of his hands under the subject’s head, his fingers contacting the space between the occipital condyle and the spinal process of the second cervical vertebra, but with no pressure at this region, simulating the technique of suboccipital inhibition . After tOutcomes were measured in the pre-evaluation, at week 2 (immediate short-term), week 4 (short-term), and week 12 (medium-term). These evaluations were carried out by a blinded and trained evaluator.Visual Analog Scale (VAS) for pain. The subjects participating in the study indicated the intensity of their pain using a VAS of 100 mm length, and had to signal on a horizontal line of 100 mm where they would place their pain, where zero mm indicated no pain, and 100 mm indicated the worst pain imaginable . Only diOverall Balance Index (OBI). We obtained this measurement through a dynamic stabilometric platform . The general stability test was applied in difficulty four (4), with one (1) being the highest and eight (8) the slightest difficulty. The platform is free in the anterior-posterior and medial-lateral axes; it allows obtaining the OBI through the deviations concerning a zero point established before the test, with the platform stable. Two 20-s tests were performed, with one minute between each test, with the second test score that was chosen for the statistical analysis. The index is calculated through the anteroposterior and medial-lateral relationship + standard deviation ,41. SubjThe sample size was calculated using the Granmo calculator v.7.12, based on: the analysis of the variance of means, estimation of an alpha risk of 5% (0.05), a beta risk of 10% (0.10), and in a unilateral contrast, a typical deviation of 12% (0.12). The minimum difference to detect was 13.5% (0.135), which was based on the minimum clinically important differences in the VAS . Finallyrandomization.com (Available from: http://www.randomized.org/ (accessed on 15 January 2019)). Only the principal investigator and auditor knew the randomization sequence, which was guarded throughout the study and kept hidden from the study participants .Subjects were divided into three groups  by a simple randomization process carried out with free software called Evaluators and participants in the study were blinded during the entire process. The evaluators were unaware of the study objectives and the allocation of patients in the study groups. The patients did not know which group they belonged to. The principal investigator and auditor obtained the randomization sequence. No participant in the study had access to the randomization sequence, hidden and saved, to guarantee correct randomization with security.Within a large-scale clinical trial, with multiple dependent study variables, a specific analysis of the variables related to stability and pain, and their correlations, was performed.t-test for paired variables was involved in the case of parametric distributions and Kruskal–Wallis H for non-parametric distributions. One-factor ANOVA was used for the intergroup hypothesis contrast in parametric distributions and Kruskal–Wallis H for nonparametric distributions. Post hoc analysis was obtained through Bonferroni’s contrast for parametric distributions and Mann–Whitney’s U for nonparametric distributions Spearman’s Rho was used to analyse associations between pain  and postural stability. The confidence level used was 95% (0.05), and the power of the study was 90% (0.1).The statistical analysis was carried out using the IBM-SPSS Statistics 24 software. The normality test applied to all the variables was the Kolmogorov–Smirnov test. For the contrast of intergroup hypotheses, the student’s Sixty-Nine of the 81 subjects interviewed started the study, of which 65 completed our trial, with a completion rate of 94%. There were four follow-up losses; three of them focused on the control group and one on the manual therapy group. A CONSORT flows diagram is presented in Participants’ baseline characteristics can be seen in The intergroup analysis showed significant improvements for both variables (VAS and OBI) in all evaluations performed in both experimental treatments (MT and TE). The control group did not show differences in VAS and OBI in any assessments. The mean values and their statistical significance are shown in Concerning VAS, the intergroup analysis showed that experimental treatments did not acquire immediate statistically significant results compared to the control group in the short-term. Nonetheless, in the second (week 4) and third evaluations (week 12), statistically significant effects were observed compared to the control group but not between experimental treatments. Improvements were 30.35 [20.98–39.72] in the therapeutic exercise group and 26.14 [1.29–36.98] in a manual therapy group, both in the short-term; in the medium-term, improvements were 23.74 [10.34–37.13] and 23.73 [12.01–35.45], respectively. All of them were higher than 15 and, thus, clinically relevant  exceeded 9.8%, so they could be considered clinically relevant. In the medium-term (week 12), differences were maintained again, obtaining statistical significance in the two experimental groups and placing their difference of means at 1.53 [0.22–2.83] for manual therapy and 1.08 [−0.21–2.38] for therapeutic exercise regarding the control group, maintaining clinical relevance in the medium-term. No significant differences were obtained between the experimental groups, placing their mean difference at 0.44 [−0.84–1.72]. All expressed values are described for a confidence interval of 95%. The values of statistical significance, mean differences and confidence intervals are shown in Regarding the OBI, in the first week of treatment, only the manual therapy group obtained statistically significant differences, obtaining a mean difference with respect to a control of 1.41 [0.32 to 2.50]. However, the intergroup analysis reflected statistically substantial improvements; the intergroup comparison did not get statistically significant results for the therapeutic exercise group when compared to the control group in the first week of treatment, so progress in the TE group was not sufficient to corroborate the hypothesis in the post hoc (Bonferroni). In the short-term (week 4), both experimental treatments achieved statistically significant differences compared to the control group. The OBI mean difference was 2.30 [0.98–3.63] for manual therapy and 0.88 [−0.44–2.19] for therapeutic exercise, exceeding 9.8% of the baseline value, which is the reference value to establish clinical differences . In addiThis randomized and blinded clinical trial examined changes in the short and medium-term in postural stability and pain perceived by non-specific chronic neck pain subjects.Our results indicate a clear improvement in VAS and OBI in both experimental groups concerning the short- and medium-term. The control group did not obtain improvements in any of the evaluations. In the immediate short-term, there were not sufficiently large differences in terms of pain between the experimental and control groups, which could be explained by the immediate neurophysiological effects of placebo, which has been observed ,44. TherOur central hypothesis was based on an alteration of the postural stability produced by a disorder in the reception of proprioceptive signals by the proprioceptive, vestibular, visual, and central nervous systems. Other authors have already theorized and opined in this regard about this unknown complex ,20,21,48However, the correlation analysis between VAS and OBI clearly shows no correlation between these two variables, which leads us to think that pain and other factors should be considered when improving postural stability.Our trial carried out two experimental treatments in two subgroups of patients with NCNP, one through manual therapy and neurophysiological effects ,50,51,52On the other hand, some authors have begun to point out the psycho-behavioral aspects that could significantly influence cervicogenic dizziness and the alteration of postural stability, such as anxiety, depression, fear of movement, or pain catastrophizing ,5,48. WeThe main limitations of our study are that the sample size is not too large and that we only measured a variable representative of postural stability, for this variable an ICC analysis has not been performed. Future studies should assess the pain–postural stability relationship through other technical methods to refute or confirm our findings. In addition, in research about this field, we would find it interesting to include additional features, such as psychosocial variables . Future studies could also check whether the observed stability improvement only occurs in patients with NCNP or other populations with acute/subacute neck pain or whiplash-associated disorders. Our findings could have a significant clinical implication, and be useful for clinicians since we provide active and passive treatment protocols which have proven efficacy and could be chosen or combined depending on the patient’s characteristics.p < 0.05) in the visual analogic scale and overall balance index concerning the control group. The correlation between pain and postural stability was not demonstrated.Both experimental protocols  produce significant improvements (


Xiphodynia, the painful xiphoid process, is a rare condition with an atypicalpresentation. Symptoms differ in severity and site, and can consist ofchest, throat, and upper abdominal pain. Primarily, other more severe causesof these symptoms need to be excluded. After this exclusion as xiphodynia isdiagnosed, treatment can consist of a multitude of options, since there isno consensus regarding the optimal treatment. The aim of this study was todescribe the outcomes and efficacy of one of the options, namely surgicalresection of the xiphoid in patients with xiphodynia.In this retrospective case series, all consecutive patients that underwentxiphoidectomy for xiphodynia between January 2014 and December 2017 wereincluded. Patients’ medical files including pre-operative work up, NRSscores, surgical outcomes, and follow up were reviewed. All patientsreceived a questionnaire with follow-up questions.A total of 19 patients were included. None of the patients hadsurgery-related complications. Response rate of the questionnaire was 84%and showed that 94% of patients had an improvement of complaints aftersurgery, with 10 patients (63%) being totally pain free, after a meanfollow-up from 34 months after surgery.Xiphoidectomy is feasible and safe for the treatment of patients withxiphodynia with an improvement of complaints in nearly all patients. Descriptions of treatment of xiphodynia consists of several options includingphysiotherapy, local anesthetic injections and surgical removal of the xiphoid(xiphoidectomy).11Literature discussing this condition is very limited. Since the first description ofxiphodynia in 1712,Theoretically, xiphoidectomy offers the only permanent treatment option, since theorigin of complaints is surgically removed. However, very little is known about thesurgical outcomes and effectiveness of this procedure.The aim of the current study was to describe the effect of surgical treatment in thelargest to date case series of patients in which xiphoidectomy for xiphodynia wasperformed.A retrospective, single center case series was performed, including allconsecutive, adult patients undergoing xiphoidectomy for xiphodynia from 1January 2014 until 31 December 2017. There were no exclusion criteria other thanthe required significant increase in pain upon direct pressure to the xiphoidand exclusion of more severe causes of chest and epigastric pain. A list ofpatients undergoing xiphoidectomy was prospectively maintained so no patientswere missed. All patients gave informed consent. The medical ethical committeeof the hospital gave permission for the study.Electronic patient files were retrospectively reviewed in order to collect studydata, which were registered in a protected Excel® database. Routine follow-upwas scheduled at four weeks after surgery in all patients. Additionally, allpatients were contacted and received a follow-up questionnaire after 2.5years.Baseline characteristics included patient demographics, duration, nature andseverity of preoperative symptoms, presence of recurring micro trauma to thexiphoid, additional examinations, previous consultations with other specialtiesand previous treatment. Severity of symptoms was measured using a Numeric RatingScale (NRS) ranging from 0 to 10, with 0 being no pain and 10 being the mostsevere pain imaginable.The primary outcome of this study was relief of symptoms, which was measured bycomparing pre and postoperative NRS scores. Secondary outcomes included patientsatisfaction and operative complications. For measurement of patientsatisfaction, a five-point Verbal Rating Scale (VRS) was used.Xiphoidectomy is performed with the patient in supine position under generalanesthesia by making a 3-cm midline incision at xiphoid level. The xiphoid isexcised with the perichondrium and/or removed with diathermy  and 2. BA total of 19 patients underwent xiphoidectomy for xiphodynia during the studyperiod. None of them had a history of surgery in the sternal area. At four weeks after surgery, 14 of the 19 (74%) patients were free of pain, 4(21%) patients experienced a decrease of pain and 1 (5%) patient did not attendthe outdoor clinic appointment.Sixteen (84%) patients returned the questionnaire, with follow-up after surgeryranging after a mean follow-up from 34 months after surgery. Of these 16patients, all but one experienced a reduction in complaints after surgery, while10 patients (63%) remained free of pain . The meaNearly all patients suffering from xiphodynia in the current study experienced arelieve of complaints after xiphoidectomy without any surgical complications,suggesting that surgical removal of the xiphoid process is an effective treatmentstrategy in these patients. the first xiphoidectomy was reported in 1852 and since then only case reportsand small case series have been published, leaving much to be debated.115 The number of patientsincluded in this study in a relative short period of time (4 years) is probablycaused more by the dense population of the Netherlands and the open health caresystem than by a higher incidence of xiphodynia in the Dutch population. Remarkableis the loss of quality of life in these group patients, caused mainly by intermittedpain and urge to avoid the trigger of the pain.Very little is known about xiphodynia and current literature is scarce. According toLipkin et al.,4In our study group, one patient had complaints fitting xiphodynia started two monthsafter given birth; however, these complaints spontaneously disappeared withinmonths, but relapsed after 4.5 years. A relationship between loss of weight andoccurring of the complaints could not be established in this study group. Thisseries shows five persons had a history of trauma to the chest wall, but only oneperson had a sternal fracture at the xiphisternal joint. Maigne et al. proposed thatmechanical discomfort and local inflammation caused by an abnormal anteriorprominence of the xiphoid might be of influence. In the patients, the resected specimens were reviewed and showed noinflammatory or other abnormalities.It is hypothesized that recurrent traumatic injury, recent weight loss, previouspregnancy or previous surgery of the xiphoid process may contribute to thedevelopment of xiphodynia.1618 We stress the importance ofexcluding any life-threatening diseases first, before diagnosing a patient withxiphodynia.Patients mostly present with long-lasting pain in epigastric, often radiating to thearms, neck, and back. In a majority of the patients, the complaints are intermittentand are provoked by certain movements, like bending down, eating large meals orexertion. The pain on clinical examination is located directly over the xiphoid andprovoked by direct pressure. One could argue that by applying downforce pressureover the xiphoid, the exact location of the pain could be confined to the xiphoidbut could also be located in the sternal-xiphoid junction, although neverestablished. The complaints can mimic more life-threatening diseases, which need tobe excluded first. This is according to the current practice in our center. Forexample, the radiating pain in an arm can be a sign of cardiac illness, likewiseradiating pain in the back can be a sign of vascular (aortic) disease orneurological disease. Pain in the epigastric region can be caused by stomach,esophagus disorders or abdominal wall hernia. The provocation of pain by certainmovements suggests a partly mechanical issue. The majority of patients treated haveseen several specialists and underwent several additional examinations to excludeother diseases. Scintigraphy was not added to the workup, because from the study ofSiberstein et al., we know that the natural uptake is increased in xiphoidcartilage, tendon, and ear cartilage, which can lead to improper conclusions.Scintigraphy can however be useful in the diagnosis of sternal fractures during theearly period after thorax trauma  or for diagnosis of deep sternalinfections after sternotomy for cardiac illnesses .15A useful addition to strengthen the decision making process could be the possibledisappearance of pain after local injection over the xiphoid with bupivacaine®. Oncediagnosed, the proposed treatment options for xiphodynia vary from physiotherapy andoral use or local injection of analgesics to surgical removal of the xiphoid.However, the optimal treatment strategy has not yet been identified.15 Theoretically, xiphoidectomyoffers a permanent solution to the complaints but can be associated with theinherent risk of complications of a surgical intervention. First of all, the currentstudy showed that xiphoidectomy offers at least a partial relieve of symptoms innearly all patients but still a few patients experienced residual pain. Only 63% ofpatients were pain free after follow-up. These results suggest that xiphoidectomy isindeed an effective treatment strategy. A difference in treatment effect on specificpatients may be expected based on their preoperative baseline characteristics. Domet al. proposed that patients suffering from xiphodynia who had undergone previoussurgery in the epigastric area might not benefit from xiphoidectomy, while patientswith pressure pain and an abnormal ventral protrusion of the xiphoid might. The current study did not identify new predictors of treatment effect. It isspeculated that patients that experience a clear relieve of symptoms after localinjection with a long acting analgesic might be the best responders to surgery.In recent literature, xiphoidectomy is described several times as treatment forxiphodynia, with mostly successful results.Furthermore, none of the patients in the current study or in the scarce literatureexperienced any complications during surgery or follow-up, clearly demonstrating thesafety and minimally invasiveness of xiphoidectomy.This study has several limitations. First, although it is a large case series aboutthis relative rare condition, the number of patients is small and the nature of thestudy is retrospective, making it necessary to interpret conclusions carefully.Second, little is known about the underlying pathophysiology which again is a causefor caution. Third are the unknown causal relationships of the condition with otherphysical or psychological factors, making any correlation sensitive to bias.In conclusion, before diagnosing xiphodynia, other, more severe diseases must beexcluded. Once diagnosed, xiphoidectomy is likely to offer a relieve of symptomswith very little risk of postoperative complications.


Lumbosacral radicular pain (LSRP) can be caused by disc herniation, spinal stenosis, and failed back surgery syndrome. The clinical effect of pulsed-radiofrequency (PRF) combined with transforaminal epidural steroid injection (TESI) for radiating pain in different population remains unclear.We retrospectively reviewed the medical recordings of patients with LSRP caused by different etiologies, who underwent PRF and TESI treatment. The primary clinical outcome was assessed by a 10-point Visual Analog Scale (VAS) pre- and post-treatment.A total of 34 LSRP patients were identified and classified into 3 subgroups . The overall immediate pain reduction was 4.4 ± 1.1 after procedure. After a median follow-up of 9.5 months, the VAS decreased from 6.5 ± 1.0 to 2.4 ± 1.9 at the last follow-up.PRF combined with TESI is an effective approach to treat persistent LSRP in distinct population. Lumbosacral radicular pain (LSRP) is defined as a radiating pain affected one or more lumbar or sacral dermatomes . LSRP isA complex interplay between mechanical, inflammatory, immune and neurophysiologic mechanism of dorsal root ganglion (DRG) attributes to the chronicity of radicular pain . Thus, iDespite PRF therapy, spinal injection is another important technique to treat radicular pain when conservative therapy is ineffective. To treat chronic LSRP, different approach of epidural injections, including transforaminal epidural steroid injection (TESI) and interlaminar epidural steroid injections, can be considered. The overall percentage of the patients with significant functional improvement and pain relief receiving TESI treatment was higher than interlaminar routine . Given tWe conducted a retrospective analysis of medical recordings in the Department of Pain, the Third Xiangya Hospital between August 2019 and February 2021. All participants presented unilateral or bilateral LSRP. DH or SS was confirmed with either computed tomography or magnetic resonance imaging. We also enrolled patients present with sustained radiating pain after back surgery. One or more oral analgesic medication, or nerve block was administrated prior to surgery. This study was approved by the local ethics committee of the Third Xiangya Hospital (No. 21035) and conducted in accordance with the Declaration of Helsinki. Patients with pathologic history were excluded for further study, including tumor, fractures, and infection. The enrolled patients were subsequently divided into three subgroups according to the etiology , as shown in All interventional procedures were performed under the guidance of C-arm fluoroscopy (TOSHIBA). Patients were placed prone position, and kept awake during the procedure to respond the test of sensory stimulation. Local anesthesia was administrated to the skin entry with 1% lidocaine in a total volume of 5 mL.To perform PRF therapy, a 22-G curved-tip cannula was applied to place adjacent to the DRG . One catThe primary outcome was the pain scores in LSRP patients. Visual analog scale (VAS) was used to evaluate the pain intensity, ranging from 0 (“pain free”) to 10 (“worst pain imaginable”). Patients who achieved reduction of pain over 50% compared with baseline were considered as “responder.” Patients were assessed pre- and post-treatment. To identify the long-term therapeutic effect, a telephone interview was conducted after discharge from hospital.t-test. P < 0.05 was considered significant.Statistical analysis was performed with GraphPad Prism 8 . Variables are presented as the mean ± standard deviation. The pain score changes were assessed pre- and post-therapy with paired Student’s We identified 34 patients  with LSRP who underwent 57 PRF procedures combined with TESI from August 2019 until February 2021. The average age of participants was 65 ± 11.8 years. The L4-5 spinal nerve accounted for the most common lesion, affected 49 of 73 (67.1%) painful dermatomes. Patients presented moderate to severe radiating pain at admission, with a mean baseline VAS of 6.5 ± 1.0. In this study, about 76.4% patients (26 out of 34) underwent one or twice procedures during hospitalization. The general demographics of enrolled patients is given in All patients were evaluated pre- and post-surgery. We performed one routine follow-up 1 month after discharge from hospital for all participants. The median time of the last follow-up was 9.5 months, ranging from 1 to 18 months.The initial relief from pain is given in Next, we compared the effect of PRF and TESI on pain scores between different groups at 1-month after discharge and the last follow-up . In geneLSRP is common and results from diverse etiologies, including DH, SS, and FBSS. One general feature of LSRP is sensitization of spinal nerve root or DRG, caused by mechanical, inflammatory, immune and neurophysiologic factors. Thus, novel neuromodulation therapy targeted DRG may provide an alternative option to treat LSRP.The most common cause of LSRP is DH . HoweverIn recent years, radiofrequency therapy has evolved as a promising neuromodulatory technique for the management of various chronic pain syndromes, like radicular pain, trigeminal neuralgia, occipital pain, shoulder and knee pain . In currTESI is more specific and selected nerves can be targeted during treatment, compared with interlaminar or caudal route access. The degree of nerve root compression is the key factor to predict the long-term therapeutic effect . Thus, oMeanwhile, patient who underwent spinal surgery may still experience pain due to previous sensitization of the nerve root . TESI maOne novel strategy of neuromodulation for LRSP is electrical DRG or spinal cord stimulation, which is most widely applied in patients with FBSS . Unlike Current study has several main limitations. Firstly, the clinical data were collected retrospectively and the number of DH, and SS subgroup was smaller than FBSS. Actually, we found more patients presented intractable radicular pain with previous back surgery, compared with non-surgical population. Further study with larger cohort is needed to confirm the incidence of LRSP for individual etiology. Second, the uncontrolled nature of study design. Previous study has demonstrated the clinical efficacy was changed in different therapies (TESI vs. PRF vs. TESI combined PRF) . HoweverIn summary, PRF combined with TESI is an effective approach to treat LSRP in patients, providing considerable sustained relief from pain with distinct etiology.The data are not publicly available due to privacy and ethical reasons. The data presented in this study are available on reasonable request from the corresponding author.The studies involving human participants were reviewed and approved by the ethics board of The Third Xiangya Hospital, Central South University (No. 21035). The patients/participants provided their written or verbal informed consent to participate in this study.HZ and DH: conceptualization, investigation, supervision, project administration, and funding acquisition. LY, YH, RHa, GG, YN, RHu, XY, DH, and HZ: methodology. LY, YH, and ZL: formal analysis. LY, ZL, and HZ: data curation. YH and HZ: writing—original draft preparation. HZ: writing—review and editing. All authors have read and agreed to the published version of the manuscript.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.


Worldwide, knee osteoarthritis (KOA) accounts for 2.2% of total years lived with disability. There is a low correlation between joint tissue damage and pain intensity. Periarticular structures may be involved and cannot be identified in X-rays. To describe the main ultrasonography (USG) changes in symptomatic patients with primary KOA; to correlate the number of USG findings with KOA severity assessed by Kellgren and Lawrence (K&L) radiological scores, with pain intensity measured by a visual analogue scale (VAS) and with functioning scores assessed with the Timed up and go test (TUG) and Western Ontario and McMaster Universities (WOMAC) questionnaire. 100 patients with primary symptomatic KOA were assessed with X-ray and USG. Quantitative and qualitative analyses were evaluated in a systematic manner. The most frequent findings were joint effusion, pes anserinus bursitis, quadriceps tendon enthesopathy, popliteal cyst, iliotibial band tendinitis and patellar tendinitis. Pearson’s correlation analysis demonstrated a significant moderate positive association between VAS scores and the number of USG findings . The number of USG findings was different between K&L grades I and III (p = 0.041), I and IV (p < 0.001), and II and IV . There was significant association between number of USG findings and TUG  and WOMAC scores for pain  and physical function domains . The most frequent USG finding was joint effusion. Periarticular structures should be explored as potential sources of pain and disability. Among these disorders, knee osteoarthritis (KOA) is a leading cause of disability in the elderly population and a common health condition in this population2. Worldwide, KOA is the 11th leading cause of global disability, accounting for 2.2% of total years lived with disability2. With the aging of the global population, it is relevant to keep people healthy and functioning properly. Currently, there are no disease-modifying interventions for KOA, despite the understanding of the joint pathology at the molecular level4. In fact, there is a low correlation between joint tissue damage and pain intensity7. Severe joint damage visualized in the knee X-ray is present in asymptomatic people with KOA5. On the other hand, 10% of people with severe knee pain have normal X-rays6. About 10–20% of people with KOA develop generalized pain7. Lack of proper understanding of the mechanisms involved in pain generation, maintenance and amplification and therefore adequate management strategies leads to an exponential increase in the number of total knee replacements worldwide8.Musculoskeletal disorders are the group that most contribute to the need for rehabilitation, due to their high prevalence and contribution to total years lived with disability3. The main changes identified in a knee ultrasonography (USG) assessment revealed joint effusion, popliteal cysts and tendinopathies15. USG is a non-invasive, fast and operator-dependent imaging technique that allows the visualization of changes in these structures. However, there is remaining controversy about the existence of correlations between USG findings, Kellgren and Lawrence (K&L) grades14, pain scores and functionality in previous studies15.Several authors have already identified the presence of periarticular  or intra-articular changes in people with symptomatic KOATherefore, the objectives of our study were to describe the main USG changes in symptomatic patients with primary KOA; to correlate the number of USG changes and the severity of the X-ray findings using the K&L radiological scores; and to determine if there is a significant correlation between the number of the USG changes and the pain intensity measured by a visual analogue scale (VAS) and functioning scores assessed with Timed up and go test (TUG) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires.16; high or moderate pain intensity: VAS > 4; knee pain duration > 3 months; absence of severe psychiatric disorder requiring follow-up assistance; no clinical diagnosis of associated fibromyalgia; absence of associated systemic inflammatory rheumatic diseases; absence of a history of neoplasms and absence of predominant clinical manifestations in other joints. Written informed consent was obtained from all the participants.This is a prospective observational cross-sectional study without a control group. We assessed the knee USG findings in persons with primary symptomatic KOA. Data from this study were obtained by another study entitled “Inhibitory deficit as a marker of neuroplasticity in rehabilitation” approved by Hospital das Clinicas Comite de Analise de Projetos de Pesquisa CAPPesq, by the local Ethical Committee CAPPesq (CAAE: 86832518.7.0000.0068). A total of 100 consecutive consenting patients with primary symptomatic KOA (194 knees) were included following these criteria: age > 50 years; clinical and radiological diagnosis of KOAAll methods were carried out in accordance with relevant guidelines and regulations.17 and knee functioning using the WOMAC scores18 and the TUG19.We excluded secondary causes of KOA during the clinical evaluation of all patients. All patients were evaluated for pain using a VAS20  was used for the knee X-ray exams. Plain radiographic knee examinations were performed in all patients in three incidences: anteroposterior (AP) with load, lateral and axial patella. Classification of KOA severity was performed using the K&L scores20 Fig.  assessedKnee USG evaluations were performed using a Siemens Sonoline G40 USG equipment with multi-frequency linear transducers of 5–13 MHz . Patients lied down in the dorsal decubitus with the examined knee flexed at a 30-degree angle using a cushion device. Images were obtained in the axial plane  to assess the patellar region. In the sequence, we analyzed, in the longitudinal plane, the enthesis with insertion of the quadriceps tendon, the patellar tendon , as well as the medial and lateral collateral ligaments, the topography of the iliotibial tract and the components of the pes anserinus bursae. Subsequently, patients were placed in ventral decubitus where the axial and longitudinal planes allowed the visualization of the popliteal fossa. In this view, we were able to assess the presence of effusion as well as of popliteal cyst, also known as Baker’s cyst.Quantitative and qualitative analyses  were all assessed in a systematic manner.Effusion the presence of increased articular fluid (> 4 mm), visualized as a hypoechogenic or anechogenic displaceable material in the knee joint cavity  were quantified. Then, pain intensity measured by the VAS for each knee was tested in association with the number of ultrasound findings by Pearson correlation. Knee function, assessed by the TUG and the WOMAC in the pain, stiffness and difficulty to perform exercises domains, were also tested in association with the number of USG findings using the Pearson’s correlation (r). The number of knees included in the evaluations was 194, a sample size that allowed the assumption of the central limit theorem, i.e. this sample has an approximately normal distributionIn a secondary analysis, we tested whether the number of USG findings varies significantly according to the K&L classification using the analysis of variance (ANOVA) with Bonferroni correction for multiple analysis.Demographic data regarding age, gender, time of pain, body mass index (BMI) and education were analyzed as to whether they were also associated with the mean baseline pain intensity between the two knees, K&L scores ≥ 1, for a better description of demographic influence on pain.Age, time of pain, and BMI were analyzed for pain intensity by simple linear regression, gender was analyzed by Student’s t-test, and education  by variance analysis. Demographic data were not tested in conjunction with ultrasound changes because they were not related to just one knee.® statistical package.Statistical significance was considered if p < 0.05, two-tail, and analysis was performed using the Stata 14Approved by Hospital das Clinicas Comite de Analise de Projetos de Pesquisa CAPPesq. Already approved by the local Ethical Committee CAPPesq (CAAE: 86832518.7.0000.0068).One hundred patients diagnosed with symptomatic KOA were included in the study. Six patients had unilateral total knee arthroplasty; therefore, 194 knees were evaluated. A single USG finding was observed in 48 knees 24.74%), two in 47 (24.23%), three in 26 (13.40%), four in 24 knees (12.37%) and five in 27 knees (13.92%). USG findings were not observed in 22 knees . The most frequent findings were effusion , pes anserinus bursitis , popliteal cyst , enthesopathy of quadriceps tendon , iliotibial band tendinitis , and patellar tendinitis . The demographic description of the patients included in this study is presented in Table 4.74%, twWhen categorizing the sample by K&L grades, we observed that the number of USG findings was different for classifications I and III (p = 0.041), I and IV (p < 0.001) and for classifications II and IV (p < 0.001), ANOVA with Bonferroni correction. In all other comparisons in the K&L classifications, there was no evidence of a different number of USG findings.Demographically, the only characteristic that correlated with pain intensity was the education level; higher education levels correlated with less pain reported by the patients. Neither sex, age, pain duration nor BMI demonstrated significant correlations. Post hoc analysis investigated a possible correlation between the number of USG findings and the education level, suggesting collinearity and therefore education as a confounder for the analysis. It was not possible to demonstrate this event as Pearson’s correlation (r) between the variables was low, and without a statistical significance . None of the other demographic variables correlated with pain. The results are presented in Table Our study identified USG changes in 78% of the examined knees. Main USG findings were small to moderate joint effusion, pes anserinus bursitis, quadriceps enthesopathy, popliteal cyst, iliotibial band tendinitis and patellar tendinitis. Together with the high prevalence of USG findings, we identified a significant positive correlation between the number of USG findings and pain intensity scores measured by a VAS.24. Mendieta et al.9 found significant positive correlation between the presence of pain and greater K&L grades. The presence of Baker’s cyst tended to be statistically more present in patients with KOA compared with the control group (p = 0.06) and, when present, the odds ratio for pain was 5.5 . Hall et al.12 identified a positive association of the findings of joint effusion with higher radiographic scores , and of joint effusion with pain intensity. In the study of Malas et al.13, 122 knees from 61 patients were classified into two groups based on symptom severity. They observed that the presence of Baker’s cyst and joint effusion seen with USG was more prevalent in the group of more symptomatic knees when compared with the group of less symptomatic ones, such that the authors suggest that Baker’s cyst and joint effusion are associated with pain and function. Abd El Monaem et al.15 reported a positive association between pain intensity and USG detected joint effusion and Baker’s cyst volumes, as well as a correlation between functionality scores measured by WOMAC and USG features (joint effusion and Baker’s cyst volumes and thickness of the quadriceps tendon). In the study of Monteforte et al.23, joint effusion and Baker’s cyst were also the main USG findings described in patients with symptomatic KOA. They detected a statistically significant relevance for joint effusion and presence of Baker’s cyst in the symptomatic group. Naredo et al.24 reported that the presence of joint effusion was associated to the presence of Baker’s cyst and to higher pain intensity measured by VAS. Also, they found that pain intensity was not related to the BMI.Our findings are similar to the observations of several other authors11 identified the presence of joint effusion and Baker’s cyst as frequent findings, differently from our study, they were not able to demonstrate any associations between different USG features and the level of knee pain, assessed with a numerical rating scale and with the Knee Injury and Osteoarthritis Outcome Score. The authors alluded that a possible explanation of their controversial findings compared with the previous USG features described in the literature was due to selection bias. Their study included mainly patients with less severe KOA (K&L grades I and II) and people with relatively high levels of pain . Because of assessing a more heterogeneous sample than the one we did, Bevers et al., claim that their findings may be more accurate than the previous smaller trials already published, with much larger variability of KOA severity and intensity of pain. Our sample size, on the other hand, was also heterogeneous as in the previous publications. Other possible explanation for the disagreement in the results may derive from the USG machines and probes used in the different studies. Our high-frequency transducer together with experienced sonographers and a systematic assessment protocol with proper patient positioning allowed the visualization of all predefined anatomical structures and possible imaging changes.Even though Bevers et al.25. The intra-observer agreement is also higher for junior sonographers compared with beginners26. In our study, two experienced sonographers performed all USG evaluations.USG is radiation-free, non-invasive, simple to be used, practical and a low-cost and non-time-consuming evaluation tool. The inter-observer agreement is excellent for Baker’s cyst  using USG in KOA26 that USG is a reliable assessment tool for several anatomical structures that may be involved in KOA. Early diagnosis of such anatomical changes may guide the introduction of specific interventions to address these findings. Retrospective review of sonographic images evidenced a 100% sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in the diagnosis of Baker’s cyst when hypoechoic or anechoic fluid was present between the semimembranosus and medial gastrocnemius tendons25. Compared to magnetic resonance imaging (MRI), USG identified 100% (12/12) of joint effusions and 100% (5/5) of Baker’s cysts26. USG reliably demonstrated joint effusions and Baker’s cysts27. Also, differently from the MRI, USG allows the dynamic evaluation of tendons and liquid mobilization.We fully agree with the comments by Iagnocco et al.28. There is no validated protocol to measure effusion using USG29. However, examining the patients with the knees flexed at 30 degrees allow the detection of small effusion compared to the examination with extended knees30. We identified joint effusion in 77.32% of our patients. A possible explanation for this high frequency is that patients with KOA tend to present a lack of proprioception31. Joint effusion and consequently distended capsule may be a compensatory mechanism in the attempt to increase proprioception. Then, the high percentage of this finding may suggest the need to recover proprioceptive functioning.Joint effusions, on the other hand, demonstrated relatively low intra- and inter-observer reliability32. Compared with MRI, USG shows a sensitivity of 86.67%, specificity of 100% and k-value of 0.91 for bursitis and 71.4%, specificity of 100% and k-value of 0.82 for suprapatellar bursitis32. Actually, we found a higher frequency of pes anserinus bursitis (43.30%) compared with Baker’s cysts (29.38%), a result not so often described in the literature. Future studies should demonstrate whether these structures should also be a target for specific interventions.We have systematically visualized the anserine bursa, the patellar tendon and the iliotibial band in all of our patients. Interestingly, we have identified the presence of pes anserinus bursitis and patellar tendinitis in some of our patients. Very few other authors described the presence of periarticular changes including pes anserinus bursitis and patellar tendinitis in people with symptomatic KOA. However, we consider the relevance of assessing these periarticular structures since USG can be a useful tool for the evaluation of superficial bursitis in the knee33. In fact, iliotibial band syndrome, semimembranosus-tibial collateral ligament bursitis, anserine bursitis, patellar bursitis and tibiofibular cysts are common features. We fully agree with Hill et al. that periarticular lesions may contribute to knee pain and should be included in the differential diagnosis33. It is important to recall that the indication for a knee replacement is pain and not knee pathology.Periarticular lesions are quite common in patients with chronic knee pain detected on MRI35. However, to assess this structure, we suggest that MRI is the preferred imaging methodology, for its higher resolution. The higher costs involved in MRI prescription and the lower accessibility may restrain the use of MRI. And for this reason, we decided not to systematically access the meniscus using USG, because MRI is a better imaging tool for this diagnosis.Many studies have tried to correlate meniscal protrusion to pain and functionalityIn the present study, higher K&L grades were correlated to a higher number of USG findings, but specifically comparing patients with extreme grades . Maybe this correspondence, between the lower number of USG findings and lower K&L grades, as well as a higher number of USG findings and higher K&L grades, could also extend to allow differentiation between intermediate K&L grades and the number of USG findings if the studied population were larger. Although this statistic correlation covered mostly boundaries grades, this may suggest that USG has a correspondent result to X-ray and, therefore, a reliable diagnostic potential compared to the current approach.36. Abd El Monaem et al.15 described a significant positive correlation between WOMAC and USG-measured joint effusion volume and Baker’s cyst volume. Razek et al.36 reported that higher WOMAC scores were associated with the presence of joint effusion. In our study, both TUG and WOMAC pain and difficulties to perform exercises scores statistically correlated with the number of USG findings.Our findings were also similar to previous reports in the literature concerning the influence of the USG changes related to functioning assessments37. USG knee effusion was a predictor of joint replacement; being higher or equal to 4 mm versus lower than 4 mm, with a hazard ratio of 2.63; confidence interval 95% 1.70 to 4.06, p < 0.000137. The presence of Baker´s cyst, visualized in 29.38% of our patients, seems to be associated with both clinical (odds ratio (OR) 3.07 (IC95% 1.21 to 7.78) and radiological  progression in KOA after 2 years of follow-up29. This one is a very interesting finding, as the presence of Baker´s cysts can be easily identified by an USG evaluation, without the need for MRI.Despite the importance of unraveling the association of USG features with pain intensity, K&L scores and functionality in KOA patients, some of these findings may also have a role as predictors of disease progressionOur study has a limitation. The absence of a control group may have limited our findings and conclusions.To our knowledge, systematic description of these specific USG findings is limited in literature but still important, since osteoarthritis pathogenesis is not totally clear and there is a lack of disease-modifying interventions. Here, the positive association found between periarticular structures and pain questions the current clinical management because it suggests that USG is more sensitive in KOA evaluation, considering it shows changes in most patients even when these are not present in radiographic findings. Accordingly, future studies are needed to clarify if this positive association is result of interference or causality between these two variants, or if they are simply risk markers.The main USG findings were joint effusion, pes anserinus bursitis, popliteal cysts and patellar tendinitis. The number of USG findings was associated with VAS, K&L I and III, I and IV, II and IV grades, TUG and pain and difficulty to perform WOMAC scores and should be explored in patients with KOA as potential sources of pain and disability.