Ilioinguinal-iliohypogastric block (ILIHB) is a well-established procedure for postoperative analgesia after open inguinal surgery in children. This procedure is effective and safe, especially when ultrasound is used. Data availability for comparing ultrasound-guided blocks versus wound infiltration is still weak. The study was designed to determine the efficacy of ultrasound-guided ILIHB (US-ILIHB) on postoperative pain control in pediatric patients following a inguinal daycase surgery, compared with perifocal wound infiltration (PWI) by the surgeon.This randomized, double-blinded trail was conducted in pediatric patients aged from 6 months to 4 years. The total number of children included in the study was 103. Patients were allocated at random in two groups by sealed envelopes. The ILIHB group recieved 0,2% ropivacain for US-ILIHB after anesthesia induction. The PWI group recieved 0,2% ropivacain for PWI performed by a surgeon before wound closure. Parameters recorded included the postoperative pain score, pain frequency, time to first analgesics and consumption of analgesics.Results: US-ILIHB significantly reduced the occurrence of pain within the first 24 h after surgery . Moreover, the pain-free interval until administration of the first dose of opioids was 21 min longer, on average (p = 0.003), following US-ILIHB compared to perifocal wound infiltration. 72% of children who received US-ILIHB did not require additional opioids, as compared to 56% of those who received PWI.Thus our study demonstrates that US-ILIHB ensures better postoperative analgesia in children and should be prioritized over postoperative PWI.DRKS00020987. Registered 20 March 2020 – Retrospectivley registered.UIHBOPWIIC,  The ratio of surgeries performed in an outpatient setting has been increasing rapidly for years and this trend is extend to continue in the future. Open inguinal surgery in children is an outpatient procedure that requires efficient and long-acting analgesia to facilitate early discharge. However, the prevalence of compromising and persistent post-surgery pain in children remains high . Once a Our study tested the primary hypothesis that US-ILIHB provides a more adequate analgesia in pediatric inguinal surgery with correspondingly lower pain levels on the pediatric scale of discomfort and pain (KUSS) within 24 h, as compared to surgical perifocal wound infiltration (PWI). Secondarily, we tested the hypothesis that the demand for analgesics after pediatric inguinal surgery is much later in patients of the US-ILIHB group while the amount of painkillers as well as the frequency of their administration is correspondingly lower than in patients of the PWI group.The study was reviewed by the ethics committee of the Hamburg Medical Council and approved by the doctoral committee of the University of Hamburg. Parents were informed about the purposes of the study and how their children would be involved at each visit, and their consent was provided in writing. All children were recruited from the pediatric and urological clinic of the Altona Children’s Hospital of the University of Hamburg.The number of cases was calculated using G * Power 3.1. An effect size of 0.6 was derived from previous studies , 15. Then = 53, and PWI group, n = 50). After 120 envelopes were numbered 1 to 120, they were filled 1:1 with the technique protocol of the corresponding group. An computer generated simple randomisation allocated the envelops to patients. Only the anaesthesiologist was notified the group and which block technique to use immediately before the induction of anaesthesia when the envelope was opened. After performing the procedure and in accordance with a specified “standardized operation procedure” (SOP), he put the completed technique protocol back into the envelope and sealed it, so that group and corresponding procedure remained hidden from the patient and the personnel performing pain measurements.One hundred sixteen children aged from 6 months to 4 years with a minimum weight of 6 kg; with an American Society of Anesthesiologists Classification (ASA) of I or II and scheduled for a unilateral outpatient inguinal surgery were enrolled in equal randomized (1:1), double-blind, parallel group study conducted in Germany. The initial maximum age of 3 years was extended to 4 years during the study due to the little recruitment number. The following exclusion criteria were applied: mental illness, allergies to relevant drugs, renal insufficiency, coagulation disorders, local infections, emergency procedures, and additional interventions. Demographic data such as gender, age, and weight were collected. Subjects were randomized and allocated to two groups using sealed envelopes including the respective technique  or 0.9% acetate Ringer’s solution at an infusion rate of 10 ml/kg/h. Children also received 10 mg/kg ibuprofen as at rectal suppository. Lastly 0.1–0.2 μg/kg of sufentanil was administered as a “rescue analgesia” if there were signs of intraoperative pain were detected.As local anaesthetics 0.2 ml/kg of naropin 0,2% was used. This bloc was administered to all patients using sterile conditions and in general anaesthesia. Target structures of the nerve block were the ilioinguinal and iliohypogastric nerves, which run within the fasciae between the oblique abdominal muscles, the internal oblique muscle, and the transverse abdominal muscle Fig. .Fig. 1AAll patients in the US-ILIHB group were treated by well experienced paediatric anaesthesiologists from the paediatric anaesthesia department of the Altona Children’s Hospital. Immediately after anaesthesia was induced, the main anatomical structures: the external oblique muscle, the internal oblique muscle, and the transverse abdominal muscle were visualized using the ultrasound SonoSite S-Nerv, linear probe Fig. b. A weigPWI group were treated by paediatric surgeons from the Department of Paediatric Surgery of the Altona Children’s Hospital. At the end of the surgery, immediately after closing the aponeurosis of external oblique muscle, a negativ aspiration test using a 20 gauge cannula with 0.9 mm outside diameter was administered followed by weight-adapted administration of naropin in macroscopic view through a suture gap  are not yet able to adequately assess or communicate their level of pain, pain intensity was measured using third-party assessments based on an approved multidimensional pain scale , 21, nam2– and Fisher’s exact test. The effects of group, time interval, and their interaction with the dichotomous dependent variable were tested using a mixed logistic regression model. A linear mixed model was fit to the continuous dependent variable with the fixed effects of group and point in time, and with the points in time within patients as repeated measures representing repeated measurements. The group-specific course of analgesia administration was analysed and visualized using the Kaplan-Meier method and a comparison of the groups was conducted using logrank tests. The significance level for all tests was set to 0.05 and all statistical tests were set to be bilateral. All analyses were performed using SPSS version 25.0 .The Statistical data processing was carried out in cooperation with the Institute for Medical Biometry & Epidemiology of the Hamburg Eppendorf University Hospital. The descriptive statistics for continuous variables were based on the mean value and standard deviation per group. Absolute and percentage frequencies per group were determined and presented as categorical variables. Group differences with respect to continuous variables were tested using the Mann–Whitney U test, while group differences with respect to categorical variables were tested with χp = 0.000) and measurement times (p = 0.001), and between groups (p = 0.009) being highly significant.Since the mean values of the collected pain scores of both groups (US-ILIHB and PWI) demonstrated extreme differences among the four measurement episodes, the statistical evaluation was not adequate as planned initially. Pain scores assessed in PACU and OSW were very low in both groups, while pain scores measured at home were relatively high. One reason for this difference was the particularly high occurrence of reports of absolute freedom from pain in the PACU and OSW measurement episodes. In order to be able to present the difference in analgesia between both methods, we planned to analyse the pain scores within the three individual measurement episodes , and not on the entire time frame. Thus, in a second step, the data was dichotomized, i.e. divided into values = 0 and > 0. As such, all pain scores > 0 represent pain that occurred at the time of measurement, while pain scores = 0 indicate that there was no occurrence of pain. This allowed us to represent the “relative frequency of occurrence of pain” (rel.freq.), with the resulting differences in rel.freq. Within the episodes (p = 0.01). That is, the relative frequency of all pain events in the PWI group is about 50% greater than in the US-ILIHB group. Figure p = < 0.001). The time until the administration of piritramide, within the first 2 h after surgery, yielded following results . With respect to caregivers’ first administration of either ibuprofen or paracetamol, within the first 15 h of arrival at home, the following results were obtained  due to large variances in both groups. There were no significant differences regarding the frequency of postoperative nausea and vomiting in both groups within 24 h measurement period: 5 out of 53 versus 5 out of 50 patients reported nausea and vomiting in the US-ILHIB and in the PWI group, respectively. The absolute amounts of administered analgesics and the frequency of analgesia applications did not differ significantly  ILIHB performed using the landmark technique with (2) surgical infiltration, resulting in no significant difference in analgesic effects between both groups . As the After many contradictory study findings, the present study provides significant evidence that the relative frequency of pain events is approximately 50% lower in the first 24 h after surgery (12.6% versus 20.4%) when applying US-ILIHB block prior to inguinal interventions in children. In the US-ILIHB group, only every eighth child (6.7 out of 53 children) showed signs of pain, however when surgical infiltration was used, it was every fifth child (10.2 out of 50 children).We also were able to demonstrate that the frequency of pain events increased the longer the period after block. Fig. b. Thus, We also demonstrated that children who received US-ILIHB were longer pain-free, 21 min on average, than children with surgical infiltration, as measured by the time spent until the first opioid administration. Although not statistically significant, the same trend was seen in the time to first administration of peripheral analgesics administered by parents : In fact, children having received ultrasound block intervention requested an analgesic on average of 3 h later in comparison to their PWI counterparts.p = 0.048, total clonidine in μg: p = 0.049)  was lower, and they were consumed less frequently following ultrasound block. While these were only minor differences without significance, in context this effect can be interpreted as a trend due to the fact it is also reflected significantly for co-analgesics like clonidine (frequency of clonidine: 49) Tab. b. Howeve49) Tab. a. Even tOne reason for our findings is the slow release of anaesthetics, as the preoperative ultrasound-guided application of local anaesthetic in-between fascia of the oblique abdominal wall muscles results in the formation of a deposit. This deposit is then slowly absorbed, thus generating a long-lasting effect Fig. b. AnotheEven though the study’s findings are promising, there are several limitations to address. Firstly, the investigated techniques were not performed by a single person but by several people. However, despite the fact that the group of investigators consisted of a fixed number of specialists within each of departments, all of which have high levels of experience with regional anaesthesia in children, the methods employed were implemented according to a well-established SOP. Therefore, this bias presumably has little effect, given the large number of patients included. Secondly, pain assessments were carried out by nursing staff in the hospital, and by parents at home. Both groups were provided with precise instructions on how to use the same pain scale prior to data collection. The KUSS pain scale is a commonly used and approved scale for the assessment of pain in neonates and small children, however it might still permits a degree of objectivity. Lastly, the temporal offset between applications of local anaesthetics  could influence pain assessment due to the different residence times of local anaesthetics. However, a clear difference between preoperative or postoperative block in terms of the reduction of pain has not been demonstrated so far , 26. ThiBoth methods, ILIHB and PWI, have proven to be effective, with the evidence for better analgesia by one or the other method being thin and ambiguous. Taking into consideration all results presented here, this study demonstrates that the use of pre-operative ultrasound-guided ILIHB could be an improved analgesia method in children (< 4 years old) subjects undergoing open inguinal surgery.


Introduction: Irritable bowel syndrome (IBS) is included as one of the functional gastrointestinal (GI) related disorders presenting with pain in abdomen of chronic duration in the absence of any identifiable organic cause. Bloating, distension of abdomen, and defecation in disordered manner are other features commonly associated with IBS. It is a complex disorder with mixed physiological, psychological, and social interactions. The present study was carried out with the aim to determine the frequency of IBS in patients presenting with abdominal pain in a population of a developing country.Materials and methods: A descriptive cross-sectional study was undertaken at the outpatient department of a large tertiary care hospital. Patients of either gender aged between 20 and 50 years presenting with abdominal pain were included. The diagnosis of IBS was established using Rome III criteria. Prevalence of IBS was calculated and confounding factors such as age, gender, marital status, duration of abdominal pain, and economic status were stratified to see their effect on outcome variable by applying chi-square test and taking p-value of <0.05 as significant.Results: A total of 186 patients were included in this study. Some 100 (53.76%) were male and 86 (46.24%) were female. Mean age of the patients was 33.67 ± 7.08 years. Some 58.6% were married and 41.4% were single. Some 61.83% had mild abdominal pain and 38.17% had moderate pain. Out of the total 186 patients, the frequency of IBS was found to be 35.48%. There was no significant effect of confounding variables such as age, gender, duration of abdominal pain, marital status, and economic status on IBS.Conclusion: In our study the frequency of IBS in patients with abdominal pain is high with no significant effect of gender, marital status, economic status, and duration of abdominal pain on IBS. Irritable bowel syndrome (IBS) is a functional bowel disorder without any organic identifiable etiology, and presents with pain or discomfort in abdomen which is associated with symptom of defecation or as a result of change in bowel habits. Other features that are usually and commonly associated with IBS include a feeling of bloating, distension of abdomen, and defecation in disorderly manner . Its symThe studies based on population have estimated the IBS prevalence to be around 10%-20% . AccordiIrritable bowel syndrome is a highly prevalent gastrointestinal (GI) motility disorder and has chronic duration with bothersome nature of symptoms and it often affects the patients’ QoL and activity level negatively. It also has a substantial economic burden on patients as well as healthcare facilities -9. In onIrritable bowel syndrome is a disorder of significant morbidity occurring as a result of interaction of psychological, physiological, and social factors. In a developing country such as Pakistan, very limited data exist regarding prevalence of IBS. The aim of the current study was to determine the frequency of IBS by using the Rome III criteria in outpatients. The purpose of the study was early identification of IBS patients followed by their prompt treatment and to prevent misdiagnosis among such patients.The current descriptive cross-sectional study was carried out from 1st June 2017 till 1st January 2018 at the outpatient department of a large tertiary care hospital. Patients of either gender aged between 20 and 50 years presenting with abdominal pain for a duration of three months or more were included.Abdominal pain was assessed on a visual analog scale (VAS). On VAS scale, the score ranging from 1 to 3 was regarded as mild pain, score ranging from 4 to 6 was regarded as moderate pain, and a score of greater than 6 was regarded as severe pain.For IBS diagnosis as per Rome III criteria, the patient should have had pain in abdomen of recurrent nature or any abdominal discomfort for three days per month at least during past three months with onset of symptoms almost six months before to the diagnosis, having association with two or more of the following features:• Pain that got relieved after defecation.• The onset of pain had an association with a change in frequency of stool passing.• The onset of pain had an association with a change in the form of stool.By taking prevalence of IBS as 14%, margin of error as 5%, and confidence interval (CI) as 95%, the calculated sample size came out to be 186 patients by using the WHO’s sample size calculator for Health Sciences. Nonprobability consecutive sampling technique was undertaken.Patients were excluded if they had any known infectious cause of diarrhea and constipation based the history such as abdominal tuberculosis, celiac disease, or HIV. Patients were also excluded if they were taking laxatives, antibiotics, nonsteroidal anti-inflammatory drugs, chemotherapy, medications causing constipations such as antidepressants, antipsychotics, calcium supplements, diuretics, and ironsupplements. Patients having red flag symptoms such as weight loss ≥ 5 kg in a month, hemoglobin level of >10 g/dL, bleeding per rectum (two teaspoon in quantity) were also excluded.Data were analyzed by using statistical package for social sciences (SPSS) version 21. Mean and standard deviation were computed for quantitative variables, i.e. age, duration of abdominal pain. Frequency and percentage were calculated for qualitative variables, i.e. gender, marital status, socio-economic status, severity of abdominal pain outcome variable (IBS). Age of the patients, gender, marital status, status ofeconomy, duration of abdominal pain, and severity of abdominal pain were stratified to see their effect on outcome (IBS) by using chi square test and considering p ≤ 0.05 as significant.A total of 186 patients were included in the present study. The average age of the patients was 33.67 ± 7.08 years and median duration of abdominal pain was eight. There were 32.8% patients between age 20 and 30 years, 49.46% between age 31 and 40 years, and 17.74% between age 41 and 50 years. Out of 186 cases, 100 (53.76%) were male and 86 (46.24%) female. Some 58.6% were married and 41.4% were single. Most of the patients were from economic class. Regarding severity of abdominal pain of the patients, 61.83% tolerated mild pain and 38.17% tolerated moderate pain. Baseline characteristics are summarized in Table Prevalence of IBS in our study was 35.48%. There was no significant effect of confounding variables such as age, gender, duration of abdominal pain, marital status, and economic status on IBS Table .Irritable bowel syndrome included as one of the GI disorders manifested as altered habits and chronic abdominal pain without any identifiable organic etiology. Among GI related abnormalities, it is the most frequently diagnosed. Almost 30% of the GI referrals are due to this condition . Pain inA study conducted on 755 patients suffering from IBS showed that the abdominal pain was a main factor that was a predictor of patient perceived severity. Among other factors affecting the severity, straining with defecation and myalgias were also included . The stuOur study was conducted on 186 patients and included both males and females. The results of our study have shown a high prevalence of IBS in our population. We reported IBS prevalence of 35.4%. Our reported prevalence is higher than the one reported in Lebanese population . A studyIn our study, males had higher presence of IBS as compared to females, but there was no significant difference noted. According to a previous study, IBS was significantly higher in females . This coInitially, IBS was diagnosed based on Rome II criteria after a careful evaluation of patient's medical history and general physical examination to look for any alarming or red flag features. Recently, the Rome III criteria have been published . The RomFew limitations are present in this study. This was a single institute study. Moreover, in this study the educational status was not considered. According to a study, IBS is usually found more in patients with higher education status  and thisIrritable bowel syndrome has high frequency in our population. Although the frequency of IBS was high in males, there was no statistically significant difference observed. Moreover, no significant difference was observed with age group, marital status, socioeconomic status, and duration of abdominal pain.


Chronic kidney disease is considered as a global health problem. Hemodialysis (HD), following renal transplantation, is the most common form of renal replacement therapy. However, HD may impact the quality of life (QOL). Pain is a frequent complaint among this population that also affects their QOL. The purposes of this study were to assess pain and QOL among end-stage renal disease (ESRD) patients on HD and to examine their association.This was a multicenter, cross-sectional study that occurred in Palestine between August and November 2018. Brief Pain Inventory and European Quality of Life scale 5 dimensions (EQ-5D) scale, including its European Quality of Life visual analogue scale (EQ-VAS) component, were used to assess pain and QOL, respectively.p < 0.001). The association between pain interference score and EQ-5D score was also found to be statistically significant . Similarly, pain severity score was significantly assocsiated with EQ-VAS score , the same as was the pain interference score . Moreover, age, gender, BMI, employment, educational level, income level, dialysis vintage, previous kidney transplantation, and chronic medication use were all significantly correlated with QOL. Regression analysis showed that patients aged < 60 years (p < 0.001), those with lower pain severity scores (p = 0.003), and those with lower pain interference scores (p < 0.001) had significantly higher QOL scores.A total of 300 participants were included in the final study. The average age of the subjects was 54 ± 16 years. Their median EQ-5D score was 0.68 [0.54–0.88], whereas their median EQ-VAS score was 60 [40–75]. A statistically significant association of pain severity score with EQ-5D score was found (r = − 0.783, Pain has a significant negative impact on QOL in ESRD patients undergoing HD. The subgroups that were at higher risk included elderly patients, females, those with higher BMI, those without a formal education, those unemployed, those living with low monthly income, smokers, those who have multiple comorbidities, and patients with longer dialysis vintage. Our findings provide reliable data for educators and clinicians working with HD patients. In many patients with chronic kidney disease (CKD), their condition progresses to end-stage renal disease (ESRD). Eventually, it involves certain types of renal replacement therapy (RRT) such as renal transplantation, hemodialysis (HD), or peritoneal dialysis –3. The pIn the West Bank in Palestine, the overall number of HD patients continued to increase from 1,119 in 2016  to 1216 Pain, a frequent complaint among ESRD patients, negatively affects the HRQOL and has mental, physical, and social consequences among these patients , 14. AccThe cause of pain has been investigated by many studies –20, inclOur main aims in the current study were to assess chronic pain in ESRD patients on HD in Palestine, in terms of its severity and interference with activity, as well as to measure the impact it has on the QOL of these patients. We also examined the factors associated with QOL among this group of patients. The findings of this assessment may help healthcare professionals plan and develop pain assessment and management protocols and strategies that aim to address the common signs and symptoms and improve the QOL of this group of patients.This was a multicenter, cross-sectional study that was conducted between August and November of 2018 and occurred in the hemodialysis units of five different hospitals: Tulkarem Governmental Hospital, Qalqilya Governmental Hospital, Jenin Governmental Hospital, Tubas Governmental Hospital, and An-Najah National University Hospital (NNUH).http://www.raosoft.com/samplesize.html), with 5% margin of error, 95% confidence interval, a population size of 570. The calculated minimal required sample size was 220. Then we recruited a total of 330 patients by convenient sampling as follows: 74 from Tulkarem Governmental Hospital, 36 from Qalqilya Governmental Hospital, 88 from Jenin Governmental Hospital, 24 from Tubas Governmental Hospital, and 108 NNUH. HD patients were chosen from each kidney dialysis unit using the proportional quota sampling approach to represent the general HD population  and 16.5 [0.00–30], respectively. Additionally, the interreliability indices for the pain severity and pain interference subscales were good, with a Cronbach’s alpha of 0.947 and 0.963, respectively.Our sample's median EQ-5D score was 0.68, with an interquartile range of 0.51–0.84], whereas the mean EQ-5D was 0.63 with a standard deviation of 0.34. Internal consistency was measured by Cronbach’s alpha, and the result was 0.936. On the other hand, the median EQ-VAS score was 60.00 [60.00–80.00], whereas the mean EQ-VAS score was 57.53 ± 25.09. We found that the distribution of patients who reported the worst health status across all dimensions of EQ-5D was as follows: mobility 3.3%, usual activity 3%, self-care 4%, pain and/or discomfort 2%, and depression and/or anxiety 3.3%, whereas the percentage of patients who reported the worst in any dimension was 2%  between participants according to age, gender, BMI, educational level, employment, monthly income, dialysis vintage, history of kidney transplantation, chronic medication use, and smoking history in association with EQ-5D scores. Table p < 0.001) and pain severity score  with the EQ-5D score.Table p < 0.001) and pain interference score , as well as a significant positive association between the EQ-5D score and EQ-VAS score . The results of the linear regression analysis showed that patients aged < 60 years (p < 0.001), with lower pain severity scores (p = 0.003), or with lower pain interference scores (p < 0.001) had significantly higher QOL scores. Table Table  p = 0.00, or withThe current study administered a thorough analysis of QOL in ESRD patients on HD in the Northern West Bank in Palestine. We used the EQ-5D scale and its EQ-VAS component to measure QOL and the Brief Pain Inventory scale to assess chronic pain symptoms. Many demographic and clinical factors can affect QOL. In this study, demographic factors correlated with lower QOL included old age, high BMI, female sex, residing in a camp, having no formal education, being unemployed, and living with a low income.Patients with ESRD receiving maintenance HD suffer from many physical symptoms, including pain, which affects the QOL . Many stThe participants’ mean EQ-5D score was 0.63 ± 0.34. This result is close to results from previous studies that occurred in Singaporean, Thailand, Switzerland, and the UK, which reported EQ-5D scores of 0.704 ± 0.199 , 0.65 ± The association that we found between advanced age and lower QOL is similar to the findings of previous studies from Iran  and KoreWe also found that gender and BMI were significantly associated with QOL, with females and those with higher BMI having worse QOL. It has been suggested in previous studies that higher levels of physical inactivity among females , 56, witMoreover, our results showed that having a lower level of education, being unemployed, and living with a low income negatively impact the QOL, similar to results from previous studies , 61, 62.In addition to that, our study showed that some clinical and HD-related characteristics were associated with QOL, including time since starting dialyzing, history of kidney transplantation, level of knowledge about the cause of their disease, smoking, and the number of other comorbid diseases. For example, we found a longer duration since starting on dialysis was significantly associated with lower QOL, which is similar to the findings from other studies , 45. MorThe mean EQ-VAS score for our participants was somewhat higher than the mean score reported by a similar survey in Thailand . In our We also found a positive association between EQ-5D score and EQ-VAS, which indicates that using more than one scale may increase the accuracy of the result for QOL assessment. Finally, there was a significant negative association between the severity of pain and interference in daily life, on the one hand, and QOL on the other. Many studies have reported this correlation, which emphasizes the need to pay more attention to any complaints of pain and adopt an early management protocol to decrease the negative complaints on QOL , 72, 73.Our study’s strengths include its multicenter setting and its relatively large sample size. This was also the first study in the West Bank, Palestine, to examine the effect of pain and other social, demographic, and clinical characteristics on QOL among ESRD patients on HD. Furthermore, the current study used the EQ-5D and BPI scales, which are widely accepted assessment tools to study QOL and pain symptoms, respectively. However, this study had some limitations, including its cross-sectional design, which left any speculation on causality unreliable. Moreover, using the convenience sampling technique may have reduced the generalizability of the results of this study to other HD patients. Finally, even though the scale we used to assess QOL is a widely used and accepted tool, using other scales in addition to or instead of it might have yielded additional data that would have helped us better characterize QOL in our target population.We found that pain symptoms have a significant negative impact on life quality among ESRD patients who were on HD treatment. The subgroups of this population that were at higher risk of having worse QOL included elderly patients, females, those with obesity, weight range, BMI, those without formal education, unemployed, those living with low monthly income levels, smokers, and those who have multiple comorbidities, as well as patients with longer dialysis vintage. Our findings provide a source of reliable data for educational institutions, as well as clinicians working with ESRD patients and managing their symptoms, including chronic pain to achieve a high level of pain relief. Healthcare professionals and policymakers should give special attention to chronic pain and overall QOL in patients with HD, especially those with ESRD. Standard guidelines for the management and follow-up of chronic pain and life quality should also be implemented, and programs to increase the public awareness of the causes of ESRD should be designed to decrease patient suffering and healthcare costs.


Osteoarthritis (OA) pain implies an indication for joint replacement in patients with end-stage OA. However, chronic postoperative pain is observed in 10–40% of patients with OA. Here, we identified genes whose expression in the peripheral blood before surgery could denote the risk of postoperative pain development. We examined the peripheral blood of 26 healthy subjects and 50 patients with end-stage OA prior to joint replacement surgery. Pain was evaluated before surgery using the visual analog scale (VAS) index and neuropathic pain questionnaires, Douleur Neuropathique 4 Questions (DN4) and PainDETECT questionnaires. Functional activity was assessed using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Three and six months after surgery, pain indices according to VAS of 30% and higher were considered. Metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)1 protein levels were measured using ELISA in the peripheral blood mononuclear cells (PBMCs). Total RNA isolated from whole blood was analysed using quantitative real-time RT-PCR for caspase-3, MMP-9, TIMP1, cathepsins K and S, tumour necrosis factor (TNF)α, interleukin (IL)-1β, and cyclooxygenase (COX)-2 gene expression. Seventeen patients reported post-surgical pain. Expression of cathepsins K and S, caspase-3, TIMP1, IL-1β, and TNFα genes before surgery was significantly higher in these patients compared to pain-free patients with OA. Receiver-operating characteristic (ROC) curve analyses confirmed significant associations between these gene expressions and the likelihood of pain development after arthroplasty. High baseline expression of genes associated with extracellular matrix destruction , inflammation , and apoptosis (caspase-3) measured in the peripheral blood of patients with end-stage OA before knee arthroplasty might serve as an important biomarker of postoperative pain development. Osteoarthritis (OA) is a systemic disease that involves single or multiple joints. It produces articular cartilage degradation, remodelling of the subchondral bone, and is associated with synovial inflammation . Pain inIn OA, pain is classified as (1) nociceptive, which occurs when damage or inflammation, or both, of the joint tissues is induced by activation of tissue nociceptors and ensures a protective function, or (2) neuropathic, which is caused by the damage or dysfunction of the nervous system and includes impaired peripheral and central sensitization mechanisms ,6. PeripPostoperative chronic pain is also associated with a patient’s sociodemographic and clinical factors , as well as with predictive psychological factors (depression and anxiety) , metabolRecent studies of molecular mechanisms of pain have revealed a number of molecular markers, which include some cytokines, chemokines, calcium or glutamate transporters, caspases, and proteases . In a siTherefore, this preliminary prospective study aimed to identify genes whose expressions in the peripheral blood before knee arthroplasty could be associated with the post-surgical pain development in patients with end-stage OA.The inclusion criteria for control subjects: 26 individuals  who were free from any serious illnesses and were recruited from the Moscow area. The control subjects were of comparable age to the examined patients with end-stage OA. The exclusion criteria for control subjects included any degree of knee pain. The inclusion criteria for patients with end-stage OA: 50 unrelated subjects with primary OA of the knee who underwent primary total knee replacement surgery at the Nasonova Research Institute of Rheumatology between March 2018 and June 2019. The average age of patients with OA was 67.6 ± 7.5 years (range 54–82 years). These patients had radiographic Kellgren and Lawrence (K&L) OA grades of III–IV, experienced constant pain during the last three months, and had walking problems (lameness). The exclusion criteria: decompensated chronic diseases, active infectious process and foci of chronic infection, neurocirculatory disorders of the lower extremities, opioid-type analgesic therapy prior to surgery.The following NSAIDS were used as pain medications: meloxicam (15 mg/day) (n = 2), nimesulide (200 mg/day) (n = 22) or diclofenac (200 mg/day) (n = 11), etoricoxib (60 mg/day) (n = 4), ketoprofen (100–200 mg/day) (n = 2), and celecoxib (200 mg/day) (n = 2). Patients were also treated with the symptomatic slow-acting drugs for osteoarthritis (SYSDOA) such as chondroitin sulphate (800 mg/day) (n = 10), and glucosamine sulphate (1500 mg/day) (n = 12). Medium molecular weight hyaluronate  (n = 15) and a steroid bethametasone (1 mL) (n = 13) were also applied.All of the patients with end-stage OA fulfilled the criteria of the American College of Rheumatology regarding OA . The excAll total knee replacements were performed under spinal anaesthesia by a surgical team comprising two orthopaedic surgeons. The standard protocol was used for surgery, including a midline skin cut, a standard medial parapatellar method and a measured resection technique. Intravenous tranexamic acid was applied 5 to 10 min before the skin incision (20 mg/kg) and 3, 6, 12, and 24 h later (10 mg/kg) along with 1 g of topical tranexamic acid in 50 mL of normal saline solution. All patients were evaluated by a physician 3 times daily until hospital dismissal. Walking with partial weight-bearing and a knee brace to protect the surgical locus was advised on the second day after surgery. To prevent deep venous thromboembolism (DVT), all patients used graduated compression stockings. In addition, a full-dose of nadroparin was prescribed daily until discharge. If no bleeding events occurred, 10 mg of rivaroxaban was recommended orally for 14 days after discharge. All patients were discharged 7 days after surgery. Doppler ultrasound was used to evaluate for DVT periodically during 3-month follow-up.Patient demographics, including age and sex, were recorded. The radiographic grade of OA was determined by the analysis of the weight-bearing anteroposterior radiographs of the knees and was counted according to Kellgren and Lawrence . The WesPeripheral blood (10 mL) was gathered in vacutainers containing ethylenediaminetetraacetic acid (EDTA) . The blood samples were taken in a standard manner between 07:00 a.m. and 09:00 a.m. Whole blood was fractionated in a Ficoll density gradient. Peripheral blood mononuclear cells (PBMCs) from the interphase were collected and washed twice in phosphate-buffered saline . The obt4P2O7, 20 mM Na3VO4, 1% Triton X-100, 10% glycerol, 0.1% SDS, and 0.5% deoxycholate  supplemented with Protease Inhibitor Cocktail  and 1 mM PMSF  according to the manufacturer’s instructions. Total DNA content in PBMC lysates was measured spectrophotometrically using a GeneQuant device . Results were expressed per µg of DNA. Concentrations of MMP-9 (BMS2016-2) and TIMP1 (BMS2018) were determined in isolated PBMCs using commercially available enzyme-linked immunosorbent assay (ELISA) kits  according to the manufacturer’s instructions. Results were expressed per µg of DNA measured in PBMC lysates. PBMC lysates were acquired using Cell Extraction Buffer containing 10 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM NaF, 20 mM Na260/290 > 1.9. The RT-reaction was performed using a M-MLV RT kit containing Moloney Murine Leukemia Virus (M-MLV) Reverse Transcriptase, random hexanucleotide primers and total RNA according to the manufacturer’s recommendations .Total RNA was isolated from 100µl of whole blood immediately after withdrawal using Extract RNA reagent  in accordance with the manufacturer’s recommendations. Total RNA had an Aβ-Actin served as an endogenous control. The TaqMan primers and probes  for expression of human genes cathepsin S (Hs00175407_m1), cathepsin K (Hs00166165_m1), caspase 3 (Hs00263337_m1), TNFα (Hs00174128_m1), IL-1β (Hs00174097_m1), COX-2 (Hs00153133_m1), MMP-9 (Hs00234579_m1) and TIMP1(Hs00171558_m1) were used. Quantification of gene expression was conducted using a Quant Studio 5 Real-Time PCR System . A volume of 1 μL of RT product was subjected to real-time PCR in a 15 μL total reaction mixture including 7.5 μL of TaqMan Universal PCR Master Mix (Applied Biosystems), 900 nM sense and antisense primers, 50 nM probe, and cDNA template. After a first step of 50 °C for 2 min and initial warming at 95 °C for 10 min, reaction mixtures were exposed to 40 amplification cycles  .T method, as described by the manufacturer (Applied Biosystems) [T value was calculated by subtracting the CT value for the housekeeping gene β-Actin from the CT value for each sample. A delta-delta CT value was then calculated by subtracting the deltaCT value of the control  from the delta CT value of each OA patient. Each PCR was performed in duplicate. Three “no template” controls were consistently negative for each reaction. Relative mRNA expression was determined using the delta-delta Csystems) . The delAll steps and measurements made in the study are presented at p-values ≤ 0.05 were considered significant. A Kolmogorov-Smirnov and Shapiro-Wilk normality tests were applied for data distribution analysis. Spearman’s rank correlations and Mann-Whitney U-test were used to non-normally distributed data which was expressed as median (quartiles). The receiver operating characteristic (ROC) curve analyses are presented as the areas under the curve (AUCs) and the 95% confidence intervals (CIs). The diagnostic efficacies of the gene expression values were assessed using the sensitivities and specificities at the cut-off points. Logistic regression was used to model the relationship between expression of the examined genes prior to surgery and postoperative pain preservation six months after surgery. The logistic regression model was built using the stepwise inclusion method. To compare percentages, a two-tailed Z-test for percentages was applied. Statistica for Windows and Statistical Package for the Social Sciences (SPSS) version 19 software  were used for all of the statistical analyses. The study protocol was approved by the Local Committee on the Ethics of Human Research and informed consent was obtained from all subjects (Protocol No. 32 from 20 December 2018).Analysis of the demographic and clinical characteristics of 50 patients of both genders with end-stage OA revealed that the K&L OA grades of the examined subjects varied from III to IV . The average age of these patients was 67.6 years (range 54–82 years), whereas the average disease duration was 9.9 years (range 3–30 years). The majority of patients demonstrated an increased Body Mass Index (BMI) average 30.5 (range 21.3–39.6). The total WOMAC scoring was estimated as 1065 (range 300–1435), whereas average total pain was 222.8 (range 70–360), total physical function, 746 (range 360–1040), and total stiffness, 93.9 (range 40–130).All patients complained of permanent pain during the last three months. Pain scoring according to VAS revealed moderate rates of knee pain of 64.4 (range 20–90) in these patients with OA. According to the Brief Pain Inventory (BPI) questionnaire, the average pain severity was 4.8 (range 2.3–6.3). Neuropathic pain evaluation using the DN4 questionnaire had an average score of 1.9 (range 1–7) and revealed only one patient with a score of seven. The average score according to the PainDETECT questionnaire was 6.0 (range 1–18), indicating no patient with neuropathic pain. According to Hospital Anxiety and Depression Scale (HADS), abnormal anxiety was observed in three patients (with the scores of 11 and 16) and 10 patients out of 50 exhibited borderline levels (scores 8–10). In addition, 8 of 50 patients were depressed because they had a total score >11, whereas 14 of 50 patients had borderline values (scores 8–10) according to the HADS depression scale.p = 0.26). Average pain improvement in patients who developed pain after surgery did not exceed 20%. Patients were interviewed about pain sensation according to VAS after 3 and 6 months post-surgery. Post-surgical pain complaints at both time points were observed in 17 (34%) out of 50 patients. The average pain levels reported after surgery were 34.3 ± 2.3% (3 months) and 38.6 ± 2.5% (6 months) (range from 30% to 50%) according to VAS, and they did not differ significantly (p = 0.07) prior to surgery was observed in patients who were satisfied with the surgery. In addition, patients who developed post-surgical pain had more often arterial hypertension.Comparison of clinical traits in both examined subsets of patients with OA revealed essentially similar baseline levels for the majority of indices . HoweverExamination of gene expression in the whole blood of the examined patients with end-stage OA revealed a significant upregulation of cathepsin S and cathepsin K, caspase-3, TIMP1, IL-1β, and TNFα in those who developed post-surgical pain compared to 33 pain-free subjects . However, the gene expression of MMP-9 and COX-2 was not significantly different in both cohorts of patients with OA.To assess the clinical significance of relative expression of the examined genes in the whole blood of the subjects with end-stage OA, we analysed the protein concentrations of MMP-9 and TIMP1 in the PBMC fraction. The protein levels of TIMP1 in the examined seventeen end-stage patients with OA who developed post-surgical pain was also significantly higher, compared to pain-free subjects, while MMP-9 protein concentrations were not significantly different between the examined subsets .p = 0.03), cathepsin K , caspase 3 , MMP-9 , and TIMP1  gene expression. TIMP1 gene expression also negatively correlated with total pain  and total WOMAC  indices. Neuropathic pain-related DN4 scores positively correlated with TNFα  and IL-1β  gene expression. IL-1β gene expression also positively correlated with PainDETECT scores .Bivariate correlation analyses using Pearson Spearman’s correlation coefficients for normally distributed data and Spearman’s correlation coefficients for the remaining results have revealed a positive correlation between the K&L radiological grade, PainDETECT index, and pain at night, although its baseline scores were moderate, 33.0 (range 10–80) . BPI paip = 0.000, sensitivity of 0.82% and specificity of 0.73%), 7.67 for caspase 3 , p = 0.008, sensitivity of 0.65% and specificity of 0.64%), 5.96 for cathepsin K , p = 0.005, sensitivity of 0.71% and specificity of 0.67%), 1.88 for TNFα , p = 0.006, sensitivity of 0.76% and specificity of 0.73%), 3.3 for IL-1β , p = 0.003, sensitivity of 0.65% and specificity of 0.65%), and 9.12 for TIMP1 , p = 0.006, sensitivity of 0.67% and specificity of 0.64%). The prognostic values of these gene expressions were assessed using ROC curve analyses , which cp = 0.014), cathepsin K (p = 0.011), cathepsin S (p = 0.015), IL-1β (p = 0.011), TIMP1 (p = 0.05), and TNFα (p = 0.01) were independent predictors of postoperative pain development. However, these results require further studies due to the small number of patients in both subsets. Logistic regression modeling demonstrated that high expression of caspase 3 , apoptosis (caspase-3), and inflammation (TNFα and IL-1β) as prognostic markers of post-surgical pain. In our study group, these genes were expressed significantly higher before surgery in those patients with end-stage OA who developed post-surgical pain compared to OA subjects who were satisfied with the surgery results. The high predictive values of the abovementioned gene expressions in the development of pain after knee replacement surgery were confirmed by the ROC curve profiles for expressions of these genes and could be used in clinical settings for prediction of post-surgical pain development. Our results are in line with previous observations stating that increased concentrations of cytokines in the synovial fluid both correlated with pain in the early stages of OA  and wereConsidering baseline clinical and psychosocial variables of the examined subjects with end-stage OA, our observations support the results of previous studies. For example, the examined patients with OA demonstrated essentially similar traits in both examined subsets according to radiographic K&L grade, the disease duration, ESR values, and WOMAC scores. This finding indicates that in our cohort the level of sensitivity for clinical determinants as predictive factors for the postoperative pain development is not sufficient. Similar observations were also noted by others , althougFurthermore, the psychological factors, primarily depression, were previously found to have the greatest effect on postoperative pain  and are In summary, our study demonstrated that high baseline expression of genes associated with extracellular matrix degradation , inflammation (TNFα and IL-1β), and apoptosis (caspase-3) measured in the peripheral blood of patients with end-stage OA before knee replacement surgery might serve as important biomarkers of postoperative pain development. Our study also confirmed previous results on the importance of considering comorbidities, such as obesity and hypertension, as well as depression in association with post-surgical pain. Further research involving larger patient cohorts is required to validate our findings on the importance of preoperative examination of gene expression for the prognosis of the post-surgical pain development in order to provide the best possible care for patients with end-stage OA, undergoing joint replacement surgery.


An increasing number of patients come to the operating room in use of opioid analgesics. They have different levels of tolerance to opioid effects which challenge the anesthesiologists in search of safe and effective opioid dosing perioperatively. The tested hypothesis is that simple measures introduced will allow us to measure tolerance qualitatively. Opioid effects on pain  and dyspnea sensations (relieving effect) are tested. Patients were allocated to three groups according to pre-operative analgesics: (1) control, without any opioid analgesics, (2) weak opioid, and (3) strong opioid. Pressure pain threshold (PPT) and no-respiratory sensation period (NRSP) were measured at two points: before and 3 min after intravenous fentanyl administration.p < 0.0001, NRSP: 17.8 ± 10.8 s to 22.8 ± 18.7 s, p < 0.005, paired t test). However, preoperative opioid use, though with tendency, did not show a significant decrease of the opioid effect. Due to an insufficient number of participants, no conclusion could be drawn. Further analysis of the data from control patients showed a significant difference between the two sexes in sensitivity to PPT and NRSP, as well as fentanyl effect on PPT.A total of 58  patients were enrolled. PPT and NRSP, after iv 2 μg/kg ideal body weight (IBW) fentanyl, were significantly elevated in the control patients (PPT: 6.2 ± 2.1 N to 9.2 ± 3.9 N, Current data showed a simple method of measuring the opioid effect on two dimensions: pain and respiration. Though not able to show a qualitative measurement of tolerance formation in opioid-users, data from control patients showed females to be more sensitive to pain and dyspnea but is less sensitive to the opioid effect. Further studies are necessary to show whether these gender differences serve as clinical relevance.https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013352&language=JUMIN, UMIN 000011580. Registered 27 August 2013,  Opioid analgesics have widely been used for not only cancer pain, but also for chronic non-malignant pain. The same opioid drugs are now extensively used during and post-operatively. Not only the variability of surgical stimulus but also the patient’s individual sensitivity to opioid is considered the two major components for successful opioid analgesia. Opioid-consuming patients have a variety of tolerance levels to opioid analgesic effects, probably depending on the dose and duration of their opioid use. In addition, tolerance develops in different manners depending on the opioid effect, such as analgesia, constipation, nausea, and respiratory depression . TailoreThe study was approved by our institutional ethics committeeand registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000011580). Written informed consent was obtained from all patients prior to study enrollment after the aim and potential risks of the study were fully explained.ASA 1 or 2 patients for elective surgery from 2015 to 2019 were selected for the study. Patients were grouped to non-opioid users (control), weak-opioid users , and strong-opioid users  according to the analgesics used preoperatively. Exclusion criteria were those with respiratory complications, the presence of any skin trouble on the forehead where the pressure test is to be applied and change in opioid dosing within 2 weeks of surgery. In the operating room, ECG, blood pressure, and oxygen saturation were monitored. All patients received 2 L/min oxygen using a nasal cannula. Capnometer  was attached to the nasal cannula for measurement of respiratory rate.2 < 90%.First, the pressure pain threshold (PPT: Neutone(N)) was obtained by applying an algometer  on the patient’s forehead. The pressure which produced the first pain sensation was measured. Next, the patient was told to stop breathing at end-expiration, and the time-lapse to the first sensation of dyspnea was recorded as no respiratory sensation period (NRSP: second(s)). Both procedures were repeated twice, after which the data were averaged. For safety reasons, PT measurement was terminated at 25 N, and NRSP at SpOTwo parameters were measured pre- and 3-min post intravenous injection of fentanyl 2 μg/kg ideal body weight (IBW). Both PPT and NRSP measurements were explained and practiced once at the ward, after informed consent was taken.p values were two-sided, and a value of p < 0.05 was considered statistically significant. Variable changes between pre- and post-fentanyl were compared using Student’s paired t test. Analysis of covariance (ANCOVA) was used to analyze the effect of variables on the rate of changes between the groups (primary endpoint). Secondary analysis of control patients was performed, and backward regression analysis was performed to evaluate the predicting factors for PPT and NRSP and also their difference after fentanyl. Linear regression between NRSP and RR changes was also determined.Since we had no basis for the sample size in this observational study, clinical decisions were made according to the availability of patients during the study period. All values are expressed as mean ± SD. All A total of 60 patients participated in the study during the 2015 ~ 2019 study period. The original plan was to recruit 90 patients, including 50 controls and 40 opioid users; however, due to the difficulty in recruiting patients consuming a steady amount of analgesics with fair physical status (ASA PS 1 ~ 2) within the study period, the study had to be terminated. Two patients in the control group were eliminated due to the decreased level of consciousness after intravenous fentanyl, resulting in the inability to perform NRSP measurements. Data from 58 patients are included in the final assessment. Demographic data for 43 control, 9 weak opioid, and 6 strong opioid groups are shown in Table p > 0.15 for PPT, p > 0.9 for NRSP). Unfortunately, with the limited participants in opioid users, we could not detect any relevant effect changes. However, simultaneous measurement of analgesic and respiratory depressant effect with experimental measures showed interesting results and further analysis was performed only for control patients.PPT and NRSP change after fentanyl administration was compared among the three groups, as to detect the presence of tolerance to the opioid effect. PPT difference (ΔPPT post-pre) and NRSP difference (ΔNRSP post-pre), though with tendency, no significant correlations were detected with pre-operative opioid use , PPT increased from 6.2 ± 2.1 N to 9.2 ± 3.9 N after iv fentanyl 2 μg/kg IBW administration , showing the analgesic effect of fentanyl. Backward regression analysis was performed by using 7 background variables , pre-operative mean blood pressure, heart rate, and respiratory rate) to determine individual predictors for pre-operative PPT and PPT difference (ΔPPTpost-pre). The female sex was identified as a statistically significant predictor for pre-operative PPT  while female sex, BMI, and PS were identified as statistically significant independent predictors for ΔPPT (post-pre) .In the control patients  without any significant decrease in SpO2, showing dyspnea relieving effect, in another word, respiratory depressive effect of fentanyl. The same 7 background variables were used to detect predictors for pre-operative NRSP: sensitivity for dyspnea and ΔNRSP (post-pre): sensitivity for fentanyl on respiratory effect. Female sex was again identified as a statistically significant predictor of NRSP . However, the fentanyl depressive effect on NRSP difference (ΔNRSP (post-pre)) was not correlated with any of the variables. Six background variables were compared between male (n = 18) and female (n = 25) and found no statistical difference (Table NRSP in the control group was 17.8 ± 10.8 s which increased to 22.8 ± 18.7 s after fentanyl iv (t test p < 0.0001). No clinically relevant decrease in the vital sign was observed in all patients including oxygen saturation with 2 L supplemental oxygen. None of the three vital sign changes showed a gender difference. When comparing two respiratory measures, a decrease in RR had no significant correlation with ΔNRSP .Three minutes after fentanyl administration, HR and RR significantly decreased in the control group  effect on two modalities, analgesia and dyspnea relieving effect, and apply these methods to detect opioid tolerance qualitatively, so as to provide an effective and safe analgesia peri-operatively in opioid-consuming patients. Not all patients with opioid analgesia develop tolerance at the same level. The duration of the dosing is likely to play an important role; however, individual sensitivity to opioid also differs amongst patients. Accordingly, this simple method may give us a reliable guide for us anesthesiologists for correct dosing.Several studies have tried to qualitatively measure the opioid effect with experimental pain , 3; howe2 decrease below 90%. NRSP is known to show a significant correlation to CO2 ventilatory chemosensitivity [PPT measurement was quick, reliable, and non-invasive. NRSP measurement was also non-invasive and easy to measure without any equipment. The total time to perform the two measurements was within 5 min, and with supplemental 2 L oxygen, no case was observed with SpOsitivity , 5. As msitivity , we expeOur data demonstrates that there is a significant sex difference in the perception of pain and also dyspnea. Female tendency for being sensitive to pain has been reported with several experimental measures . HoweverNRSP measurement was easy to perform without any equipment and with the least risk to the patient. However, unlike pain sensation, to some patients, the meaning of the first sensation of dyspnea seemed difficult to comprehend and tended to perform breath-holding close to maximum. These may explain the wide range of individual variability observed in NRSP measurement. However, in most cases, in those with longer NRSP, repeated measurement showed similar results such that the change rate after fentanyl is likely to be reliable.As we could not recruit enough patients under opioid analgesia in a constant dosing with fair physical status, no statistically significant results could be drawn. Patient selection criteria may need to be changed. However, during this study period, many patients under opioid analgesia came to the operating room for surgical treatment. Among these patients, there were those whose opioids were either recently started, increased pre-operatively, changed from oral to intravenous intake, or switched types due to pain escalation before surgery. These unfortunately did not meet our inclusion criteria, however needed special care for perioperative opioid dosing. If we were able to measure the level of tolerance to these patients, more rationale use of intra and postoperative dosing for opioid may be planned. Accordingly, we believe that these measures are clinically important and need further investigation.Preoperative simple measurement for fentanyl effect on pain and respiration was proposed. If sensitivity to two modalities may be measured preoperatively, safer and efficacious peri-operative analgesic protocol may be possible, not only in opioid-tolerant patients but also in all patients to be treated. The sex difference in the effect of the opioid effect needs further studies to elucidate its importance in the clinical practice.


To evaluate the feasibility of arthroplasty with varisized three‐dimensional(3D) printing lunate prosthesis for the treatment of advanced Kienböck's disease (KD).From 2016 November to 2018 September, a retrospective study was performed for the patients of KD in our hospital. Five patients  were included in this study. The mean age of the patients at the time of surgery was 51.6 years . Varisized prosthesis identical to the live model in a ratio of 1:0.85, 1:1, and 1:1.1 were fabricated by 3D printing. All patients  were treated with lunate excision and 3D printing prosthetic arthroplasty. Visual analog scale score (VAS), the active movement of wrist  and strength were assessed preoperatively and postoperatively. The Mayo Modified Wrist Score (MMWS), Disabilities of the Arm, Shoulder and Hand (DASH) Score, and patient's satisfaction were evaluated during the follow‐up.P < 0.05). The mean flexion range of the wrist significantly increased from preoperative 40° ± 10.6° to postoperative 51° ± 6.5° (P < 0.05). The active movement of wrist and strength were improved significantly in all patients. VAS was significantly reduced from 7.3 preoperatively to 0.2 at the follow‐up visit (P < 0.05). The mean DASH score was 10 , and the mean MMWS was 79 . There were no incision infection. All patients were satisfied with the treatment.Prosthesis identical to the live model in a ratio of 1:0.85 or 1:1 were chosen for arthroplasty. The mean operation time  was 51.8 ± 4.44 min. Follow‐up time ranged from 11 months to 33 months with the mean value of 19.4 months. The mean extension range of the wrist significantly increased from preoperative 44° ± 9.6° to postoperative 60° ± 3.5° (For patients suffering advanced Kienböck's disease, lunate excision followed by 3D printing prosthetic arthroplasty can reconstruct the anatomical structure of the carpal tunnel, alleviate pain, and improve wrist movement. Ischemic necrosis of lunar bone, namely Kienböck's disease (KD), was initially described by a Viennese radiologist (Robert Kienböck) in 1910. Since KD was first described, numerous surgical treatments have been proposed for patients unresponsive to nonoperative treatmentThree‐dimensional (3D) printing, also termed as additive manufacturing, refers to a process wherein a 3D object is manufactured based on a digital model by means of successive layering of materials following the direction of a computerThis study was approved by the Committee on Clinical Investigation of our hospital. From November 2016 to September 2018, a retrospective chart review was performed for the patients who underwent lunate replacement arthroplasty with a 3D printing lunate for treatment of KD in our hospital.Indications for lunate replacement arthroplasty were the patients who suffered KD of Lichtman stage III or stage IV with: (i) continued pain after conservative care; (ii) incapability to fulfill employment because of wrist symptoms; or (iii) unwillingness to pursue further conservative care. Surgical contraindications included: (i) history of septic arthritis; (ii) psychiatric illness; and (iii) systemic illness or condition making surgical intervention hazardous.Five patients were included in this study. The demographic information of patients is listed in Table 3D prototypes were constructed and manufactured by the doctor in cooperation with the design and manufacturing industry engineer through specialized software and rapid‐prototyping techniques. Briefly, computed tomography (CT) and magnetic resonance imaging (MRI) scans of the bilateral wrists of the patients, taken at 1‐mm intervals, were converted to 3D digital models using image software  Fig. A,B. AfteThe injured lunate was subsequently designed using the mirror image of the 3D information of the impaired lunate to ensure the same morphological characters. The original anatomical model was modified in three aspects Fig. . First, During the preoperative surgical simulation, the lunate prosthesis matched the wrist precisely. The final prosthesis, made of titanium alloy (Ti‐6Al‐4V) by means of electron beam melting technology, was fabricated by the company  with the certification by the China Food and Drug AdministrationAll procedures were performed by the same surgeon, and the specific process was listed in the following five steps.After general anesthesia or brachial plexus block, the patients were maintained at supine position in a standard operating table., the injured arm was elevated and exsanguinated from the fingers down for visualization of the vessels. Then, a 5‐cm “S” incision was made on the dorsal of the wrist with sharp dissection down to the retinaculum. During the process, special attention was paid in identifying and protecting the sensory branch of the radial and ulnar nerves. Then, a longitudinal incision (4–5 cm) was made between the third and fourth compartments of the extensor retinaculum. Dorsal joint capsule was exposed and opened to approach the radiocarpal joint. The lunate was also exposed.After completed skin preparation and drapingSome pathological changes were observed as follows: yellowish lunate, lunate bone mass decrease and fragility, carpal collapse, cystic degeneration, hyperplasia of local synovial membrane, etc. Lunate volar dislocation and adhesion with surrounding carpus were also observed in some patients. Local lunate gap was filled with granulation tissue. Furthermore, degeneration might be present at midcarpal joint, the radiocarpal joint, or both. After removal of the necrotic lunate and the surrounding synovial tissue, saline irrigation was applied to remove the residual trivial pieces Fig. A,B. NextAfterwards, three different sizes of prosthesis were carefully inserted into the empty spaces Fig. . This prFinally, the joint capsule and extensor retinaculum was repaired and the incision was primarily closed.The patients were postoperatively immobilized in a removable orthosis or plaster slab for 2 weeks. After removal, wrist exercises were started and continued for 4 to 16 weeks according to the patient's needs and progress.After the surgery, all patients had radiographs  and received a clinical examination at the preselected time points.A Jamar dynamometer  was applied for measurement of the grip strength and a hand‐held goniometer  for range of movement  with the healthy side selected for comparison.VAS is a psychometric scale that is generally used in pain scale surveys to understand varying degrees of pain experienced by a patient. It is also used in surveys to measure characteristics and attitudes across a range of continuous values; for example, if a person suffering from pain can rate that pain from a degree ranging continuously from “no pain” to “pain as bad as it could possibly be”. This scale was essentially developed to measure the basic element in continuity for pain measurement. For measurement of the magnitude of pain, the most used scale is “no pain”  and “pain too intense to be tolerated” . Respondents indicate their degree of acceptance to a statement by specifying a point on the continuous scale in between two endpoints. Intermediate numbers or pointers should be avoided in the VAS to avoid congregation. VAS was used to evaluate pain before surgery and at the time of final follow‐up.The Disability of Arm, Shoulder, and Hand (DASH) questionnaire is a standardized measure which captures the patient’s own perspective of their upper extremity health statusMMWS is a clinician‐completed scoring system that is used to evaluate the level of disability in the wrist. The MMWS system mainly includes four aspects: pain, functional status (able to work), range of motion, and grip strength. The score standard had a maximum of 100 points (best possible outcome). A total score <60 is considered a poor score, 60–80 is satisfactory, 80–90 is good, and 90–100 is excellent. At the final follow‐up, MMWS were used to evaluate postoperative recovery of wrist function.Patient satisfaction is an important component of healthcare or treatment quality reflecting the healthcare or treatment provider's ability to meet patients’ needs and expectations. Our patient satisfaction was related to surgery and patient endorsements for the treatment effect. Patient satisfaction mainly includes five grades: very satisfied, satisfied, neutral (fair satisfied), dissatisfied, and very dissatisfied. The questions were measured on a five‐point scale from “very satisfied” to “very dissatisfied”. The patient chose relative point according to their own evaluation of treatment at last follow‐up.P < 0.05. The statistical analysis was performed using SPSS 17.0 software . Statistical comparisons were performed with Student t‐test.All data were displayed as mean ± standard deviation (SD) with the statistical significance set at Patients were followed for 11–33 months, with an average follow‐up duration of 19.4 months. The mean operation time  was 51.8 ± 4.44 min . The mean flexion range of the wrist significantly increased from preoperative 40° ± 10.6° to postoperative 51° ± 6.5° (P = 0.04 < 0.05). The grip strength of the affected side compared with the unaffected side improved from 47% ± 7.8% to 88.6% ± 5.9%.The mean extension range of the wrist significantly increased from preoperative 44° ± 9.6° to postoperative 60° ± 3.5°(P = 0.0001 < 0.05). Furthermore, four of the five patients were free from pain and the remaining patients had mild wrist pain during strenuous activity.The VAS for wrist pain was 7.3 ± 1.2 preoperatively and 0.2 ± 0.5 at the last follow‐up , satisfied (one patient), or neutral (one patient) with the surgical outcome. The treatment outcomes were list in Table It was difficult to suture prosthesis with surrounding tissue during operation. Prosthesis fixation was difficult and important for preventing postoperative subluxation or dislocation.There were no incision infections and the wounds healed well. No cysts or synovitis in the radial or carpal bones were observed. Osteoarthritis was observed in two patients before surgery. Among them, no significant aggravation in arthritis was observed compared with the pre‐operative manifestation. As for the patients at grade 3, arthritis was partially reversed.KD is characterized by ischemic necrosis of the lunate and often results in a predictable pattern of carpal change and degeneration and lunate collapse. The goals of pain relief, motion preservation, strength maintenance, and good functional outcomes are essential for successful treatment. Various therapeutic proposals, including lunate revascularizationIn case of a completely necrotic lunate bone, revascularization procedures are unlikely to be the optimal treatments, whereas salvage options such as proximal row carpectomy and total wrist fusion may lead to degenerative arthritis resulting from the abnormal loading at the radiocarpal or midcarpal articulation, and are typically reserved for older patients with lower functional demandsThe surgical process for arthroplasty using a 3D‐printed lunate is quite simple with only two steps: excision of the lunate and insertion of the prosthesis. Despite few reports comparing the surgical duration of different procedures, the mean operative time in our series was 51.8 min, which is relatively short for KD procedures. For other arthroplasty procedures, partial radial styloidectomy and partial resection of the scaphoid and the capitates are routinely required. Meanwhile, in these procedures, to facilitate the insertion of prosthesis and improve the postoperative ROM of the wrist, surgical procedures such as deepening the radial glenoid concavity or capsular plication may also be neededThe prevention of synovitis, arthritis, or cyst formation by the prosthesis is a major factor in the success of arthroplastyA disease classification scheme is good for as long as it can direct the definitive procedure to be suggested in a large variety of clinical circumstances. The classification for KD devised in 1977 and modified in 1993 by Lichtman is based on the osseous classification and is the most widely used to guide treatment at various stages of the diseaseAlthough our initial results are promising, there are several limitations and unanswered questions. One limitation is that our study has a short follow‐up period and the number of patients in the series is limited. Clinical and radiological studies of larger cohorts with longer follow‐up durations are warranted to determine the advantages of 3D‐printed implants for treatment of advanced KD and its specific indications in terms of different disease stage and classification. In addition, the 3D‐printed lunate is costlier than routine surgery. Therefore, epidemiological data about the long‐term costs of different interventions, taking into account complications and treatment effects, are needed. Nevertheless, our study demonstrated that arthroplasty using a personalized 3D‐printed titanium lunate provides a completely novel option for the treatment of advanced KD.For patients suffering advanced Kienböck's disease, lunate excision followed by 3D‐printed prosthetic arthroplasty can reconstruct the anatomical structure of the carpal tunnel, alleviate pain, and improve wrist movement. The current study provides evidence that arthroplasty using a personalized 3D‐printed titanium lunate is a completely novel option for the treatment of advanced KD and this cutting‐edge technology may be employed to improve outcomes in this difficult group of patients. Meanwhile, this study may be beneficial for the accumulation and spread of experience for designing and fabricating the individualized titanium lunate. Further research on the feasibility of this new approach on a large scale with a long follow‐up are warranted.The study was supported by National Key R&D Program of China  and National Nature Science Foundation of China , China Postdoctoral Science Foundation , National Postdoctoral Program for Innovative Talents (BX20180194), Project of Shanghai Jiading National Health and Family Planning Commission (KYXM 2018‐KY‐03), Project of Shanghai Clinical Medical Center (2017ZZ01023), Shanghai Municipal Key Clinical Specialty.All authors declare that they have no conflict of interest.


In total, >78% of the patients experienced no or only mild post-operative pain in both the groups at all time intervals, without any significant difference in pain scores between the two groups (p > 0.025). An overall flare-up rate of 14.8% was found. The results suggest that either of these medicaments can be used as an inter-appointment medication for the prevention of postoperative pain in necrotic cases.Propolis is a potent anti-microbial and natural anti-inflammatory by-product obtained from the beehive. Studies have demonstrated the superior biocompatibility and anti-microbial properties of propolis as compared to calcium hydroxide. However, its effect on postoperative endodontic pain is unknown. Therefore, this study aimed to investigate the impact of Chinese propolis paste as an intracanal medicament on postoperative endodontic pain intensities compared with calcium hydroxide (control) at different time intervals in necrotic teeth with periapical radiolucency. Eighty patients with single-rooted necrotic teeth with visible periapical radiolucency were recruited and randomly allocated to either the calcium hydroxide or propolis groups. After chemo-mechanical preparation and intracanal medicament insertion, patients were given the VAS  to record pain scores. Inter-group data were compared and analyzed using two-way repeated measure ANOVA (Bonferroni test). A  Pain is a common occurrence after endodontic treatment. Up to 40% of patients may experience some level of post-operative endodontic pain . It is eAntimicrobial intracanal medicaments are considered as a method of disinfection of the root canal system . In addiMorinda controflia, and the extract of Arctium lappa [Apis mellifera L.) [Recently, the focus of research has shifted towards finding natural alternatives to synthetic medications. Several natural products have been tested as intracanal medicaments for this purpose, namely: Liquorice extract, propolis, um lappa . Propolium lappa . Moreoveum lappa  and to cum lappa . It is pfera L.) . It possfera L.) ,17. Simifera L.) ,19. The mechanism by which propolis induces its anti-inflammatory and analgesic action is through the suppression of the lipopolysaccharide-induced inflammatory response of key cells . Becausewww.isrctn.com (Study ID: ISRCTN66816132) and the www.clinicaltrials.gov (Study Identifier: NCT03723980) database. The study was conducted from 16 November 2017 to 15 October 2018 in a secondary healthcare center, the out-patient department of operative dentistry/endodontics in Dow International Dental College, D.U.H.S, Karachi. All patients were informed about the trial in detail. Only those patients who signed the written informed consent form were included in the study. The primary outcome was defined as the mean pain score difference between the two groups at time intervals of 4, 12, 24, 48, and 72 h post-operatively. The secondary outcome was the evaluation of the incidence of a flare-up  using a simple randomization technique by an independent person. The allocation concealment was done by placing the sequence in a sealed envelope, which was then given to the dental assistant. The eligible patients were given serial numbers and assigned to the groups by the dental assistant according to the randomized sequence. The principal investigator, the patients, and the analyst (biostatistician) were blinded from the type of intracanal medicament used.This study was a single-center, parallel-group, double-blind, randomized-controlled (1:1) clinical trial. It was structured and reported following the CONSORT statement. The study was approved by the Institutional Review Board (Ethics Committee) of Dow University of Health Sciences . The protocol of the study was registered at interval . Two indGlossary of Endodontic Terms [The teeth that did not respond to electric pulp testing  and cold sensibility test  were diagnosed as necrotic. The periapical diagnosis was made according to the ic Terms . The heaWith the help of the randomized sequence, the dental assistant informed the secondary operator about the type of medicaments (characterized as group I and group II) to be inserted. The medicament group I consisted of teeth in which the usual standard of care, calcium-hydroxide paste , was inserted. It consisted of 20% calcium hydroxide, barium sulphate, and excipients. Approximately, 100 to 150 mg of calcium hydroxide were dispensed to be inserted in the root canal of a single tooth. The same paste has been used in previous studies as an intracanal medicament . The medBefore dismissal, the patients were informed about, and given, the prescription of analgesics and the visual analogue scale (VAS). They were also educated regarding the adverse effects of codeine-containing medications and instructed to use these medications only if the OTC medicaments did not work. Patients self-recorded their pain intensity score on VAS pre-operatively, then at 4, 12, 24 (day 2), 48 (day 3), and 72 h (day 4). VAS consisted of a 100-mm line, with 0 indicating the absence of pain and 100 indicating the worst pain possible. The scale was further divided into 4 groups according to the severity of pain and requirement of analgesic: (1) 0 to 24 denoted as “no or only mild pain” with no requirement of analgesic; (2) 25 to 49 denoted as “moderate pain” requiring over-the-counter analgesic; (3) 50 to 74 denoted as “severe pain” requiring codeine-containing analgesic; and (4) 75 to 100 denoted as “extreme pain” with no medicine effective [p-value < 0.025 was considered as significant. Descriptive statistics were reported for a flare-up and pain intensity according to each group.For data entry and analysis, IBM SPSS version 24  was used. For analysis of the distribution of age and pre-operative pain scores between the groups, the Mann–Whitney U test was applied; for the distribution of genders, the Chi-square test was applied; and for the distribution of the type of teeth, the Fisher exact test was applied. For multiple comparisons of the mean pain scores between groups and between time points, two-way repeated measure ANOVA with Bonferroni test was employed. A p > 0.05, Analyses of the baseline characteristics revealed that both the study groups were homogenous in terms of age, gender, ethnicity, pre-operative pain status, and the type of teeth included in the study (p > 0.50) , day 2 (−1.57), day 3 (−0.82), and day 4 (−0.72). Only at 4 h did the patients in the propolis group have lesser pain scores (2.96). However, the difference in pain scores between the groups was statistically non-significant at all the time intervals ( > 0.50) . More thThe acute increase of pain scores (flare-up) was evaluated for four days. Overall, the incidence of flare-up was found to be 14.8% , with a In the literature, several methods have been described for the prevention of post-instrumentation pain. It includes the usage of the instrumentation technique that extrudes less debris, for instance, the crown-down technique with copious and frequent irrigation ; persistIn the present study, necrotic teeth with periapical pathosis were specifically chosen for the study because intracanal medicaments are highly recommended in such teeth . Single-Overall, there was a continuous reduction of inter-appointment pain as time elapsed. However, the inter-group comparison revealed that pain intensities did not significantly differ between the two groups at any time interval. This is because most of the patients (>78%) experienced no or only mild inter-appointment pain (pain score <25) in both the medicament groups at all time intervals, which is in accordance with the results of a previous study. Additionally, the previous study also reported an insignificant difference in post-operative pain between the different intracanal medicament groups. However, due to the low incidence of inter-appointment pain, the authors recommended the use of either of those medicaments routinely . The curThe flare-up rate varies widely in the literature due to differences in the variables studied, and the methods used to characterize flare-up ,4,6,37. One possible limitation of this study was the absence of spontaneous pain. The presence of pre-operative spontaneous pain is a predictive factor for postoperative pain . HoweverBased on the findings, it can be concluded that there was no statistically significant difference in post-operative pain between calcium hydroxide and propolis groups. However, as the effect of propolis was observed to be similar to the calcium hydroxide group on postoperative endodontic pain without any adverse effects, it can be recommended for use as an intracanal medicament in necrotic cases. Additionally, in the future, a similar clinical trial is needed for a comparison of propolis with the no-treatment group, and other medicament groups.