Background and Objectives: Studies have shown that centrally sensitized patients have worse clinical outcomes following total knee arthroplasty (TKA) than non-centrally sensitized patients. It is unclear whether central sensitization (CS) affects patient-reported outcomes (PROs) and/or level of osteotomy site pain in patients undergoing medial opening-wedge high tibial osteotomy (MOWHTO). The purpose of this study was to determine whether CS is associated with PROs and osteotomy site pain following MOWHTO. Materials and Methods: A retrospective evaluation was conducted on 140 patients with varus knee osteoarthritis (OA) who were treated with MOWHTO and monitored for two years. Before surgery, the Central Sensitization Inventory (CSI) was used to assess CS status, and a CSI of 40 or higher was considered indicative of CS. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and pain visual analogue scale (VAS) were used to assess PROs. The minimal clinically important difference (MCID) for the WOMAC was set as 4.2 for the pain subscore, 1.9 for the stiffness subscore, 10.1 for the function subscore, and 16.1 for the total based on the results of a previous study. The WOMAC score, pain VAS score of the osteotomy site, and the achievement rates of WOMAC MCID were compared between the CS and non-CS groups. Results: Thirty-seven patients were assigned to the CS group, whereas 84 were assigned to the non-CS group. Before surgery, the CS group showed a higher WOMAC score than the non-CS group . While there was a statistically significant improvement in WOMAC subscores  for both groups at two years after surgery , the CS group had a higher WOMAC score than the non-CS group . The CS group showed significantly inferior results in pre- and postoperative changes of WOMAC subscores  relative to the non-CS group . In addition, pain at the osteotomy site was more severe in the CS group than in the non-CS group at two years after surgery . Patients with CS had worse MCID achievement rates across the board for WOMAC pain, function, and total scores  compared to the non-CS group. Conclusions: Centrally sensitized patients following MOWHTO had worse PROs and more severe osteotomy site pain compared to non-centrally sensitized patients. Furthermore, the WOMAC MCID achievement rate of patients with CS was lower than that of patients without CS. Therefore, appropriate preoperative counseling and perioperative pain management are necessary for patients with CS undergoing MOWHTO. Level of Evidence: Level III, case-control study. Medial compartment osteoarthritis (OA) with varus deformity ,2 is theWhile total knee arthroplasty (TKA) is effective in eliminating pain by cutting off the source at the joint periphery, about 20–40% of patients are dissatisfied with the results and complain of persistent pain . Due to PROs have gained traction in recent years, and patient-reported outcome measures (PROMs) are widely used to assess the success of orthopedic procedures . One of It is currently unclear whether CS affects PROs and/or osteotomy site pain in patients undergoing MOWHTO. Therefore, the purpose of this study was to determine whether CS is associated with PROs and osteotomy site pain following MOWHTO. We predicted that centrally sensitized patients would have worse PROs and increased osteotomy site pain than those who were not centrally sensitized.As part of a retrospective record review research, we included 140 patients who received MOWHTO between May 2015 and April 2019 at a single hospital. The criteria for inclusion were age < 70 years and isolated medial compartment OA with varus deformity. Patients with lateral compartment and patellofemoral OA, osteonecrosis, inflammatory or traumatic OA, missing data, and/or loss to follow-up within two years were excluded from the study to reduce the potential impact of preoperative variables on MOWHTO outcomes. The final study contained 121 patients, after excluding 19 for various reasons . InformeSurgical procedure®, DePuy Synthes, Oberdorf, Switzerland) was used to secure the osteotomy site. No bone grafts or artificial materials were used to fill the opening gap space.A tourniquet was placed in the proximal femur and maintained during surgery with a pressure of 300 mmHg. Arthroscopy was performed prior to osteotomy in all cases. If the meniscus tear was present including medial meniscal root tear, partial meniscectomy was performed. Multiple drilling was also performed for cartilage defects. A 7 cm long skin incision was made in the middle between the tibial tuberosity and the posteromedial border of the tibia, beginning 1 cm below the knee joint. Same skin incision was used in all patients. The Dugdale method  was usedPostoperative rehabilitationFollowing surgical procedures, all patients participated in the same rehabilitation regimen. To improve knee flexion range, exercise on a continuous passive motion machine was started on postoperative day one at 60 degrees and progressed by 5 degrees daily up to 130 degrees of flexion. Within four weeks, patients were allowed to walk with crutches, and after six weeks, they were permitted full weight bearing.Clinical assessment and Radiographic evaluationThe Central Sensitization Inventory (CSI) was used to assess the status of CS, and patients were given the questionnaire the day before the surgery . The CSIPreoperatively and at two years postoperatively, the WOMAC scores were used to assess knee PROs . The 24-Age, sex, operation side, body mass index (BMI), American Society of Anesthesiologists (ASA) score, comorbidities (diabetes and hypertension), alcohol intake, smoking, and preoperative OA severity were also recorded. The Kellgren and Lawrence (K-L) grade was used to quantify the severity of OA . Hip–knePreoperative and postoperative HKA angle and WBL ratio were analyzed twice by two orthopedic surgeons. They were orthopedic surgeons with more than five years of experience. Each analyzer was blinded to the results of the other and to all patient information. The average of the two analyzers’ results was used. Using the intraclass correlation coefficient (ICC), intraobserver and interobserver reliability were evaluated to determine the reliability of the measurement. In this study, both intraobserver and interobserver ICC values were greater than 0.8.Statistical Analysist-test. The rate of WOMAC MCID achievement was compared between the two groups using the chi-square test. A post hoc power analysis was conducted to evaluate whether our findings had sufficient statistical power. SPSS was used conduct statistical analyses . A p-value less than 0.05 was considered statistically significant.The mean and standard deviation are presented as descriptive statistics for all continuous variables, and frequency statistics are supplied for all noncontinuous variables. We compared preoperative PROMs, two-year postoperative PROMs, and osteotomy site pain between the CS and non-CS groups using Student’s The 121 patients included 37 (30.5%) patients with CS and 84 (69.4%) patients without CS. The mean follow-up period was 2.0 ± 0.1 years. p < 0.05, p < 0.05), the CS group had a significantly lower two-year postoperative score and lower WOMAC subscores  than in the non-CS group  compared with the non-CS group  after TKA ,10,11.Although MOWHTO is a surgical procedure that also involves bone cutting, there has been no research on the relationships between clinical outcomes and CS. As such, this study investigated the relationships between CS and clinical outcomes following MOWHTO.Even though the PROs of the CS group showed significant improvement after surgery, scores for the preoperative, postoperative, and amount of change in WOMAC in patients with CS were worse than those for patients without CS. Two years after surgery, pain at the osteotomy site of patients with CS was more severe than in non-CS patients. Therefore, surgery outcome, including osteotomy site pain, may be inferior for CS patients who undergo MOWHTO.Most recently, the MCID  has been given more weight ,35. Due p = 0.064). Women have been shown in several studies to be more sensitive to centrally mediated pain than males [Although there was no statistically significant difference in sex between the two groups, the proportion of females in the CS group tended to be higher than in the non-CS group (an males ,37,38. Tan males , increasThe reason for the differences in PROs and osteotomy site pain between patients with and without CS is not well understood. It is considered that individuals with and without CS have different clinical results after surgery ,10,11. EThere were limitations in this study. First, as seen in previous research with Koreans who have been diagnosed with OA, patients in this study were all Korean, with females as the majority of patients, which limits the application of the study to other environments ,43. In KThe PROs and severity of osteotomy site pain of patients with CS following MOWHTO were worse than those of patients without CS. Moreover, the MCID achievement rate of patients with CS was lower than that of patients without CS. Therefore, appropriate preoperative counseling and perioperative pain management should be considered for patients with CS undergoing MOWHTO.


Background: Piriformis syndrome (PS) is a painful musculoskeletal condition characterized by a deep gluteal pain that may radiate to the posterior thigh and leg. This study was designed to compare the effectiveness of ozone and BTX to lidocaine injection in treating piriformis syndrome that was resistant to medication and/or physical therapy. Study design: Between November 2018 and August 2019, we involved eighty-four subjects diagnosed with piriformis syndrome in a double-blinded, prospective, randomized comparative study to receive an ultrasound-guided injection of lidocaine (control group), botulinum toxin A, or local ozone (28 patients each group) in the belly of the piriformis muscle. Pain condition evaluated by the visual analog score (VAS) was used as a primary outcome, and the Oswestry Disability Index (ODI) as a secondary outcome, before, at one month, two months, three months, and six months following the injection. Results: The majority (58.3%) of patients were male, while (41.7%) were female. At one month, a highly significant decrease occurred in VAS and ODI in the lidocaine and ozone groups compared to the botulinum toxin group (p < 0.001). At six months, there was a highly significant decrease in VAS and ODI in the botulinum toxin group compared to the lidocaine and ozone groups (p < 0.001). Conclusion: Botulinum toxin may assist in the medium- and long-term management of piriformis syndrome, while lidocaine injection and ozone therapy may help short-term treatment in patients not responding to conservative treatment and physiotherapy. A lesser-known cause of extra-spinal sciatica is piriformis syndrome (PS), in which a number of conditions affecting the piriformis muscle or its vicinity may irritate the nearby sciatic nerve and cause unilateral deep gluteal pain radiating to the ipsilateral thigh. This pain may be worsened by actions that increase piriformis muscle tension, such as rotation of the hip in flexion or knee extension, in addition to sitting intolerance, tenderness over the sciatic notch, and limitation of straight leg raising. These signs are consistent with morphological changes in the piriformis muscle and sciatic nerve ,2. PirifWith a wide range of therapeutic alternatives, conservative treatment for PS significantly reduces pain and enhances function. Non-steroidal anti-inflammatory drugs, muscle relaxants, and neuropathic pain medications are among the pharmacological treatments included, along with physiotherapy, psychotherapy, lifestyle changes, and local injection procedures . The pirOzone is a soluble allotropic form of oxygen produced by a direct exposure of oxygen to the electric current in ozone generators, and it has excellent oxidizing activity in biological tissues producing reactive oxygen species and lipid oxidation products. These molecules function as biochemical regulators of inflammation through the downregulation of the tumor necrosis factor, as well as tumor necrosis factor receptor 2 . Ozone tFurthermore, due to its distinct mechanism of preventing the release of acetylcholine at the muscle plaque level, botulinum toxin (BTX) has been widely used in numerous sectors of medicine to treat focal hypertonia, muscle spasticity, dystonia, and other diseases ,9. The cHowever, piriformis syndrome frequently develops into a chronic condition; thus, pharmaceutical treatment is only advised for a short time . In ordeThis prospective comparative study was conducted between November 2018 and August 2019 at Al-Azhar University Hospitals  after local and institutional ethics committee approval. The study included 84 patients, all of whom gave their written informed consent to participate. The research followed the rules of the Declaration of Helsinki regarding human research. We included patients diagnosed with primary piriformis syndrome by history, physical examination, external gluteal tenderness near the sciatic notch, and clinical tests: Freiberg, Pace, and Fair ,17,18. T®, FUJIFILM Sonosite, Bothell, DC, USA), according to the patient’s build. The transducer was parallel to the piriformis muscle (PM), with the medial side directed to the sacrum and the lateral side towards the great trochanter  was advanced under direct ultrasound guidance in an in-plane orientation, traversing the skin, subcutaneous fat, and gluteus maximus, and passing from lateral to medial through the piriformis sheath and into the muscle belly itself  diluted to 3 mL, with 0.9% sodium chloride, a mixture of 3 mL of oxygen-ozone (O2-O3) with an ozone concentration of 20 μg/mL , or 3 mL of 1% lidocaine , according to the group. All patients were evaluated for pain intensity and disability before the intervention, and then at one month, two months, three months, and six months after the intervention.The intervention area  was sterilized with chlorhexidine and draped. After local infiltration anesthesia, a 22-gauge needle , which is a self and subjective expression of the extent of disability and is composed of ten questions, each with six choices. The questions cover the pain intensity; ability to work, stand, sit, lift, and perform personal care; travel; sleep pattern; and sexual life. A score of 0–5 is given to each question to sum it and present the sum as a percentage of 100 .Regarding sample size calculation, we planned a study of a continuous response variable from independent control and interventional subjects with one control(s) per interventional subject. In a previous study , each su−2. All patients completed the study. The average age of all patients was 39.5 ± 8.58 years, and the average body mass index was 29.5 ± 2.9 kg mMost patients were male , with a mean symptoms’ duration of 10.9 ± 2.5 months, a VAS score of 8 ± 0.92, and an ODI score of 45.6 ± 9.9. The demographic data in each group are shown in .No significant statistical difference was seen between the three groups for all demographic data. . RegardiOverall, the values of VAS and ODI decreased after one month  and then remained almost stable, with a general trend of slight progressive increase in the second month , third month , and sixth month after injection . The comparative analysis between the three groups showed a highly significant decrease in the first and second month, in both VAS and ODI, in the LD and OZ groups, compared to the BTX group, with the inter-group differences demonstrated in After two months, both VAS and ODI scores remained almost stable for the OZ group, while we noted a progressive increase in the LD group; the reduction in both scores started to occur in the BTX group after two months . From thNearly all patients in the three study groups experienced success with the US-guided technique, and no problems or adverse effects were noticed.This study shows promising options for chronic cases of PS after the failure of conservative therapy. By injecting lidocaine, ozone, or BTX, we can significantly improve both short- and long-term pain and disability scores. Nearly all patients involved in the three study groups experienced success with the US-guided injection technique, with no adverse events noticed.A significant portion of PS cases remain undiagnosed even though the incidence ranges from 5% to 36% ,21,22. TInjections into the peri-sciatic nerve, the medial aspect of the muscle, or the side, are just a few of the different injection strategies discussed in the treatment of PS . However−2. Regarding the gender of the studied patients, the majority (58.3%) were male, while 41.7% were female. As the female: male ratio in PS was reported to be 6:1, these results did not accord with those previously recommended in the literature. Additionally, Shah et al.’s [The recruited patients’ average age was 39.5 ± 8.58 years, and the average BMI was 29.5 ± 2.9 kg mp < 0.001), which concurred with the finding of Kongsagul et al. [After 1 and 2 months of follow-up, our study showed that VAS and Oswestry Disability scores in the lidocaine and ozone groups significantly decreased compared to the BTX group . This result is supported by a placebo-controlled trial on 145 myofascial pain patients, which revealed that BTX is valuable for controlling pain severity and duration in myofascial pain syndrome for 4–6 weeks after the injection [The results from our comparative study among the three groups at 3 and 6 months also showed a highly significant decrease in VAS and Oswestry Disability scores in the BTX group compared with the lidocaine and ozone groups (njection . Moreovenjection . Moreovenjection . They innjection .P < 0.05) or the physical performance when compared to sodium chloride at 0.9% or bupivacaine at 0.25% in 27 patients complaining of low back pain [In contrast, some studies claimed that BTX did not improve the VAS (20% at 15 days and 30 days, and 22% at 90 days after treatment, ack pain . The samack pain  and Ojalack pain  in patieack pain  also repack pain . Additioack pain . Our finack pain . It has ack pain ,13. Acetack pain .Thus came the significance of ultrasound-guided BTX or ozone injections, as preferred to electromyography, fluoroscopy, CT, or MRI-guided injection procedures, which have been utilized to increase the accuracy of needle placement into the PM for the treatment of chronic resistant cases of PS. However, it was shown that these methods were not adequate for determining the needle depth required to reach the PM . AdditioWhile lidocaine and ozone therapies may aid short-term treatment in patients who are not responsive to conservative treatment and physical therapy, BTX may help with the medium- and long-term management for PS patients. The precise mechanism of BTX and ozone therapy on various chemical and inflammatory mediators, as well as their impact on reducing pain and functional disability in chronic resistant PS cases, requires further study with a large sample size.


Dexamethasone could be an effective prophylactic agent for the prevention of pain flares after palliative radiotherapy (RT) for uncomplicated bone metastases. To date, there are no data on its prophylactic coanalgesic (opioid-sparing) effect after RT in patients with complicated bone metastases compared to uncomplicated ones, which is the aim of our study. n = 14) or complicated ones , were examined retrospectively. All patients received parenteral dexamethasone  along with their background and breakthrough pain opioid intake  during their 5-day in-hospital stay. Pain severity  and analgesic consumption were recorded at admission, daily during the hospital stay, and for 10 days following treatment. Binary logistic regression was used to determine predictive factors for pain flare occurrence.  Twenty-nine American Society of Anaesthesiologists (ASA) III-IV patients, aged ≥18, treated with single-fraction 8 Gy/1 or multi-fraction 20 Gy/5 RT for painful uncomplicated bone metastases  and pain flare as well . Lower dose 4 mg dexamethasone was revealed as a moderate analgesic agent in steroid naïve patients with no side effects, whereas in steroid non-naïve patients the predominantly higher dose 8 mg dexamethasone had minimal impact on pain flares prevention at the expense of more pronounced immunosuppression (P = 0.039).  A higher ASA score is the only determinant positively influencing opioid consumption . Further dose-effect bigger studies are needed, identifying optimal doses of dexamethasone intake and its optimal duration in high-risk patients. Bone metastases are a frequent occurrence in advanced cancer, especially cancers of the breast, prostate, and lung. Metastatic bone destruction leads to increased morbidity and an impaired quality of life as a result of pain, fractures, and other skeletal-related events. Not all patients with bone metastases are symptomatic, but up to 70% of patients with metastatic bone disease experience severe pain . For patAfter RT for painful bone metastases, up to 44% of patients report pain flares . Dexametn = 14) or complicated ones , were examined retrospectively. The inclusion criteria included patients aged ≥18 who had pathologically proven primary solid malignancy with uncomplicated or complicated bone metastases, with indications for single or multiple-fraction radiotherapy and corticosteroid coanalgesic administration, with pain intensity on a numeric rating scale (NRS) ≥2 and able to give a verbal pain score along with data concerning their analgesic consumption on admission, during the hospital stay and follow-up. The exclusion criteria included patients who had not completed the planned course of radiotherapy, with contraindications to steroids such as uncontrolled hypertension, diabetes, infection, or an active peptic ulcer, with painless bone metastases, as well as with incomplete medical records regarding the assessment of pain and analgesic consumption. All patients received parenteral dexamethasone , along with their background and breakthrough pain opioid  and/or nonopioid analgesics (in case of NSAIDs coupled with PPI), which have already been prescribed before the admission and continued until the end of the follow-up. Data regarding demographics, the eastern cooperative oncology group (ECOG) [Twenty-nine American Society of Anaesthesiologists (ASA) III-IV patients, aged ≥18, treated with single-fraction 8 Gy/1 or multi-fraction 20 Gy/5 RT for painful uncomplicated bone metastases  , the comp (ECOG) ) and anaUncomplicated bone metastases were defined as metastatic tumour masses without massive infiltration towards soft tissue, characterized by a low risk of imminent pathological fracture and no evidence of spinal cord compression or cauda equina compression, and which were not previously irradiated . ComplicPain flares were defined as a worsening of basal pain, recorded as a 2-point increase in the NRS of 0–10 , without a reduction in the analgesic intake or an increase of 25 percent of the analgesic intake without an improvement of the worst pain score . For patPrimary endpoints were the assessment of coanalgesic opioid-sparing effect, efficacy, and safety of implemented dexamethasone prophylaxis in steroid naïve and steroid non-naïve patients. The secondary end point was to determine which factors among demographic, clinical, and treatment variables were associated with the occurrence of pain flares.The study protocol for this single-center retrospective observational study was reviewed and approved by the local ethics committee. Owing to the retrospective nature of this study and the anonymization of data, the need for informed consent was waived. Another consideration for the waiver was that all the studied patients had already given signed informed consent to begin in-hospital treatment. The study was performed according to the Declaration of Helsinki principles and the EU General Data Protection Regulation.χ2 test or Fisher's exact test (as appropriate). Continuous variables were compared with independent samples T-test in normal distribution or Mann–Whitney U test for distribution of the different from the normal (between-group comparisons) and with paired samples T-test or Wilcoxon Signed Ranks Z-test, respectively (within-group comparisons). Binary logistic regression was used to determine predictive factors for pain flare occurrence. All statistical analyzes were performed at α = 0.05.Data were analyzed using SPSS v.20 . Categorical data were compared using the Within 1 year, a total of 70 patients were admitted, 41 were excluded, and 29 charts were abstracted .P = 0.059).There were no between-group differences in terms of demographics, ECOG, ASA, comorbidities, malignancy, implemented RT, or analgesic consumption . There wAs can be seen from P = 0.039).All dexamethasone side effects were in the steroid non-naïve group, with significantly more immediate adverse effects associated with hyperglycemia and immunosuppression . The immP = 0.005).A higher ASA score is the only determinant positively influencing opioid consumption Figures  and 3 anPainful bone cancer metastatic lesions are very challenging to manage due to the etiology of the pain generator involved. The inflammatory process and the constant remodeling activity are the main pain generators at the bony site. However, depending upon the growth of the tumor bed, additional pain generation may occur, such as neuropathic pain secondary to spinal cord compression or nerve root compression . OpioidsRT is an effective and standard modality for the treatment of painful, complicated, and uncomplicated bone metastases . It is tP = 0.011) [Multiple studies have demonstrated a single 8 Gy fraction to be as efficacious as a multiple-fraction course for painful bone metastases . Use of = 0.011) , it had The observed pain flare rate in our corticosteroid naïve patients (28%) is in line with that for uncomplicated bone metastases reported by others (24% after EBRT) . HoweverP = 0.039), which to some extent might reflect the more pronounced systemic inflammatory response to tumor activity in complicated bone metastases as well [Our higher dose of 8 mg Dexamethasone prophylaxis was implemented at the expense of more pronounced immunosuppression in terms of WBC count elevation  on opioid analgesics. The authors suggested further research to compare cancer patients admitted to the in-patient palliative care unit, who are already on adjuvants with those who would start their adjuvants in the hospital . Our stuOur patients were treated with nonopioid analgesics, as NSAIDs and paracetamol, which had already been prescribed before the admission and were continued until the end of the follow-up. This could probably mask the dexamethasone opioid-sparing effect, but our nonopioid and opioid consumptions were evenly distributed between the groups , and we In all-patients comparison, however, the implemented non-opioid analgesics  do reveal their opioid-sparing effect in ASA III patients compared to ASA IV patients . The latP < 0.001) in patients with advanced cancer [P < 0.0001) in patients with painful bone metastases [P = 0.005). The resulting wide CI here to some extent are due to the small sample size, which with its retrospective design can be considered as limitations of our study. Another limitation is the implemented EBRT only in patients with painful bone metastases which does not allow a generalization of our results in other modalities of RT such as SBRT.On the other hand, opioid use itself is associated with an increased hazards of death (HR = 1.59 (95% CI: 1.38–1.84), d cancer , almost tastases . In our A recent debate on the use of dexamethasone to prevent pain flares concluded that consensus for routine use has not been achieved. Thus, the choice to use dexamethasone prophylactically should be between radiation oncologists and patients. Factors including symptom burden, comorbidities, performance status, and quality of life as well as the radiation dose and fractionation should be considered on an individual level . We confIrrespective of the supporting evidence in a RCT of dexamethasone potential for prevention of RT-induced pain flares, our data failed to reveal its efficacy in the real practice world (a case mix of uncomplicated and complicated bone metastases). Further dose-effect bigger studies are needed, to identify optimal doses of dexamethasone intake and its optimal duration in high-risk patients.


In the 2012 WHO guidelines for the treatment of chronic pain in children, the recommendation for the use of the weak opioids tramadol and codeine was removed, and in 2017 the indication for the use of these drugs for the treatment of postoperative pain in the paediatric population was also withdrawn. For the treatment of pain associated with cancer treatment, the recommendations of non-opioid analgesics and, in cases of insufficient analgesia, the use of strong opioids remained. Nalbuphine, a weak opioid commonly used in the treatment of perioperative pain in children, can also be used effectively in the treatment of cancer-related pain. Our study is the first to evaluate the quality of analgesia, side effects, and withdrawal syndrome in children receiving nalbuphine for the treatment of cancer pain. The results indicate that nalbuphine is an effective and safe analgesic that is less likely than morphine to cause adverse side effects when used to treat cancer-related pain in children.p < 0.05). After the discontinuation of nalbuphine, signs of withdrawal syndrome were much less frequent than after morphine (p < 0.05). In Conclusion, nalbuphine used as a pain killer in children with oncological disorder is a safe drug. It provides stable analgesia in most children. Compared to morphine, the side effects typical of opioid use are less common, and the incidence decreases over time.Contemporary pain management regimens in children do not include the use of the middle step of the analgesic ladder, i.e., weak opioids. The aim of this study was to analyse the comparison of side effects and the therapeutic efficacy of morphine and nalbuphine in pain management in children with cancer. We conducted an observational, prospective study and analysed medical records of patients treated at the Clinic of Paediatric Haematology and Oncology of the University Hospital in Wroclaw (Poland), who developed mucositis during treatment. The efficacy and safety of both drugs were analysed, and the efficacy of pain relief and the incidence of adverse effects characteristic of opioid drugs were compared. The cases of 96 of children treated with opioid drugs nalbuphine or morphine were analysed. Nalbuphine therapy was accompanied by a statistically significantly lower incidence of side effects such as skin pruritus, constipation, and micturition disorders compared to morphine ( Pain is inherent in oncological disease in children and there are many causes of pain in patients undergoing oncological disease treatment. The components of suffering include the pain resulting from the process of tumour growth and tissue damage, neuropathic pain resulting from damage to the nervous system, and iatrogenic pain accompanying the treatment process itself ,2. PaediIn addition to morphine, other potent drugs such as fentanyl, oxycodone, methadone, and buprenorphine are recommended for the treatment of chronic pain in children. Contemporary pain management regimens in children do not provide for the use of the middle step of the analgesic ladder, i.e., weak opioids. This creates a gap in the therapeutic regimen, which can to some extent be filled by nalbuphine, classified as a weak opioid.Nalbuphine is a synthetic opioid of the phenanthrene derivative group, similar to the opioid antagonist naloxone and the agonist oxymorphone in its chemical structure. It exhibits receptor agonistic and antagonistic effects—agonistic for the ĸ receptor and antagonistic for the µ receptor. It is used to treat postoperative pain but also for the management of acute pain in the emergency setting—outpatient or emergency medicine. Its analgesic and sedative effects are used in premedication as part of balanced anaesthesia. It can also be used for anaesthesia or deep sedation for non-inducing treatments and procedures. The antagonistic effects on the µ-receptor can be used to reverse the side effects of opioids used both systemically and epidurally—pruritus, urinary retention, or respiratory depression—without affecting their analgesic effect ,5,6,7. TNalbuphine provides fairly strong analgesia and a marked sedative effect, particularly expressed in the paediatric population. Agonistic influence on the ĸ receptor and its mediated interaction through G-protein and β-arestin 2 are responsible for a lower incidence of opioid-specific side effects such as nausea or pruritus  The antaNalbuphine can be administered intravenously, intramuscularly, and subcutaneously. After oral administration, its bioavailability is very poor and is estimated to be around 12% in children and 11.8–44% in adult patients ,20,21. TThe aim of this study was to analyse the comparison of side effects and the therapeutic efficacy of morphine and nalbuphine in pain management in children with cancer. A prospective single-centre observational study analysed medical records of paediatric patients treated at the Clinic of Paediatric Haematology and Oncology of the University Hospital in Wroclaw (Poland), who developed mucositis during treatment. The study was conducted over two years between March 2019 and March 2020. The study followed the STROBE  guidelines. The study included a group of 96 children with cancer during primary disease treatment. Children with severe pain (VAS > 4) caused by inflammatory changes of the gastrointestinal mucosa of the mucosal type, which is a side effect of the primary disease therapy, were included in the study. This level of pain in children requires the use of opioid analgesic  in therapy. Children were included in the study at the time of treatment with opioids. Individual opioid selection, dosage, and treatment of side effects were applied according to the therapeutic regimens adopted in the Department of Haematology and Oncology. The analysis focused on comparing the analgesic efficacy, incidence of adverse effects, and withdrawal syndrome associated with the use of both opioids. The safety and efficacy of nalbuphine in children treated for cancer was also evaluated.Pain levels were monitored regularly, twice daily, using age-appropriate pain rating scales: the Visual Analogue Scale (VAS), the Face, Legs, Activity, Cry, Consolability (FLACC), and the Wong–Baker Faces Pain Rating Scale (WB). The incidence of opioid side effects such as nausea and vomiting, constipation, difficulty urinating, pruritus, and the occurrence of post-treatment withdrawal syndrome were assessed daily during the study.This study was approved by the independent Bioethics Committee of the Wroclaw Medical University (decision no. 517/2018). The study was carried out in accordance with the tenets of the Declaration of Helsinki and recommendations of good clinical practice. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed in reporting. Written consent to the child’s participation in the study was obtained from every child’s parents or legal guardians. The statistical analysis was performed using Statistica 13 software . Arithmetic means, medians, standard deviations, quartiles, and range of variation  were calculated for measurable variables. In the case of qualitative variables, their frequency was calculated (%). All studied quantitative variables were verified with the Shapiro-Wilk test used for determination of a distribution type. Comparisons of qualitative variables between groups were made using the Chi-squared test. Comparison of quantitative type results between groups was performed using the Mann-Whitney U test or the Kruskal-Wallis test. A comparative, within-group analysis between results obtained on consecutive days of therapy was performed using the Friedman test. The Spearman rank–order correlation analysis between selected variables was also conducted. An α = 0.05 was used for all comparisons.n = 20) of children were aged up to 4 years, 40.00% (n = 26) of young patients were aged 4 to 12 years, and 29.23% (n = 19) of them were aged over 12 years. In the group of children receiving morphine, 19.35% (n = 6) of children were aged up to 4 years, 45.17% (n = 14) were aged 4 to 12 years, and 35.48% (n = 11) of children were aged over 12 years. There were no statistically significant differences between the groups in terms of age. As many as 29.23% (n = 19) of those receiving nalbuphine therapy were doing so after a bone marrow transplant procedure. In the morphine-treated group, 35.48% (n = 11) of children were receiving the opioid after a bone marrow transplant procedure. There were no statistically significant differences in terms of age between the two groups of children after bone marrow transplantation. No significant differences were observed in the drug choice (p > 0.05) between the two groups.The study examined 96 cases of opioid drugs  used in the treatment of children. Among the children receiving nalbuphine therapy, 30.77% (p > 0.05).p < 0.05) were observed on the second day of therapy. The mean pain score for patients receiving nalbuphine was 6.22 , and for those treated with morphine the mean score was 4.38 . This indicates that on the second day of treatment, children receiving morphine experienced less pain compared to those receiving nalbuphine. No statistically significant differences in pain intensity were observed between children receiving both drugs on other days of therapy. In both cases, a statistically significant (p < 0.05) decrease in pain was observed on subsequent days of therapy.p > 0.05)  .p < 0.05)  .p < 0.05) incidence of drowsiness in children receiving nalbuphine compared with those receiving morphine  of patients receiving nalbuphine and in 19.35% (n = 6) of children receiving morphine. The difference was statistically significant (p < 0.05)  .p < 0.05) on days 1, 2, 3, 5, and 7  receiving morphine and did not occur at all in the nalbuphine treatment group .n = 6) of patients receiving nalbuphine, and in 38.71% (n = 12) of patients receiving morphine. The difference was statistically significant (p < 0.05)  .n = 13) of patients treated with nalbuphine, a drug change to morphine was required. Such a change was made in five patients aged less than 4 years, and in eight patients aged between 10 and 15 years. In nine cases the reason for changing the drug was inadequate analgesia, while in four cases  the reasons were anxiety, malaise, and irritability reported by the child.In 20% . The mean pain level in children treated with nalbuphine was 6.2, and in patients treated with morphine it was 4.4. On other days, no statistically significant differences in the level of pain were observed between the two groups of patients. A comparison of the pain relief efficacy of the two drugs showed that both nalbuphine and morphine were effective in relieving pain. Only on the second day of treatment, the comparison of the efficacy of both drugs showed a significantly greater effectiveness of morphine  in the incidence of this adverse event between the compared drugs, but it should be remembered that in children receiving chemotherapy, anti-emetic prophylaxis is an integral component of the therapy. Most of the children in the study received antiemetics as part of the treatment protocol, which greatly influences the assessment of the frequency of this side effect.In the analysed material, nausea occurred in 19.3% of children receiving morphine on the first day of treatment, and only in 9.2% of children receiving nalbuphine. A slightly higher proportion of patients receiving morphine reported nausea throughout their treatment. Statistical analysis showed no statistically significant differences  of children receiving morphine, and on the last day of treatment, the incidence was 32.3% (n = 10) in patients receiving the medication. No similar correlation was found for nalbuphine.The occurrence of dysphoric disorders was the adverse effect of opioid drugs that was of greater concern for children and their caregivers than drowsiness. The disorders manifested in different forms: excessive anxiety, agitation, and unusual behaviour. In one case, auditory hallucinations were reported. Behavioural disturbance tends to be dominated by dysphoric disorders, which are not altogether pleasant for patients and were assessed negatively as an emotional state rather than as euphoria, whose positive emotional consequences might consequently induce the patient to abuse the drug . In the When both nalbuphine and morphine were used, there was not a single case of respiratory depression.Another important aspect of the use of opioid drugs is the occurrence of withdrawal symptoms after the end of treatment. They involve somatic disorders such as tremors, tachycardia, excessive sweating, food intolerance, abdominal pain, vomiting, diarrhoea, and psychiatric disorders: anxiety, malaise, insomnia, disorientation, or behavioural disturbances. Opioid dependence leading to withdrawal syndrome can be expected as early as after 5 days of drug use, although such symptoms are most commonly found in children treated for longer than 7 days. However, in children who have received opioids for more than 14 days, the development of such dependence can be expected with a high degree of certainty . This stThis study has some limitations. Firstly, it was not a randomised study because of the great difficulty in designing a randomised trial of pain treatment in this group of patients. It was a single-centre observational study based on the therapeutic regimens used in the Department of Paediatric Haematology and Oncology. The wide range of drug doses and the wide age range of patients posed an additional difficulty in assessing the efficacy of analgesia. Another limitation was related to the relatively small number of patients. The reason for this was that the COVID-19 pandemic significantly limited the possibility of continuing the study in the Department of Paediatric Haematology and Oncology. The focus was therefore on assessing the safety of nalbuphine over a longer period of time and comparing the incidence of side effects of both drugs.Nalbuphine is a drug that can be successfully used in children during cancer treatment for a period of several days or even weeks. Compared to morphine, the side effects typical of opioid use are less common, and the incidence decreases over time. The development of tolerance requiring dose escalation was not observed during nalbuphine use and features of post-therapy abstinence syndrome were much less frequent than in morphine use. This is the first study to evaluate this aspect of long-term nalbuphine use and the results encourage further research in this direction.


Introduction: Pain after cervicofacial cancer surgery with free flap reconstruction is both underestimated and undertreated. There is a rational for regional anesthesia at the flap harvest site, but few studies describe it. We assessed the influence of common peroneal nerve infiltration on pain and opioid consumption in patients having oropharyngeal cancer surgery with fibular free flap mandibular reconstruction. Methods: After institutional review board (IRB) approval and written informed consent, fifty-six patients were randomly allocated to perineural catheter with ropivacaine infiltration (ROPI) or systemic analgesia (CONTROL). In the ROPI group, an epidural catheter was placed by the surgeon before closure, and ropivacaine 0.2% 15 mL, followed by 4 mL/h during 48 h, was administered. The primary outcomes were pain scores and morphine consumption during the 48 h postoperative period. We also measured ropivacaine concentration at the end of infusion. Finally, we retrospectively assessed long-term pain up to 10 years using electronic medical charts. Results: Perineural infiltration of ropivacaine significantly reduced pain scores at the harvest site only at day 1, and did not influence overall postoperative opioid consumption. Ropivacaine assay showed a potentially toxic concentration in 50% of patients. Chronic pain was detected at the harvest site in only one patient (ROPI group), and was located in the cervical area in the case of disease progression. Discussion: Although the catheter was visually positioned by the surgeon, continuous ropivacaine infiltration of the common peroneal nerve did not significantly reduce postoperative pain, but induced a blood concentration close to the toxic threshold at day 2. Further studies considering other infiltration locations or other dosing schemes should be tested in this context, both to improve efficacy and reduce potential toxicity. Controlling postoperative pain after major cancer surgery is a daily goal for anesthesia teams and a major expectation for the patients.Efficient postoperative analgesia is reported to positively affect not only the patient’s comfort, but many outcomes including mortality, surgical outcomes, hospital stays and costs . It is aDespite the combination of several classes of drugs, constant improved knowledge over years and anticipation, pain is still insufficiently relieved, especially in major cervicofacial cancer patients, both because it is underestimated by communication impairment after tracheotomy and because the needs for analgesia differ enormously between patients ,3.Moreover, after oropharyngeal cancer surgery, reconstruction is often necessary, and harvesting a disease-free bone or muscle flap might induce a second location of severe postoperative pain . TraditiWhen the flap is taken from a limb such as the fibula flap, additional regional analgesia can be proposed for the common peroneal nerve to provide a postoperative sensory block. This is expected to decrease pain at the harvest site and improve rehabilitation, although the benefit on opioid consumption is unpredictable, since regional analgesia on the limb has no influence on the pain at the cervical site. n = 8) [Few studies have looked at regional analgesia after free flap reconstructive cervicofacial surgery. Zhang, using a double block bolus , and Fern = 8) .However, as the pain at the harvest site is expected to last several days , there iThe purpose of this randomized controlled open study was first to describe the influence of a continuous local anesthetic perineural infiltration at the harvest site  on early postoperative pain and opioid consumption after fibula free flap for mandibular reconstruction.Subsequently, we assessed the risk of systemic ropivacaine toxicity by collecting blood samples for ropivacaine assay at the end of infusion on postoperative day 2, i.e., at the supposed maximal value of blood concentration. Finally, we retrospectively assessed possible long-term postoperative pain at the cervical and harvest site.The protocol was approved by the ethical committee of Henri Mondor Hospital, Créteil France (CPPRBP # 04-006), and by our local hospital institutional review board (CSET # 03-1042) in April 2004. Patients scheduled for oropharyngeal cancer or post-cancer (radionecrosis) surgery with fibula free flap reconstruction were eligible. Written informed consent was obtained for each patient during anesthesia preoperative consultation.Patients were then allocated by a computerized list of random numbers in a 1:1 ratio between ropivacaine regional analgesia of the harvest site associated with systemic analgesia (ROPI group) and systemic analgesia alone (CONTROL group).Premedication was at the discretion of anesthesiologists. The medical team was aware of randomization, while the patients were not.2/N2O 50% each) and bolus injections of atracurium if needed.Anesthesia was started with remifentanil effect-site target-controlled infusion , propofol and atracurium for tracheal intubation, and maintained with remifentanil, inhalational anesthesia (desflurane or sevoflurane in a mixture of OTM PCA pump).Before skin closure, an epidural catheter with end-tip holes only was placed in the ROPI group next to the proximal end of the common peroneal nerve by the plastic surgeon and was fixed by a suture in the skin. After skin closure, 15 mL of ropivacaine 0.2% was injected through the catheter. No further control of the tip of the catheter was performed. This was followed by continuous infusion of ropivacaine 0.2% 4 mL/h initiated in a post-anesthesia care unit (PACU) and administered during 48 h  and morphine 0.15–0.2 mg/kg was administered to all patients.All patients had planned tracheotomy performed during surgery: postoperative pain assessment took into account this communication difficult, which was explained to the patients preoperatively (day-1).In the PACU, intravenous (IV) morphine titration was started until visual analog scale < 30/100, and continued with patient-controlled analgesia (PCA) of morphine .The following parameters were recorded: demographic characteristics, duration of anesthesia, remifentanil consumption, intraoperative morphine doses, PACU titration doses and postoperative morphine consumption.Pain was assessed regularly using a 100 mm visual analog scale (from 0 to 100) both at the fibula site (harvest site) and cervical site.−1. The intra- and inter-day coefficients of variation were 6 and 8% at 0.2 µg⋅mL−1 [One blood sample for ropivacaine assay was collected at postoperative hour 48 or at the time of catheter removal (if removed earlier) in 16 of the patients who were allocated to receive ropivacaine. Venous blood was sampled in heparinized tubes. The plasma separated by centrifugation was stored at −18 °C until assayed. Ropivacaine was measured using gas chromatography with a limit of quantification of less than 0.01 µg⋅mLFor late postoperative assessment, which was not part of the initial study, a second IRB approval was obtained to extract additional information on possible late postoperative pain  from the electronic chart of patients in September 2020. Retrospective electronic medical chart review up to 10 years was performed. The presence of pain at the cervical and harvesting site and requirement of analgesic treatment was recorded 1, 3, 5 and 10 years after the reconstructive surgery.The sample size was chosen in order to decrease postop VAS at rest from 40  to 30 mm in the ROPI group with a common standard deviation of 13 mm, with a bilateral risk error alpha = 0.05 and a power > 90%. For this purpose, 29 patients were necessary in each group.t-test or a Mann–Whitney U test and expressed as the mean ± standard deviation or median , as appropriate. For categorical data, a chi-square test or Fisher’s exact test was used. p < 0.05 was considered as statistically significant. Statistical analysis was performed with Medcalc v15.4 statistical software .We checked the normality of distribution of variables using the Shapiro–Wilk test. Continuous variables were compared with a Student’s The study was conducted from June 2004 to November 2007. The flowchart is displayed in No difference was noticed in demographic and intraoperative characteristics  except fPostoperative pain score at the harvest site was significantly less at post-op day 1 H 28,  only.No significant difference was observed between groups in pain score at the cervical site .Opioid consumption, which is a global consequence of pain at both sites, did not differ significantly between groups .No adverse events related to the postoperative analgesic catheter and no complications at the harvest site were observed in any group.Time to discharge from the hospital was not different between groups .The catheter was removed 48 after ropivacaine infusion initiation in 25 patients and earlier in the remaining two. In these patients, removal occurred at 12 and 20 after infusion initiation. Analgesic data were analyzed until the time of removal.Ropivacaine blood concentration in 16 patients in the catheter group was 2.1 ± 1.1 µg/mL with a minimum 0.36 of and maximum of 3.96 µg/mL . AlthougAll patients had at least 1-year follow-up and one third of them had retrospective electronic assessment up to 10 years. In this long-term retrospective analysis, only one patient, in the ROPI group had moderate chronic pain sequelae in the fibula harvest site, which lasted up for 6 years. No other pain in the harvest site was reported.Few patients developed chronic pain at the cervicofacial site due to initial surgery. However, some of them declared new cervicofacial pain developed later in relation to cancer evolution, new cervicofacial cancer or infection .This long-term follow-up was not planned in the initial randomized study; therefore, these data cannot be considered as the result of the initial study, but rather as retrospective observational results with an important percentage of lost follow-ups.This study shows that a continuous infiltration of ropivacaine 0.2%, administered next to the upper extremity of the common peroneal nerve for 48 h, only significantly reduced pain scores at the harvest site of a fibular free flap at day 1, without significant influence on pain scores at other time points, nor on cumulative morphine consumption. Ropivacaine assay performed in 16 patients revealed a high concentration of local anesthetic in 8 patients.Among numerous free flap reconstructive options available after major cervicofacial surgery, we focused on the fibula because it is considered as the most efficient flap regarding aesthetic and functional rehabilitation  for mandibular reconstruction. It is often proposed in cancer surgery, may gather an homogeneous population and is eligible for limb regional analgesia. In addition, it is known for delayed healing and chronic pain, estimated between 2% and 60% of the patients ,11,12, wTherefore, there was a strong rational for regional infiltration at the harvest site. It should last at least for 24 h, but may not be necessary later than day 2, since pain markedly decreased after 48 h ,7.Among the few studies available, a double block  decreased pain score until the 12th postoperative hour at rest and the 8th hour in movement . RepeateSeveral explanations may be proposed to explain the discrepancy between these results and ours.First, infusing in front of the peroneal nerve may be too distal to cover the whole surgical harvest zone. Combining a femoral block or placing the catheter more proximal in the poplitea fossa in front of the sciatic nerve may improve the efficacy on postop pain. Additionally, in our study, the catheter was placed by the surgeon resident and its placement may have been imperfect. Preoperative block performed with ultrasound control by the anesthesiologist may cover a wider zone and be more reproducible.Moreover, placing a catheter for postoperative reinjections induces a risk of catheter displacement after only a few hours, as observed by Marhofer , which mOn the other hand, the doses given might have been inappropriate to achieve pain relief. Firstly, an initial 15 mL bolus, which we used in this study, is reported to be the most adapted dose before reaching a ceiling effect , while AHowever, in this special localization, a more important diffusion volume or systemic absorption and increased local inflammation might explain the high blood concentrations observed.Ferri et al. gave boluses of 20 mL every 8 h ; by doinBesides its disappointing efficacy, the ropivacaine infiltration, as administered in our study, induced, at the end of infusion, venous blood concentration above the maximal usually tolerated threshold of 2.2 µg/mL in 50% of patients . In 2 ofAnother study infusing ropivacaine in the extra-pleural space after thoracotomy observed lower concentrations than in our study, despite higher doses (6 or 9 mL/h) . FortunaToxicity is correlated not to the total, but to the unbound fraction, which was not recorded in our study. Hypoprotidemia due to preoperative denutrition or to intraoperative hemodilution may worsen the risk. However, usually this hypoprotidemia involves mainly albumin, whereas Ropivacaine binds mainly to alpha-1-acid glycoprotein (AAG), which increases after trauma or inflammation , ConsequIn recent studies on cervicofacial surgery, pain is maximum in the first postoperative hours or day, but 50% of patients already have no pain at discharge . This re2O, nefopam or ketamine were not used, whereas they were used in our study.Finally, the influence on chronic pain did not appear as relevant as expected from the literature ,21. SomeOur study had a few shortcomings; firstly the sample size has a statistical power insufficient to detect differences in postoperative pain scores, morphine requirements or potential chronic pain at the harvest site. Average values were similar to the assumption used for the number of subjects calculation, but interindividual variability was underestimated. In other words, some patients have very high levels of pain and analgesic requirements, and risk factors for these outliers are not easy to establish .This result supports the recommendation to regularly assess the pain scores of patients after this surgery, and to adapt analgesia protocol to the individual needs of outliers .The higher remifentanil rate of infusion may be due to stronger pain in the ROPI group, which may have offset a potential benefit of regional anesthesia. However, it may also be due to a random effect in this rather small groups of patients.In this study, the epidural catheter placed by the surgeon near the proximal side of the common peroneal nerve can partly be assimilated to wound infiltration, despite the fact that the epidural catheter has holes only in its terminal end. Nevertheless, the complexity of this type of surgery may yield heterogeneous pain results as in our study; we reference regional techniques such as popliteal ultrasound guided block with intermittent reinjection, which might be more effective and more reproducible .Other shortcomings were that allocation to one or the other group was unblinded to professionals, which could have yielded bias in harvest site pain-score assessment, but not in morphine PCA consumption. Finally, long-term assessment was retrospectively performed through electronic chart database consultation, which could provide some bias or missing data.Ropivacaine continuous infiltration of 4 mL/h for 48 h in front of the common peroneal nerve cannot be recommended for analgesia after fibular free flap because of both insufficient analgesic efficacy and high, potentially toxic, blood concentrations.Future research and clinical practice should consider more proximal blocks and/or different drugs delivery schemes including repeated boluses and continuous search of the lower dilution efficient for each type of block, and drug assay on a few patients for every new block or scheme tested.A huge variability in pain and analgesic requirements between patients supports the recommendation of repeated pain assessment and individualized analgesic drug adjustments, especially in the first days after surgery.


By using data from the Norwegian Registry for Spine Surgery, we wanted to develop and validate prediction models for non-success in patients operated with anterior surgical techniques for cervical degenerative radiculopathy (CDR).This is a multicentre longitudinal study of 2022 patients undergoing CDR surgery and followed for 12 months to find prognostic models for non-success in neck disability and arm pain using multivariable logistic regression analysis. Model performance was evaluated by area under the receiver operating characteristic curve (AUC) and a calibration test. Internal validation by bootstrapping re-sampling with 1000 repetitions was applied to correct for over-optimism. The clinical usefulness of the neck disability model was explored by developing a risk matrix for individual case examples.Thirty-eight percent of patients experienced non-success in neck disability and 35% in arm pain. Loss to follow-up was 35% for both groups. Predictors for non-success in neck disability were high physical demands in work, low level of education, pending litigation, previous neck surgery, long duration of arm pain, medium-to-high baseline disability score and presence of anxiety/depression. AUC was 0.78 . For the arm pain model, all predictors for non-success in neck disability, except for anxiety/depression, were found to be significant in addition to foreign mother tongue, smoking and medium-to-high baseline arm pain. AUC was 0.68 .The neck disability model showed high discriminative performance, whereas the arm pain model was shown to be acceptable. Based upon the models, individualized risk estimates can be made and applied in shared decision-making with patients referred for surgical assessment. Cervical degenerative radiculopathy (CDR) is caused by nerve root compression by a herniated or bulging disc and/or ligament hypertrophy and bony spurs. The incidence rate is reported to be approximately 80 per 100,000 people , and surThe primary objective of this study was to develop and validate a prediction model for non-success in neck disability 12 months after surgery for CDR. Secondary objectives were to provide the same analysis for arm pain and to develop a risk matrix for the primary outcome to exemplify the use of the model in a clinical setting.This is a multicentre longitudinal study following the recommendations for reporting in observational studies, STROBE criteria  and the Our research protocol was approved by the Norwegian Committee for Medical and Health Research Ethics Midt (2014/344). Written informed consent was obtained from all patients.p = 0.02 and p = 0.002, respectively). Also, arthroplasty patients were operated in significantly lower number of levels (p < 0.001). Patients undergoing posterior cervical procedures due to CDR, as well as all patients operated for myelopathy symptoms, were excluded. Patients operated for tumours, fractures and primary infections are not included in NORspine.Data from the Norwegian Registry for Spine Surgery (NORspine) from 2011 to 2016 was used. NORspine is a government-funded comprehensive clinical registry receiving no industry funding and used for quality assessment and research. Informed consent is obtained from all patients before they enter the registry. Currently, all centres performing cervical spine surgery in Norway report data to NORspine (coverage = 100%), and the operation recording rate is 78% (completeness) . PatientPatients completed data at admission for surgery (baseline), after 3 and 12 months. Surgeon’s forms containing information about diagnosis, treatment and comorbidity were completed during the hospital stay. Only cohort participants responding to the 12-month questionnaire were included in the present study. Follow-up was conducted by the central registry unit without involvement of the treating hospital. The patients responded by questionnaires sent and returned by mail. One reminder with a new form was sent to non-respondents within 2 weeks.For the primary outcome, the Neck Disability Index (NDI) (0–100), non-success was defined as an absolute score of > 26 at 12-month follow-up. For the secondary outcome, arm pain intensity assessed by numerical rating scale (NRS-AP) (0–10), non-success was defined as a score ≥ 3 at 12-month follow-up. These estimates are based on a previous study for patients undergoing CDR surgery in Norway .Candidate predictors for non-success were selected from the comprehensive NORspine questionnaire administered before surgery, which consists of information about sociodemographic factors, lifestyle, work and clinical variables in addition to patient-reported outcome measures (PROMs). Data from the surgeons’ forms were used for information about diagnosis, treatment, comorbidity, the American Society of Anaesthesiologists physical status (ASA), surgical indication and type of operation. The selection of the final set of predictors was made after a thorough literature review where we identified the factors that have been found to be significantly and consistently associated with outcomes after CDR surgery.The following predictors were selected for the model: gender, age groups , work status prior to operation , physical demands in work , educational level , mother tongue (Norwegian or non-native speaker), pending litigation (yes/no) (pending litigation defined as unresolved claims or litigation issues against the Norwegian Public Welfare Agency Fund concerning permanent disability pension or compensation claims against private insurance companies or the public Norwegian System of Compensation to Patients), duration of arm pain , duration of pre-operative paresis , body mass index (BMI) , smoking (yes/no), comorbidities (yes/no), previous neck surgery (yes/no), number of surgical levels (one or more than one), daily use of analgetic drugs (yes/no), ASA level (level 1–2 or level 3–4), arm pain neck pain ratio  [Since no consensus on sample size in prognostic modelling exists, we chose to follow the recommendations by Steyerberg : (a) aimStatistical analyses were performed using IBM SPSS Statistics version 26 for Windows and the STATA version 16 for Windows. Missing data was checked for all variables and are reported together with descriptive data. Frequencies were used for categorical data and mean and standard deviation (SD) for continuous data. Continuous variables, such as baseline disability, were categorized to be adapted into a risk matrix. The distribution of baseline and 12-month scores of the two outcome measures are presented by mean scores and SD.p < 0.1 in these analyses were entered into two multivariable logistic regression models (for primary and secondary outcome), where a stepwise backward elimination method was used. Variables that were not statistically significant (p > 0.05) in the multivariable models were removed from the model. The performance of the two final models was evaluated with (1) the explained variance by Nagelkerke’s R2, (2) the Hosmer–Lemeshow test p > 0.05) and (3) the discriminative ability of the model  assessed by calculating the area under the receiver operating curves (AUC), also often referred to as the c-index [First, a univariable analysis of the candidate predictors was performed to assess the crude association between each candidate predictors and the two outcomes. Associations between outcomes and predictors are expressed as odd ratios (OR) with a 95% confidence interval (CI). Predictors reaching  c-index . The larR2 and the c-index.Internal validation was conducted by a bootstrap procedure (1000 samples) to estimate the amount of optimism in the two final models , 39. A sWe assessed the potential clinical utility of the final prediction model for non-success in neck disability by developing a risk matrix for two hypothetical patient case profiles with few and many predictors present. Regression coefficients from the final disability model were converted into probabilities, and a risk score for each of the two individual case profiles was calculated by the sum of the products of individual values of each predictor variable and its regression coefficient. Depending on the presence or absence of the risk factors, the matrix was then calculated as probability for a non-substantial improvement after 12 months for each of the patients.There were 3142 patients who had undergone either anterior discectomy and fusion (3109) or arthroplasty (33) due to CDR during the study period. Out of these, 2022 (64.4%) completed 12-month follow-up and were included in the analyses . Compared to responders at 12-month follow-up, non-responders were less likely to be female, significantly younger, had higher neck disability, more neck pain, lower quality of life, were less educated and more likely to be smoking.Demographic and clinical characteristics at baseline for the included participants are summarized in Table The mean scores of the NDI and NRS arm pain at 12-month follow-up was 23.4 (SD 18.8) and 2.9 (SD 2.8), respectively. A total of 38.0% had non-successful outcomes in neck disability and 35.3% in arm pain.Table R2 of 28.3%, non-significant Hosmer–Lemeshow test and AUC 0.78 . The prediction model for non-success in arm pain included six of the same predictors  in addition to foreign mother tongue, smoking and medium or high levels of arm pain. This model showed acceptable performance with Nagelkerke R2 of 15.5% and AUC of 0.68 . The calibration plots for the two models are displayed in Figs. Table Two risk matrices were developed for cases with low and high risk for non-success in neck disability, respectively. “Low-risk” was defined as having three out of the eleven risk factors in the prognostic model, while “high-risk” was defined as having six out of the eleven factors. The matrices are displayed in Table In this study, we found that more than one third of the patients reported non-successful outcome in neck disability or arm pain at 12-month follow-up after surgery for cervical degenerative radiculopathy. Patients with high risk for non-success in neck disability were characterized by physical demanding work, low level of education, pending litigation, previous neck surgery, duration of arm pain > 3 months and medium-to-high levels of baseline disability as well as anxiety/depression. The predictors for non-success in arm pain were foreign mother tongue, smoking, medium-to-high levels of baseline arm pain and all neck disability model predictors except for anxiety/depression.The discriminative performance of the neck disability model was found to be good with an AUC of 0.78, whereas the arm pain model was slightly less accurate but still acceptable (0.68). A recent study on patients undergoing elective cervical spine surgery by Archer et al. reports slightly lower AUCs for a predictive model of worse NDI scores (0.64–0.69) and of worse arm pain scores (0.63–0.65) 1 year after intervention . There iThere exists conflicting evidence regarding gender and its impact on PROMs and other outcomes, such as length of hospital stay and complication rates after degenerative neck surgery , 18, 34.The present study could not find that high age was a predictor of non-success in neither neck disability nor arm pain. This is supported by other multivariate studies , 29, 34.In the current healthcare environment, value-based thinking has brought more focus on quality and appropriateness of care. Also, as degenerative neck surgery is becoming increasingly safe and efficient, there is a need for more knowledge about which patients are not improving from surgery. The two present models can be used in a clinical setting to predict which patients will benefit from a surgical intervention and who will be better off being treated conservatively. To exemplify how these models can be used in a surgical practice, we produced a risk matrix constituted of two hypothetical patient scenarios for disability; one where the patient had several of the risk factors and another where the patient had only a few risk factors Table . The patThe present models can be further developed into a risk calculator to assess the probability of success or failure to achieve substantial change for every patient in a surgical practice. However, the model will first need to be further validated in other study populations. The feasibility of a risk calculator should also be evaluated.An advantage of the present study is the large sample size of data captured in a national registry. NORspine was designed to prospectively capture important candidate predictors and PROMs prior to and during the year following surgery. The registry covers all the hospitals and private clinics conducting surgery on spinal disorders in Norway. A total of 78% of the operations are recorded in the registry . FurtherIn our study, we chose to include patients operated with both arthroplasty and fusion. The baseline characteristics and 12-month outcome data were similar between the groups, except for slightly higher NDI and NRS-NP scores for the arthroplasty patients at baseline, as well as a lower number of operated levels. There is no current consensus about the use of arthroplasty vs fusion in patients with degenerative cervical disease , 42, 46.Loss to follow-up was 35.6% at 12-month follow-up and could represent a selection bias. However, two recent Scandinavian spine registry studies based on similar cohorts have found that a loss to follow-up did not bias conclusions about treatment effects , 37.Another potential limitation is related to the cut-off estimates of the applied PROMs. In the present study, we decided to use estimates of non-success instead of the concept of MCID. The main reason is that MCID often show to be less than measurement errors or estimates for smallest detectable change , making The major limitation of the present study is that we did not externally validate the final models. External validation is necessary before these models can be further developed into a risk calculator used in clinical settings. Risk calculators may help inform discussions of surgical treatment options between surgeons and patients and lead to more accurate judgement of operative risk. In a clinical decision-making process, the probability of successful or non-successful outcomes of conservative treatment strategies also needs to be taken into consideration. The present study only investigated outcomes after surgical treatment and cannot be generalized to outcomes after non-surgical treatment options. Thus, there is a large need for exploring prediction models for both surgical and non-surgical treatment trajectories and outcomes.The final prediction model for non-successful outcome in neck disability 12 months after CDR surgery showed high discriminative performance, whereas the prediction model for arm pain was slightly less predictive. Based upon the two prediction models, individualized risk estimates can be made and used in shared decision-making with patients referred for surgical assessment. The models need to be externally validated and further tested in a clinical setting.


A receiver operating characteristic curve was used to calculate the symptom duration at which the prediction of unstable flaps was maximized, and the cutoff point was 14.0 months. (4) Conclusions: More than two thirds of patients suffering intractable pain from MMHT had hidden unstable flaps. However, APM should not be considered when the symptom duration is more than 14 months or high-grade cartilage wear of the medial femoral condyle is noted.(1) Background: The medial meniscus horizontal tear (MMHT) is known as a lesion that can be treated nonoperatively. However, some patients show persistent pain despite conservative treatments. In arthroscopic surgery for MMHT, surgeons often encounter unexpected unstable flaps, which can explain the intractable pain. This study aimed to determine whether preoperative factors could predict the hidden unstable flaps in MMHT. (2) Materials and Methods: Medical records of 65 patients who underwent arthroscopic partial meniscectomy (APM) for isolated MMHT during 2016–2020 were retrospectively reviewed. APM was indicated when there was no severe chondral degeneration and intractable localized knee pain in the medial compartment did not resolve despite conservative treatments. Unstable flap was confirmed based on arthroscopic images and operation notes. Each of the following preoperative factors were investigated using logistic regression analyses to determine whether they can predict an unstable flap: age, sex, body mass index, lower limb alignment, trauma history, mechanical symptoms, symptom duration, visual analogue scale (VAS), Lysholm score, cartilage wear of the medial compartment, and subchondral bone marrow lesion (BML). (3) Results: Hidden unstable flaps were noted in 45 (69.2%) patients. Based on univariate analyses for each preoperative factor, age, symptom duration, cartilage wear , and subchondral BML were included in the multivariate logistic regression analysis. The results showed that symptom duration ( The paradigm has been shifted from “If it is torn, take it out!” to “Save the meniscus!” in the treatment of meniscal tear ,2. SeverSome previous studies found that APM was more effective in patients with mechanical symptoms than in those without these symptoms ,13. The Recent studies attempted to identify a subgroup of patients who could show particularly favorable surgical outcomes after APM ,22. If sMedical records of 65 patients who underwent APM for isolated MMHT during 2016–2021 were retrospectively reviewed after approval was obtained from the institutional review board of Chungnam National University Hospital (No. 2022-05-075). Patients with a discernable meniscal flap on preoperative magnetic resonance imaging (MRI) scans were not included in this study. The exclusion criteria also included combined ligament injury, lateral meniscus tear, and previous knee surgery. APM was indicated when intractable localized knee pain in the medial compartment did not resolve despite conservative treatments, such as non-steroidal anti-inflammatory drugs and muscle strengthening exercises. Patients showing severe medial OA on radiographs (Kellgren–Lawrence grade ≥ 3) were not deemed suitable for APM.All APMs were performed by a single senior surgeon. Arthroscopic findings were documented as photos, videos, and intraoperative notes. To resolve mechanical symptoms such as catching, locking, and pain during squatting, the displaceable meniscal flap and unstable superior or inferior leaves of MMHT were resected, while, at the same time, every effort was made to preserve intact meniscal tissue. No patient underwent subtotal or total meniscectomy. Full range of motion and muscle strengthening exercises were encouraged immediately after surgery.The unstable flap was confirmed on arthroscopic images and operation notes . An unstt-test. When continuous variables were found to be significant factors in the multivariate regression analysis, a receiver operating characteristic curve (ROC) was used to obtain the cutoff point at which the sensitivity and the specificity for the unstable flap were maximized. All statistical analyses were performed using R software version 4.1.1 , with a p value < 0.05 considered statistically significant.Predictive factors for unstable flaps were identified using logistic regression analyses. Univariate analyses for each factor were performed first; thereafter, a multivariate regression analysis was conducted to avoid overfitting problems. Between the flap group and the non-flap group, categorical variables were analyzed by Chi-square test when the expected value of the cell was 5 or more in at least 80% of the cells; otherwise, Fisher exact test was used. Continuous variables were analyzed by Of 65 patients with a mean age of 52.2 ± 12.6 years , hidden unstable flaps were noted in 45 (69.2%) patients. The mean symptom duration was 13.0 ± 5.8 weeks. The flap group and the non-flap group showed significant differences in age, symptom duration, cartilage wear of the femoral condyle and the tibial plateau, and subchondral BML. The patient characteristics among the groups are summarized in p = 0.026, odds ratio = 0.99) and high-grade cartilage wear of the medial femoral condyle  were negatively associated with an unstable flap  approximately 70% of patients suffering intractable pain had hidden unstable flaps that would have been lodged and could be a source of pain, and (2) the symptom duration and cartilage wear of the medial femoral condyle had negative correlations with unstable flaps. Pain was not likely from an unstable flap if the symptom duration was more than 14 months or high-grade cartilage wear of the femoral condyle was noted on preoperative MRI scans.MMHT usually occurs in middle-aged patients as a degenerative lesion without a definite trauma history ,30. The This study found two significant factors in the logistic regression analysis regarding unstable flaps: symptom duration and cartilage wear of the femoral condyle. Kim et al. also reported similar results on symptom duration . They foIt is noteworthy that mechanical symptoms and the severity of pain (VAS) did not differ significantly between the flap group and the non-flap group. Because a displaced flap can lead to mechanical symptoms that require arthroscopic management ,15,16, mSeveral limitations should be noted. First, patients who had conservative treatments for MMHT were not included in this study. The necessity of APM would have been determined better if these patients had been included. Second, patients who underwent APM for MMHT were relatively rare, which made it difficult to attain a large number of patients in this study. The small sample size would compromise the statistical power. Third, this study failed to identify positive predictive factors for unstable flaps. The two significant factors (symptom duration and cartilage wear) were negatively correlated with unstable flaps. Thus, preoperative factors that support the necessity of APM are not revealed.More than two thirds of patients suffering intractable pain from MMHT had hidden unstable flaps. However, APM should not be considered when the symptom duration is more than 14 months or high-grade cartilage wear of the medial femoral condyle is noted.


Patients with severe NPDR without previous history of PRP were included in the study. Both eyes of the patients were treated with a pan-retinal photocoagulation procedure. The retina was divided into four quadrants and the treatment plan for patients submitted to PRP was divided into four sessions. Different oral medications were given to patients 1 hour before the procedure. Capsules containing a combination of analgesic drugs , pregabalin capsules , a combination of N capsules and P capsules (referred to as NP), and the placebo were used in each session. Each patient scored the pain sensation immediately after the procedure using a visual analog scale (VAS).60 eyes of 30 patients were studied. The mean value of VAS in patients receiving the placebo was 3.3 ± 1.822 units, while this scale was 3.067 ± 1.507, 3.5 ± 1.479, and 3.5 ± 1.77 in the N, P, and NP consumed patients, respectively. There was no significant difference in VAS levels and the patient’s vital signs between different sessions (P = 0.512).No evidence of the pain-relieving effect of N, P or NP was found during PRP.Trial registration: IRCT20200915048724N1. Registered 20 October 2020, https://www.irct.ir/trial/51345 Diabetic retinopathy (DR) is a microvascular disorder that occurs due to the long-term effects of diabetes. It leads to threatening visual damage to the retina and, eventually, blindness. DR is the most common cause of vision loss in adult patients of working age in the world . Early dThis study was a randomized, double-blind, placebo-controlled trial (IRCT20200915048724N1) conducted at Shiraz University of Medical Sciences, Shiraz, Iran. Participants were recruited between April 2021 and April 2022 from Motahari Clinic, Shiraz, Iran. Eligible participants were informed about the study procedures. All patients gave their informed written consent to participate in the study and thoroughly explained once the risks and benefits of the intervention. This study was approved by the Human Ethics Committee of the Shiraz University of Medical Science . This study followed the CONSORT statement.Patients with severe non-proliferative diabetic retinopathy (NPDR) without previous history of PRP were included in the study.Patients with a history of hypersensitivity or contraindication to acetaminophen, nonsteroidal anti-inflammatory drug (NSAIDs), and pregabalin, previous chronic eye pain such as glaucoma and dry eye, previous PRP, current use of painkillers for any other disease, media opacity or vitreous hemorrhage were excluded from the study.In this factorial-designed study, both eyes of the patients were treated with a pan-retinal photocoagulation procedure. The treatment plan for patients submitted to PRP was divided into four sessions. The retina was divided into four quadrants, namely inferior nasal (IN), inferior temporal (IT), superior nasal (SN), and superior temporal (ST), with the center of the macula Fig. . The samPRP procedure was performed by a single retinal specialist (MKJ). The pupils were dilated using 1% tropicamide. Thirty minutes later, we used a drop of proparacaine hydrochloride 0.5% to each eye for corneal anesthesia.Laser treatment was performed with a pattern of 532 nm frequency-diode laser  using a SuperQuad 160 contact lens . Each session consisted of approximately 500 spots, with laser energy adjusted to achieve moderate white burns, the spots size of 500 micrometers, and an exposure time of 0.15 s; each session lasted between 5 and 10 min for both eyes , consisting of a 10 cm scale labeled with numbers from 0 to 10 and a face pain rating scale with a number from 0-2-4-6-8-10, which was used to determine the intensity of the pain. The blinded examiner instructed patients that 0 represents experiencing no pain and ten means experiencing the maximum pain they could imagine, an excellent clinical pain indicator of pain intensity in postoperative patients. The blinded examiner evaluated the patient’s facial expression (objective score) and asked patients to score a number between 0 and 10 regarding their pain experience during the procedure (subjective score); the mean of both numbers was recorded for each session.All data were processed with SPSS version 20.0. T-test, one-way ANOVA, and EP16 were applied for statistical analyses. Categorical data were analyzed using a chi-squared test (χ2) and reported as Mean ± SD. A P-value of less than 0.05 was considered statistically significant.In the present study, a total of 50 patients (100 eyes) receiving the first session of PRP treatment were enrolled. Ten patients discontinued the study because of difficulty adhering to third and fourth laser sessions due to COVID-19 respiratory symptoms and quarantine. Seven were removed due to taking other analgesic drugs between sessions due to musculoskeletal pain, and three were discontinued due to vitreous opacity or hemorrhage. Finally, 30 patients (60 eyes) were analyzed Fig. . The demThe mean value of VAS at the placebo-received patients was 3.3 ± 1.8 units, while this scale was 3.1 ± 1.5, 3.5 ± 1.5, and 3.5 ± 1.8 in the N, P, and NP receiving groups, respectively. The VAS average in different sessions is shown in Fig. Patients receiving P and the combination of NP showed a statistically significant decrease in IOP in their left eye after treatment. However, this decrease seems clinically non-significant. Moreover, in comparison between the four treatment sessions, systolic-diastolic pressure, pulse rate, and IOP in the right and left eye, no significant difference was observed before and after the procedure Table .No significant difference was observed in the systolic pressure values in the four treatment sessions after adjusting for sex and age variables (multiple linear regression) Fig. . The pulDespite the development of medical therapies for the treatment of PDR, PRP will likely continue as the mainstay of treatment. It is known that PRP is a painful procedure, which may lead to an insufficient remedy for the patient, increase the number of sessions, or perhaps the patient may even refuse to attend , 11. ThePain sensation and its quantification is a subjective index. In this study, we used VAS to evaluate the intensity of pain. The relationship between the pain-regulating systems and blood pressure suggests that acute pain during surgery can increase blood pressure and pulse rate by increasing sympathetic activity , 13. TheThe present paper aimed to validate the analgesic effects of N and P capsules during the PRP procedure. There was no significant difference in pain relief between the sessions in which patient taking a placebo, N, P, or a combination of both during PRP.Perioperative hemodynamic monitoring also showed no significant changes in the heart rate and systolic blood pressure during the time of using the drugs, before and after the PRP procedure. No significant drug related side effects were seen.Wu et al. assessed the analgesic effects of acetaminophen and found non-effective results for pain control during PRP . IbuprofPregabalin and its evolutionary predecessor, gabapentin, are structurally similar to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, and can be used to manage diabetic neuropathic pain, postherpetic neuralgia, and fibromyalgia . Few stuHazem et al. compared the analgesic efficacy and safety of oral gabapentin (600 mg) and pregabalin (150 mg) during PRP. They reported lower pain but more sedation and dizziness during PRP with preemptive pregabalin . We applOf course, each person’s experience of pain and its expression is the product of the sensory experience; the individual’s background, cultural differences, and anxiety levels can influence this perception . Also, aThis study was associated with some limitations. First, the sample size was small. Second, although most of the laser parameters were not significantly different, the number of laser spots differed for each patient. Also, we did not perform the cognition tests before the procedure in this study which might be related to the patient’s VAS.This study found no evidence of the pain-relieving effect of N capsules , P capsules , or a combination of both medications during PRP. Further clinical studies must suggest the best drug regimen for pain relief during PRP in DR patients