Children and adolescents are not impervious to the unprecedented epidemic of opioid misuse in the United States. In 2016 more than 88,000 adolescents between the ages of 12–17 reported misusing opioid medication, and evidence suggests that there has been a rise in opioid-related mortality for pediatric patients. A major source of prescribed opioids for the treatment of pain is the emergency department (ED). The current study sought to assess the complex relationship between opioid administration, pain severity, and parent satisfaction with children’s care in a pediatric ED.We examined data from a tertiary pediatric care facility. A health survey questionnaire was administered after ED discharge to capture the outcome of parental likelihood of providing a positive facility rating. We abstracted patient demographic, clinical, and top diagnostic information using electronic health records. Data were merged and multivariable models were constructed.We collected data from 15,895 pediatric patients between the ages of 0–17 years  and their parents. Approximately 786 (4.94%) patients were administered an opioid; 8212 (51.70%) were administered a non-opioid analgesic; and 3966 (24.95%) expressed clinically significant pain (pain score >/= 4). Results of a multivariable regression analysis from these pediatric patients revealed a three-way interaction of age, pain severity, and opioid administration . Our findings suggest that opioid administration negatively impacted parent satisfaction of older adolescent patients in milder pain who were administered an opioid analgesic, but positively influenced the satisfaction scores of parents of younger children who were administered opioids. When pain levels were severe, the relationship between age and patient experience was not statistically significant.This investigation highlights the complexity of the relationship between opioid administration, pain severity, and satisfaction, and suggests that the impact of opioid administration on parent satisfaction is a function of the age of the child. The United States is currently experiencing an unprecedented opioid crisis. More than 47,000 people die from an opioid-related overdose each year,With a rising emphasis on patient-centered care, concerns over patient satisfaction may be one contributor to the increased opioid prescribing rates observed in the ED.16Studies examining this correlation in pediatric samples have received little attention,The relationship between opioid administration, pain severity, and parent satisfaction (as a proxy of patient satisfaction) is complex and should be assessed using a multivariable analysis that simultaneously considers the impact of both analgesic administration and pain on parent satisfaction. Research that assesses only the role of either pain or opioid use, without including both, will fail to fully capture the complex contribution of opioid administration on perceived quality of care. Therefore, our goal was to determine the influence of opioid analgesic administration on parent satisfaction for pediatric patients discharged from the ED, and to assess whether the pain management-satisfaction relationship was impacted by demographic, clinical, and diagnostic factors.What do we already know about this issue?In adults, research has identified a significant association between pain management and patient satisfaction; however, this relationship is understudied in pediatric populations.What was the research question?We assessed statistical interactions between age, pain, and the prescription of opioids in relation to parental satisfaction with care.What was the major finding of the study?Parents of older patients were dissatisfied with their care when their child was prescribed opioids to treat a milder pain condition.How does this improve population health?Findings suggest that physicians should consider pediatric patient pain level and age when deciding whether to prescribe an opioid medication.The current study involved a retrospective cohort analysis of parent satisfaction with analgesia administration in the ED. We collected encounter data between May 2018–June 2019 from children who underwent treatment in a pediatric ED in a tertiary children’s hospital. This data source included demographic and clinical variables from an electronic health record (EHR) system and parent satisfaction data that we assessed using a NRC Health survey questionnaire . In total, the parents of 85,804 ED patients began to answer survey questions, and of these 24,761 respondents completed the survey, representing a response rate of 28.9%. All survey data collection methods were approved by the hospital’s institutional review board.th and 10th revisions, (ICD-9 and ICD-10) codes C00 through D49; n = 59).20The health questionnaire was sent to all parents after discharge from the ED facility. We linked the EHR data and survey responses using unique encounter identifiers present in both data sources. Inclusion criteria were as follows: treated in the ED; being < 18 years; and with an ED stay of 12 hours or less. Because we aimed to assess differences in opioid prescribing for patients without cancer-associated chronic pain or a neoplasm diagnosis we excluded from the analysis International Classification of Diseases, 9no pain) to 10 (severe pain), and was conceptualized as the maximum pain score recorded during the patient’s stay using developmentally and situationally appropriate measurement tools . Following the guidelines of Fortier et al,Patient age, ethnicity, gender, low-income insurance status ,* Emergency Severity Index score, length of stay (ranging from 16–716 minutes), and level of pain were abstracted from the EHR. Pain severity ranged from 0 . Diagnoses that captured less than 1% of patients  were not controlled for in the analyses. We used responses to the health questionnaire after patient discharge to measure patient experience. Two items assessing satisfaction with pain and discomfort management were examined .Patient analgesic records during the ED visit were also obtained from the EHR. Specifically, we assessed information on whether the patient was administered an opioid  and/or non-opioid analgesic . Administered opioids were dispensed during the patient’s ED stay and did not refer to after-visit administrations, as information on medications prescribed after the patient’s ED stay was not accessible in the EHR system. Top patient medical diagnoses were also retrieved and controlled for using the ICD-9 and ICD-10 revisions (0 = Satisfied”). All other responses represented an undesirable facility rating (coded as 0 or “Not Satisfied”). This top-box methodology is the standard approach for assessing patient satisfaction in US hospitals that use the Hospital Consumer Assessment of Healthcare Providers and Systems.28We determined parent satisfaction with their child’s emergency care using an NRC Health questionnaire item assessed as an indicator of patient satisfaction in prior research.Satisfied) and negative (Not Satisfied) facility rating scores across the levels of each variable. Odds ratios (OR) and chi-square P-values were calculated for each association. In addition, we assessed relationships between the two pain and discomfort management survey questions and opioid administration using a chi-square test of association. P-values < 0.05 were determined to be statistically significant in the bivariate analyses.Bivariate analyses estimated associations between satisfaction with admittance acuity, pain severity, administered analgesics, and the two items assessing pain management experiences. We examined the proportions of patients with positive  patients provided a positive ED facility rating, meaning that they were satisfied with their visit (providing a score of a 9 or 10 when asked how they would rate the ED facility). Approximately 3966 (24.95%) expressed clinically significant pain . Patients expressing more severe pain severities (P < 0.001) and those who were administered opioid analgesics (P = 0.018) were more likely to report they were satisfied with the ED facility. Parents who indicated that the staff and care providers “definitely” did everything they could to help the child with their discomfort were most likely to be satisfied with their patient experience in the ED .Relationships between all key variables with satisfaction are shown in P = 0.006). Similarly, compared to parents whose children did not receive an opioid , those whose child received an opioid analgesic were more likely to indicate that care providers “definitely” did everything they could to ease their child’s discomfort  = 11.52, P = 0.021).We also assessed associations between the two pain and discomfort management survey items and opioid administration. Parents of patients administered opioids were more likely to indicate that staff “definitely” did everything they could to help with the child’s discomfort  than patients who were not given opioids  = 14.54, P < 0.001). Staying in the ED for a shorter time  and being administered an opioid analgesic (P = 0.007) were both associated with a greater likelihood of indicating a positive facility rating. Interestingly, the administration of non-opioid analgesics was not associated with parent satisfaction (P = 0.131). Also, parents who reported that staff and care providers “definitely” did everything they could to help the child manage their discomfort were more likely to be satisfied than parents that responded “Yes, mostly,” “Yes, somewhat,” or “No” .A multivariable model see  controllP = 0.007). To decompose the three-way interaction, simple slopes of the relationship between age and facility rating were estimated and graphed on the pain severity moderator at one standard deviation (SD) below the mean, at the mean, and one SD above the mean for patients who were and were not administered an opioid analgesic during their ED stay.not administered an opioid analgesic, there was no statistically significant relationship between age and facility rating when pain severity was high . However, when pain was mild  and patients did not receive an opioid, parents of older patients reported greater satisfaction than parents of younger patients. Specifically, for patients who did not receive an opioid, parents of older patients, expressing mild pain, were the most satisfied with their experience in the ED.We assessed the complex relationships between pain, opioid administration, and parent satisfaction by estimating several interaction terms. Findings revealed a significant three-way interaction of age, pain severity, and opioid administration . Thus, for patients experiencing higher levels of pain, patient age did not impact parent satisfaction. However, when the level of pain was mild  or moderate  parents of younger children were more likely to provide a positive facility rating than parents of older patients. In other words, pain level did not strongly impact the parent satisfaction of the youngest patients. These patients were the most satisfied when their child received an opioid, regardless of pain severity. In contrast, pain level had an important influence on the parent satisfaction scores of the oldest patients who were given an opioid during their ED stay. The least satisfied group in this sample were parents of 17-year-old patients who were administered an opioid analgesic, despite expressing mild pain severity. For example, parents of the oldest patients .For patients who were Under the conditions of this study, results from the multivariable regression model revealed that parents of patients admitted with a resuscitation or emergent acuity score were more likely satisfied with the ED facility than patients who were admitted with a less urgent or non-urgent acuity rating. A multivariable analysis controlling for demographic, clinical, and top diagnostic covariates showed that opioid analgesic administration was related with parent satisfaction in a pediatric ED setting but non-opioid analgesics were not. Specifically, parents of patients administered an opioid analgesic were more likely to provide a positive facility rating compared to parents of patients who did not receive an opioid. Further, relationships between opioid administration and parent satisfaction were shown to be multifaceted and complex, as demonstrated by the significant interaction of age, pain, and opioid administration. That is, parents of younger patients who received an opioid were the most satisfied with their quality of care, regardless of pain severity; whereas likelihood to provide a positive facility rating substantially decreased for parents of the oldest patients who were administered an opioid to manage mild pain. Additionally, it is important to emphasize that diagnosis  did not impact the pattern of results shown in this study, as the regression analyses controlled for common medical aliments.With the current opioid epidemic, rates of pediatric opioid-related overdose and death continue to increase.The finding that opioid administration negatively impacted the patient satisfaction of parents with adolescent children admitted to the ED with lower levels of pain should be interpreted in the context of the opioid public health crisis. Studies with different samples of youth patients show that adolescence represents a transitional developmental period characterized by an increase in risky health behaviors, including illicit substance use experimentation.This result implies that the administration of opioid medications does not always improve patient satisfaction, and that in some situations, it can actually make perceived clinical care worse. Thus, physicians should consider pain level and age when making decisions about whether to administer an opioid medication to pediatric patients. Also, from a methodological perspective, results of this study highlight the importance of examining pain, opioid use, and satisfaction simultaneously in one model, and imply that future studies should examine and control for all three variables to understand complex relationship between pain and discomfort management and patient experience.Findings should be interpreted in the context of several limitations. Patients in this study were admitted to the ED of a single, tertiary pediatric institution; thus, findings might not be generalizable to all pediatric ED facilities. Parent satisfaction was measured via self-report. Therefore, parent responses might be impacted by acquiescence bias. Specifically, parents might have felt pressure to provide a positive ED rating although the survey was conducted after the parents left the ED. Information on opioid prescribing after discharge home could not be obtained, which might have served as a confounding variable potentially impacting parent satisfaction. The response rate in this study was 28.9%, which could have biased findings. However, research suggests a small association between response rates and nonresponse bias for surveys such as the NRC health questionnaire.Findings from this investigation point to the multifarious nature of the relationship between pain severity, opioid administration, and parent satisfaction, and highlight a potential conflict in patient-physician interactions at the intersection of parent satisfaction and controlled substance administration. Multivariable analyses showed that parents of patients who were given opioids during their stay in the ED were more satisfied but that this relationship was also impacted by pain level and the age of the patient. Parents of older adolescent patients were dissatisfied with their ED experience when their child received opioids to treat a milder pain condition. Although encounters in the ED can be challenging due to time limitations and physician unfamiliarity with a patient’s background, our findings and the cited literature suggest that factors such as patient age, pain, acuity score, and possible risk of opioid misuse should be considered when administering opioid medications. Consequently, ED facilities might consider designing and implementing evidence-based policies and tools that help physicians quickly determine whether opioids should be administered for pain management based on the patient’s characteristics and unique risk of misuse.


The use of sublingual buprenorphine (SLBup) for acute pain after major abdominal surgery may offer the potential advantages of unique analgesic properties and more reliable absorption during resolving ileus. We hypothesized that complete opioid transition to SLBup rather than oral oxycodone (OOxy) in the early postoperative period after major abdominal surgery would reduce hospital length of stay, and acute pain and total OMEDD  requirements in the first 24 h from post-parenteral opioid transition.We reviewed 146 patients who had undergone elective and emergency abdominal surgery under our quaternary referral centre’s Upper Gastro-Intestinal and Colo-Rectal Surgical Units 6 months before and after the introduction of complete postoperative transition to sublingual buprenorphine, rather than oral oxycodone, in July 2017. Our primary endpoint was 24-hourly post-transition OMEDDs; secondary endpoints were 24-hourly post-transition Mean NRS-11 pain scores on movement (POM) and length of hospital stay (LOS). Univariate analysis and linear multivariate regression analyses were used to quantify effect size and identify surgical, patient & other analgesic factors associated with these outcome measures.p = 0.04) and NRS-11 POM at POD1 . When adjusting for patient, surgical and special analgesic factors, SLBup was associated with a similar reduction in OMEDDs , but not NRS-11 POM (p = 0.47) or hospital LOS (p = 0.16).Patients transitioning to SLBup had reduced 24-hourly post-transition OMEDD requirements on postoperative day 2 (POD) (26 mg less, Our change of practice from use of OOxy to SLBup as primary transition opioid from patient-controlled analgesia delivered full opioid agonists was associated with a clinically significant decrease in 24-hourly post-parenteral opioid transition OMEDDs and improved NRS-11 POM, but without an association with hospital LOS after major abdominal surgery. Further prospective randomized work is required to confirm these observed associations and impact on other important patient-centred outcomes. Major abdominal surgery carries the risk of persistent postoperative pain in 5–50% of cases . MoreoveThe use of buprenorphine in the treatment of acute pain has enjoyed a growing resurgence in perioperative pain management . CurrentGiven that the application of IV opioid patient-controlled analgesia (PCA) techniques, with concurrent use of regional analgesia, neuraxial opioids or ketamine infusions are commonplace after major surgery, the use of buprenorphine is an attractive analgesic alternative. However, when transitioning postoperatively from PCA to oral analgesia in the context of major upper gastrointestinal or colorectal surgery, it is unknown whether sublingual buprenorphine (SLBup) offers improved analgesia and reduced oral morphine equivalent drug dose (OMEDD) requirements compared to orally administered oxycodone (OOxy). We primarily hypothesised that use of SLBup would be associated with significant reductions in post-parenteral OMEDD requirements compared with OOxy. Our secondary hypotheses were that use of SLBup would be associated with improved analgesia and reduced hospital LOS without any increase in opioid related critical incidents. We conducted a retrospective study to evaluate these hypotheses and inform our institution whether a prospective randomised trial is justified.Following Human Research Ethics Committee approval (LNR/19/Austin/35), we performed a single centre retrospective cohort study of patients who underwent elective and emergency upper gastrointestinal and colorectal surgery between July 2016 – July 2019. Austin Health is a quaternary surgical service which undertakes > 150 major abdominal resections annually. Inclusion criteria included adult patients (age > 18 years) undergoing surgery of greater than two hours duration, requiring at least one overnight hospital received stay, and who received opioid patient-controlled analgesia (PCA) as part of their postoperative analgesic strategy. Both open and laparoscopic approaches were included. We excluded patients who had emergency surgery due to trauma, those with opioid tolerance , and patients who received percutaneous jejunal feeding. Given the retrospective nature of the study, the ethics committee waived the need for patient consent.All surgeries were performed by specialist gastrointestinal surgeons and all patients underwent a standardised enhanced recovery after surgery program that included preoperative optimisation of comorbidities if required and prehabilitation, standardised intraoperative anaesthesia with goal directed therapy to optimise fluid intervention and guide the use of vasoactive medications, and a standardised postoperative care pathway, which included daily physiotherapy and acute pain service reviews. In the absence of contraindications, all patients received paracetamol and non-steroidal anti-inflammatory medications as part of a multimodal analgesic approach.Two independent investigators extracted data from Austin Health Cerner® electronic medical records, which allows comprehensive electronic data capture and retrieval of patient health information in the perioperative setting. This study is reported in accordance with Strengthening the Reporting Of Cohort Studies in Surgery (STROCSS) guidelines . CollectIn July 2017, the Austin Health Acute Pain Service initiated a practice change that transitioned patients from a postoperative regime of OOxy to a protocol using SLBup exclusively. Between July 2016 and July 2017 patients were transitioned to pro re nata (prn) OOxy immediate-release from opioid PCA therapy at 50% of the equianalgesic dose and frequency relative to their opioid PCA use over the preceding 24 h. This was done once patients required less than 150 OMEDDs by PCA in the last 24 h and were transitioned from nil-by-mouth to oral sips of fluid following surgical and dietetics review. Transition timing was a clinical decision based on multiple factors, including observed reduction in nasogastric (NG) fluid drainage, reduced abdominal distension, the appearance of bowel sounds or flatus, and absence of associated nausea and vomiting.Patients receiving SLBup were transitioned from opioid PCA to SLBup at 50% of the equianalgesic dose and frequency relative to their opioid PCA use in the preceding 24 h, with transition timing determined by the same PCA OMEDD threshold as those receiving OOxy, and clinical indicators for the resumption of oral medication.Pain endpoints were assessed by taking the mean score derived from the 11-point Numerical Rating Score  (NRS-11) per 24-h period on movement. Pain on movement was defined as the NRS-11 rating on attempted deep breathing and coughing. The outcome measure for our primary hypotheses was total opioid analgesics delivered in the 24 h post-transition, compared to the 24 h period pre-transition, for those transitioned to SLBup compared to OOxy, and converted to OMEDDs as per the Australian & New Zealand College of Anaesthetists & Faculty of Pain Medicine Official Conversion Table 2019 . All opiPain improvement 24 h post-transition, compared to the 24 h period pre-transition, for those transitioned to SLBup compared to OOxy. This was quantified by both the absolute value of NRS-11 scale units in the 24 h post-transition period as well as the fall in NRS-11 scale units in this period as defined by(where NRS-11[24] = NRS-11 score over a 24-h period)Other secondary outcome measures assessed were frequency of pain or opioid-related Medical Emergency Team (MET) calls and hospital length of stay. Severe adverse pain or opioid-related outcomes were defined a priori as any of the following events that occurred in the 48-h period following OOxy or SLBup administration: i) thresholds of hypoxia or tachycardia where pain was deemed to be a causative factor, ii) reduced conscious state , a), a11]),To account for the effects of the acuity of surgical presentation and the size and location of the surgical incision on our primary and secondary outcome measures, we used arbitrary ordinal scales to stratify the magnitude of these factors . We inclP-values < 0.0125 considered statistically significant); otherwise p <  0.05 was considered statistically significant. To examine the effect of confounding factors on our primary and secondary outcome measures, we used multivariate linear regression to account for the relative impact of patient factors , SAT , emergency or elective surgery, ordinal scale of the expected degree of postoperative pain by surgery/incision type and ordinal scale of acuity of surgical presentation type  statistical software and graphs were prepared with Graph Pad Prism 5 . OMEDD data and hospital LOS continuous data were assessed for normality by histogram frequency distribution analysis and the Kolgomorov-Smirnoff normality test, with corresponding parametric descriptive and inferential tests used . Bonferroni correction was applied to univariate analyses where multiple comparisons were used for the same endpoint  receiving OOxy and 64 (44%) receiving SLBup. Patients transitioned to SLBup were more likely to be of higher ASA grade, more painful operation type, have received emergency surgery and more acute surgical presentation, and received open laparotomy. They were also more likely to have reached full ward diet later, and had longer length of stay. Patient, surgical and special analgesic categorical data are presented in Table p = 0.04 & p = 0.06 respectively) that did not reach Bonferroni statistical significance, when compared against those who had transitioned to OOxy. SLBup patients did achieve statistically significant improvements in 24-hourly post-transition NRS-11 pain assessments on movement (POM) on POD 1 . The 24-hourly post-transition OMEDD reductions and NRS-11 pain assessment on movement improvements are shown in Figs. On univariate analysis, patients transitioning to SLBup achieved clinically significant reductions in 24-hourly post-transition OMEDD requirements on postoperative day (POD) 1 and 2 . This result was found after adjusting for the POD at which transition was conducted, surgical factors , and other special analgesic techniques (SAT). POD of analgesic transition did not affect the total post-transition 24-hourly OMEDDs. The multivariate linear regression analysis of the covariates included in the regression model is shown in Figure p = 0.32). This result was found after adjusting for the same surgical, pain, analgesic factors and clinical markers previously outlined. Later POD of analgesic transition worsened post-transition NRS-11 POM . The multivariate linear regression analysis of the covariates included in this regression model is shown in Fig. On multivariate linear regression analysis with post-parenteral opioid transition 24-hourly NRS-11 pain improvement on movement as the dependent variable, there was no association with lower 24-hourly post-transition NRS-11 pain on movement (POM) in patients who had received SLBup over OOxy (p = 0.16). The multivariate linear regression analysis of the covariates included in this regression model is shown in Fig. On multivariate linear regression analysis with hospital LOS as the dependent variable, and after adjusting for the same surgical, pain, analgesic factors and clinical markers as above, complete postoperative transition to SLBup over OOxy had no significant effect on hospital LOS (Of note was a 92-year-old patient who had previously undergone an emergency infra-umbilical laparotomy and small bowel resection for bowel obstruction. The patient required administration of IV naloxone after a MET call for a respiratory rate of nine on day two post-surgery, the same day as complete transition to SLBup. A single 200 μg SLBup prn dose had been administered at 0900 h and second at 1900 h, with MET threshold criteria reached for respiratory rate at 2030 h. 50 μg IV fentanyl had been self-administered by a PCA device since 0000 h on the day of transition and ceased at 0800 h, with the patient’s prior 24-hourly fentanyl PCA requirement being 300 μg. No other opioids had been administered, and the respiratory rate rapidly normalised to 18 breaths per minute after a single 40 μg dose of naloxone. There were no other MET calls for pain or opioid-related presentations for any other study patients within 3 days of a complete transition to SLBup or OOxy.We performed a retrospective cohort study of patients undergoing major abdominal surgery and found that patients receiving SLBup had significantly less 24-hourly OMEDD requirements with improvement in 24-hourly analgesia on movement, without any opioid-related adverse effects. Moreover, our findings are reinforced by the observation the greatest difference in OMEDD reductions were observed at POD 1 and 2 . These results on univariate analyses were found despite patients receiving complete transition to SLBup being more likely to have surgical factors predisposing them to greater postoperative pain and OMEDD requirements.Buprenorphine’s favourable pharmacodynamic properties have long been recognised as useful in the management of chronic pain and opioid replacement therapy. The medication has low addiction potential , has antMore recent studies have not supported the hypothesis that there is a lower risk of respiratory depression associated with buprenorphine . Indeed,Our findings imply that SLBup is an efficacious analgesic in the context of postoperative pain management after major abdominal surgery. On univariate analysis, although OMEDD reduction when transitioning from IV opioid PCA to SLBup compared to OOxy did not reach Bonferroni statistical significance on POD 1 and 2, a clinically significant trend was displayed (Fig. Our study is limited by several factors. As a retrospective cohort study, our findings should be considered associative and hypothesis-forming, with prospective randomised data required to draw causative conclusions. The retrospective nature of our data collection introduces many potential sources of bias and error. Our use of arbitrary incisional pain rating and acuity of surgical presentation ordinal scales is unvalidated. However, to our knowledge, no equivalent validated scales exist in the literature, and these scales were required to account for the effect that clinically important covariates may have on our outcomes of interest. While we have demonstrated an association between clinically important acute pain and opioid requirements, other clinically important secondary patient-centric outcomes, including postoperative complications, inpatient/post-discharge mortality, persistent postoperative pain and long-term opioid use, were not assessed. While our use of multivariate linear regression falls within accepted recommendations for the number of covariates to avoid overfitting in our modelling , the relIn a retrospective cohort study of 146 patients undergoing major abdominal surgery, when transitioning from full opioid agonists delivered by PCA devices to oral oxycodone or sublingual buprenorphine, patients receiving sublingual buprenorphine experienced clinically but not statistically significant reductions in post-parenteral OMEDD requirements compared to those receiving oral oxycodone. The same patients experienced a clinically and statistically significant improvement in post-transition analgesia. After adjusting for surgical, patient and analgesic factors, use of sublingual buprenorphine was associated with reduced post-transition OMEDDs, and was not associated with inferior analgesia or a reduction in hospital length of stay. Further prospective randomised studies are justified to confirm these associations.


BackgroundOnly a few studies have reported levels of pain, discomfort, functional impairments, and patients' satisfaction after undergoing periodontally accelerated osteogenic orthodontics (PAOO). Therefore, the objectives were to evaluate postoperative pain, discomfort, functional impairments, and satisfaction following this surgical intervention.MethodsA prospective cohort study was undertaken at the Department of Orthodontics, University of Damascus Dental School, between August 2018 and November 2020. The sample consisted of 16 patients  with moderately crowded lower anterior teeth who underwent full-thickness vestibular flap elevation followed by cortical cuts using piezosurgery. Then a bovine xenograft was applied before reflecting the flap and suturing. Fixed orthodontic therapy was then initiated. Questionnaires were administered to assess the levels of pain, discomfort, and oral functional problems using a visual analog scale (VAS) at one day, seven days, 14 days, and 28 days after surgery. The level of satisfaction was also assessed at 28 days postoperatively. Friedman's test was employed, and Wilcoxon signed-rank tests were used for post-hoc tests with an adjusted alpha level.ResultsOn the first day following the PAOO, the mean values of perceived pain, discomfort, swelling, mastication difficulties, swallowing problems, limitation in jaw movements were 80.00, 80.63, 68.13, 78.13, 55.00, and 64.38, respectively. These mean values dropped significantly in the following assessment times (P<0.001). At 28 days following the PAOO, the mean satisfaction score was 84.94±22.46. All patients mentioned that they took painkillers after the surgical intervention.ConclusionsOn the first day following surgery, patients perceived high levels of pain and discomfort, moderate to severe levels of swelling and chewing difficulties, and suffered from restricted jaw movement. These levels decreased significantly in the following assessment times. Patients' satisfaction with the PAOO procedure was high. Pain complaints are a common condition during orthodontic treatment , which dThese considerations make orthodontic treatment of adults different and challenging as well as necessitate special concepts and procedures, such as the use of invisible appliances, shorter periods of treatment, the use of lighter forces, and more precise tooth movements . The devPeriodontal accelerated osteogenic orthodontics (PAOO) has recently gained popularity and acceptance because proponents of this technique claim that it is safe and effective in accelerating tooth movement as well as benefits compared to conventional orthodontic treatment . ConversStudy design and settingsTrials.gov (NCT04728464). The Local Research Ethics Committee Approval was obtained (UDDS-480-01012018/SRC-2100) and was funded by the University of Damascus Dental School Postgraduate Research Budget (Ref no: 83004660112DEN).A prospective cohort study was undertaken at the Department of Orthodontics, University of Damascus Dental School between the 29th of August 2018 and the 1st of November 2020. This study was registered at Clinical Sample size estimationThe sample size was calculated using the Minitab® 18.1 software  with an alpha level of 0.05, a power of 80%. The most important variable in the current study was pain perception. According to the study of Ma et al., the standard deviation of pain was 1.27 after one-week post-surgically assessed on a 10-mm VAS [Patients' recruitment and inclusion in the studyThe patients were examined at the Orthodontics Department of the University of Damascus Dental School. The sample was composed of patients who were planned to be treated in conjunction with the PAOO procedure. Initially, 50 patients were screened and only 28 of these patients met the inclusion criteria. The research-related information sheet was presented to the patients and three patients refused the surgical intervention. Consent forms were obtained from those who agreed to participate. Therefore, 16 patients out of the remaining 25 patients were randomly selected to enter this cohort study.The inclusion criteria were: (1) adult healthy patients from both sexes within an age range 18-28 years; (2) an absence of previous orthodontic treatment; (3) class I malocclusion; (4) moderate crowded lower anterior teeth; (5) good oral hygiene and healthy periodontium which was evaluated clinically: probing depth ≤3mm, no radiograph evidence of bone loss, plaque and gingival index <1 .Exclusion criteria were: (1) medical conditions that affect tooth movement; (2) medical, social, and psychological contraindications to oral surgery; (3) the presence of primary teeth in the mandibular arch; (4) missing permanent mandibular teeth (except third molars); (5) patients had previous orthodontic treatments; (6) poor oral hygiene or concurrent periodontal disease: probing depth ≥4 mm, radiographic evidence of bone loss, gingival index > 1, plaque index > 1 .The surgical procedure: PAOOSurgery was performed at the Department of Oral and Maxillofacial Surgery at the Faculty of Dentistry at Damascus University. A postgraduate student at the Department of Oral and Maxillofacial Surgery performed all surgical interventions under the supervision of one of the co-authors (IA). All surgical procedures were conducted according to the method suggested by Bahammam  Figure . The fulFollowing surgery, Amoxicillin 500 mg tab was prescribed three times daily for one week; paracetamol 500 mg if necessary and chlorhexidine gluconate 0.12% twice a day. The patient was directed to fill out a pain and discomfort questionnaire before taking the analgesic drug and after anesthesia has worn off. Then a schedule was set up to review the patient after 1, 7, 14, and 28 days to continue treatment. Sutures were removed after seven days.Orthodontic proceduresOn the 14th day of the surgical procedure, all participants underwent orthodontic fixed appliance treatment with an MBT prescription using a 0.022-inch bracket-slot . The first archwire was applied on the same day with a size of 0.012-in. NiTi. Follow-up visits were conducted every two weeks employing the following sequence of archwires: 0.014-in. NiTi, 0.016-in. NiTi, 0.016 X 0.022-in. NiTi, 0.017 X 0.025-in. NiTi, 0.019 X 0.025-in. NiTi and finally 0.019 X 0.025-in. stainless steel [Outcome measures: pain, discomfort and functional impairments questionnaireThe outcome measures for patients treated with PAOO included levels of pain, discomfort, and swelling, difficulties of mastication, swallowing, and jaws movement limitation. The questionnaire was given to patients one day following surgery and at the following assessment times: seven days, 14 days, and 28 days post-surgically. All patients were instructed to mark their responses on a visual analog scale (VAS). This questionnaire was first suggested by Sergl and Zentner , modifieStatistical analysisUsing Minitab® Version 18.1, Anderson-Darling Normality tests showed an abnormal distribution of the collected data, so non-parametric tests were used. Friedman's test was used to detect changes over time with an alpha level set at 5%. Wilcoxon signed-rank tests were employed for pairwise comparisons. Bonferroni's correction was employed due to multiplicity. All statistical analyses were performed using SPSS® Statisics version 24.0 .All patients had Class I malocclusion with moderate crowding on the lower anterior teeth . The sample consisted of 4 males and 12 females. Patients' age ranged from 18 to 28 years with an average of 21±3.05. Descriptive and inferential statistics of the collected scores at the different assessment times are given in Tables Regarding pain assessment, patients' responses ranged from 40 to 100 mm on the VAS scale on the first postoperative day and the mean pain value was high (80±19.66). Then, the pain level decreased after seven days, 14 days, and 28 days . This decrease was statistically significant between assessment times (P<0.001) except for the T3-T4 comparison which was not statistically significant (P=0.026).Patients' responses regarding their feelings of discomfort ranged from 60 to 100 mm on the VAS scale on the first postoperative day and the mean discomfort value was high ( =80.63±16.91). Then the discomfort level decreased after seven days, 14 days, and 28 days . This decrease was statistically significant between assessment times (P<0.001).When the level of observed swelling was evaluated, the mean value of swelling ranged from moderate to high on the first day after surgery (68.13±17.59). Then, the perception of swelling decreased after seven days, 14 days, and 28 days . This decrease was statistically significant between assessment times (P<0.001).The level of perceived difficulties in mastication ranged from moderate to high on the first postoperative day (78.13±18.69), then the difficulties in mastication level decreased after seven days, 14 days, and 28 days . This decrease was statistically significant between assessment times (P<0.001) except for the T2-T4 comparison which was not statistically significant (P=0.330).Difficulty swallowing was noted on the first postoperative day and the mean difficulties in swallowing value were moderate (55.00±23.66). The difficulties in swallowing level decreased after seven days, 14 days, and 28 days . This decrease was statistically significant between assessment times (P<0.001) except for the T3-T4 comparison which was not statistically significant (P=0.024).The mean limitation in jaws movement ranged from moderate to high on the first postoperative day (64.38±23.37). The limitation in jaws movement level decreased after seven days, 14 days, and 28 days . This decrease was statistically significant between assessment times (P<0.001) except for the T3-T4 comparison which was not statistically significant (P=0.020).After the PAOO intervention, the patients' satisfaction with the intervention was high (84.94±22.46). Also, 75% of the patients recommended this procedure to their friends. All patients took painkillers after the surgical intervention, eight patients were classified as having mild pain (50%), four patients had moderate pain (25%), and four patients had severe pain (25%).This is the first cohort study that assessed pain, acceptance, and discomfort levels in patients treated with PAOO by administering questionnaires at one, seven, 14, and 28 days after surgery. The VAS was used as a tool to measure the level of pain after the surgical procedure. The VAS is more commonly used in oral and maxillofacial surgery (OMFS) research because it is more reliable, valid, sensitive, and appropriate . This isThe current findings showed that the mean pain value was high 80±19.66) on the first postoperative day. The pain was severe on the first day due to trauma and edema as a result of the surgery. Also, 25% of patients had severe pain and took painkillers heavily during the first week following surgery; whereas a clinical trial by Chandra et al. showed that the pain level was moderate immediately after surgery in the PAOO group compared to the traditional corticotomy group without any significant difference between them .66 on th. HoweverAdditionally, the results of the current study agreed with the results of Al-Naoum et al. who conducted a clinical trial evaluating canine retraction after traditional corticotomy with flap elevation. They found that 23.33% of their patients reported severe daytime pain during the first postoperative day .The level of pain decreased statistically significantly after one week of the surgical intervention. The results of this study were also in agreement with those of a cohort study accomplished by Ma et al. who included class II and class III patients treated in conjunction with a PAOO procedure. Patients in that study experienced moderate pain in the first week following surgery . HoweverIn the present study, the level of discomfort was severe on the first day after surgery but decreased significantly to a moderate level on the seventh day following the surgical intervention. Al-Naoum et al. in their clinical trial that evaluated canine retraction after traditional corticotomy reported that 10% of patients experienced severe discomfort on the first day after the surgical intervention, using a four-point Likert scale. Subsequently, no patient experienced any discomfort after a week of the surgical intervention . The difThe difficulty in swallowing was moderate on the first day after surgery (x ®=55.00±23.66). This can be explained by limitations in jaw movement following surgical intervention. Subsequently, the difficulty in swallowing reduced significantly after one week of surgery. There are no studies that have evaluated swallowing difficulties in patients undergoing PAOO procedures, therefore, direct comparison of the current results with other studies is not possible. However, in a clinical trial evaluating the effectiveness of flapless corticotomy in leveling and alignment of severely crowded lower anterior teeth, the level of difficulty in swallowing was found mild on the first day after surgery. The difference can be attributed to the conservative nature of the surgical intervention in the study by Gibreal et al .Difficulty in chewing was reported to range from moderate to severe on the first day after the intervention (x ®=78.13±18.69) due to postoperative pain, edema, and swelling. Chewing improved after Day 7 and Day 14 of intervention. The level of chewing difficulty increased again on Day 28 after surgery due to the orthodontic tooth movement following the insertion of archwires on the 14th postoperative day. Unfortunately, the results of chewing impairments in the current work cannot be compared with others' findings due to the absence of similar studies.The swelling occurred significantly and was reported as moderate to severe (68.13±17.59) on the first postoperative day due to the surgical trauma. The swelling was visible on the patients' frontal view and was located in the chin and sub chin area. Patients were not prescribed NSAIDs after the surgical intervention, and they were instructed to place cold bandages on the chin area during the day of surgery. Subsequently, the swelling decreased significantly to a mild level in the first week following the intervention. This goes in line with the results of Ma et al., who included 12 patients treated with PAOO and showed severe swelling in the first week after surgery .Limitation in jaws movement occurred significantly and was reported as moderate to severe (64.38±23.37) on the first postoperative day. Subsequently, the limitation in jaw movement decreased and was reported as mild to moderate on the seventh postoperative day (25.00±20.97). The results of the current study agreed with those of Ma et al., who recorded a mild to moderate incidence of trismus in patients at the first week after surgery .Patient satisfaction with the therapeutic interaction was high (84.94±22.46) and this is similar to the results of Chackartchi et al., where the satisfaction score was 9.78 on the VAS scale . MoreoveLimitationsThe surgical intervention was confined to the lower jaw only. This does not probably reflect the actual level of postoperative pain, discomfort, or functional impairments if the study involved both jaws in this operation. In addition, the surgical intervention was performed on the buccal side of the alveolar bone only and not on both sides as recommended in the primary work of Wilcko et al . The curGeneralizabilityThe possibility of generalizing the results of the current study may be limited, as it included patients with specific malocclusion with a specific age group. More controlled cohort studies of different cases of malocclusion are preferred to generalize the findings.Orthodontic treatment of crowded lower anterior teeth in conjunction with the PAOO procedure was associated with a high level of pain and discomfort, moderate to severe levels of swelling, difficulty in chewing, and restricted jaw movement. Levels of pain, discomfort, and functional impairments reduced significantly after seven, 14, and 28 days following surgery (p<0.001). Patient satisfaction was high with the PAOO procedure and 75% of patients agreed to recommend this therapeutic intervention to their friends.


P = 0.04). After irrigation, those without FBs had more patients experiencing pain reduction (67%) compared to those with retained FBs  and had a greater magnitude of change in pain score . An improvement in ocular pain score ≥ 5 points after irrigation predicted the absence of FBs with a negative predictive value of 100%. Eye irrigation significantly lowered corneal FB retention; if ocular pain decreased considerably, the probability of retained FBs was low, making irrigation-associated pain score reduction a feasible diagnostic method to exclude FB retention without needing specialized ophthalmic examinations.This prospective study aimed at determine whether eye irrigation removes ocular foreign bodies (FBs) and whether ocular pain predicts FBs. Emergency department patients complaining of ocular FBs were enrolled. In the irrigation group (n = 52), pain was evaluated with a visual analog scale before and after irrigation, and the presence of FBs was determined under a slit-lamp. In the nonirrigation group (n = 27), the evaluations were performed upon arrival. The corneal FB retention rate was found significantly lower in the irrigation  than in the nonirrigation groups (13/27, 48%;  In 2010, 1.5% of patients visiting the EDs in the United States received an ophthalmic principal diagnosis, and, between 2000 and 2015, 2–3% of patients discharged from the EDs in Taiwan received diagnoses of eye-related injuries3.Eye-related problems are a common reason for emergency department (ED) visits, and the frequency of such visits is increasing5. These patients probably visited the ED because of persistent ocular FB sensation and concerns that a FB remained inside the eye. However, a recent report from New York City revealed that the time from triage to completion of an ophthalmologic consultation for patients complaining of FB sensation was long: 174–263 min5.Among patients visiting EDs with ophthalmic primary complaints, corneal abrasions and foreign bodies (FBs) on the ocular surface are among the leading diagnoses, and these two diagnoses respectively represent approximately 13–14% and 8–15% of the complaints7. Additionally, although 84% of EDs had slit-lamps available, 30% of ED physicians reported no confidence at all in using the instrument for examination6. Such a lack of confidence could lead to avoidable specialist consultations and thus entail long ED waits. In our hospital, where 24-h emergency eye service is available, 11.8% of all consultations in the ED were sent to ophthalmologists, which ranked first among all consultations8.One reason for the long wait is that, although ophthalmic problems are common, ED physicians are uncomfortable dealing with such problems. In the United Kingdom, two surveys conducted 10 years apart reported that 64–69% of senior house officers in EDs had little or no confidence in managing patients with ophthalmic complaints, despite improvements in their ophthalmic training programs9. In our ED, after excluding open-globe injuries, physicians commonly order eye irrigation for patients complaining of ocular FBs. During the ophthalmologic consultations that follow, many patients report that their ocular pain greatly diminished after irrigation, and among such patients, retained FBs are uncommon.External eye irrigation is a standard protocol in the ED for treating ocular chemical injuriesOn the basis of the above observations, we speculated that external eye irrigation could wash out ocular FBs and reduce ocular pain. Additionally, we assumed that after irrigation, an absence of retained FBs could be predicted from a patient’s considerably improvement in the subjective ocular pain sensation. If these theories tested to be true, eye irrigation could be considered as the first-line treatment and a diagnostic procedure which rendering further examinations with special ophthalmic instruments or techniques unnecessary for this common condition in EDs.This prospective observational cohort study was conducted at a tertiary ED in Chang Gung Memorial Hospital, Linkou, Taiwan. The study was approved by the hospital’s institutional review board (No. 201600962A3C101) and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all enrolled patients.Patients who visited the ED between November 2016 and July 2017 complaining of a foreign body went into the eye, accompanied by persistent ocular discomfort were initially examined by an ED physician. The onset, duration, and symptoms of the eye discomfort were obtained, and basic ophthalmic and general medical history were documented. If both eyes were affected, each eye was separately evaluated. Patients who had no obvious open-globe injury or protruding intraocular content, had a round-in-center pupil with a prompt light reflex, could count fingers at 1 m, and experienced no considerable subjective decline in visual acuity were enrolled in this study. Patients who were younger than 18 years or could not complete a questionnaire were excluded , similar to the score used for dry eye evaluation, was usedUpon confirmation of the FB being removed from the ocular surface, the patient was discharged, and one drop of chloramphenicol 0.25%  was prescribed for application to the affected eye four times a day if the patient had only minimal ocular surface defects and did not regularly use contact lenses. An ophthalmology clinic follow-up was arranged within 1–3 days. If the epithelial defect area was larger than approximately one-sixth of the corneal area, the FB was present upon examination, or the patient regularly used contact lenses, one drop of levofloxacin 0.5%  to be used four times a day, and tobramycin ointment  to be applied at night were prescribed, and an ophthalmology clinic follow-up was arranged within 24 h. The ophthalmic conditions in the follow-up clinics were collected from medical records, and patients were divided into a nonirrigation group and an irrigation group for comparison, and among the irrigation group, into FB retention and FB absent subgroups for analysis.The estimated sample size was calculated based on the preliminary results from the first 3 months of this study. The rate of finding a retained FB was assumed to be 70% without external eye irrigation, and irrigation was assumed to reduce the rate of retained FBs by 50%. Under the assumption that the irrigation group would be twice the size of the nonirrigation group, the estimated sample size was 46 and 23 for the irrigation and nonirrigation groups, respectively .χ2 test for categorical variables and independent t-test and Mann–Whitney U test for normally and non-normally distributed continuous variables, respectively. VAS scores before and after irrigation were compared using the Wilcoxon Signed Ranks test. Spearman’s Rank correlation coefficients were calculated. Receiver operating characteristic (ROC) curves were constructed using the sensitivity and specificity of the ocular pain scores for predicting the presence or absence of FBs after irrigation, and the area under the ROC curve (AUC) was analyzed. All statistical analyses were performed using SPSS Ver. 25 . A two-sided P of < 0.05 was considered statistically significant.Data are presented as mean ± standard deviations. If both eyes were affected, only the eye with the higher initial pain score was included in the analysis. The normality of the distribution of continuous variables was tested with the Shapiro–Wilk test. Variables were compared using the The study was approved by the Institutional Review Board (No. 201600962A3C101) and adhered to the tenets of the Declaration of Helsinki.P = 0.50).After two patients with an intraocular FB discovered during ophthalmologist examination were excluded, 79 patients were analyzed. The mean ages were 44.8 and 44.0 years in the nonirrigation (n = 27) and irrigation (n = 52) groups, respectively, and the majority of the patients were male Table . The ocuP = 0.04). By contrast, the proportions of eyes with FBs retained in the conjunctival sac were similar in the two groups . In total, FBs were absent from 33% and 46% of eyes in the nonirrigation and irrigation group, respectively  than that in the nonirrigation group . No significant correlation was discovered between the ocular surface injury and ocular pain scores.The ocular surface injury scores for the cornea and conjunctiva were comparable between the groups, except for the conjunctival punctate abrasion score, which was significantly higher in the irrigation group than in the nonirrigation group  returned to the ophthalmology clinic as scheduled. Among these patients, one had a retained subconjunctival sand-like FB without active inflammation. The other eight patients had recovered, and none of the patients had signs of infection. Another 16 patients (30.8%) returned to other clinics in our hospital without revisiting the ophthalmic clinic. We presumed that these patients had recovered well since no ocular complaints were documented and no further ophthalmic clinic appointments were arranged.P < 0.001 and P = 0.008, respectively). Notably, patients in the FB (−) group had a significantly greater change in pain score when compared to the FB (+) group .For the 52 patients in the irrigation group, ocular discomfort was re-evaluated after irrigation. We further divided these patients into a FB (−) (n = 24) and a FB (+) (n = 28) group based on whether a retained FB was found after irrigation  in diagnosing FB retention , 0.56–0.85; ion Fig. . FurtherWhether self-reported factors could be used to predict the retention of FBs in the eye was investigated. When a patient reported still feeling an FB, that the FB was possibly metallic in nature, or that the incident had occurred during work, the relative risks of a retained FB were 1.73 (95% CI 1.13–2.66), 1.53 (95% CI 1.78–3.91), and 1.82 (95% CI 1.15–2.89), respectively  reported that the incident had occurred at work. A majority of respondents  were metal workers or mechanics  indicated that some FBs were probably not embedded deeply in the cornea and could therefore be removed through gentle irrigation. ED nurses experienced in performing eye irrigation for chemical burns can learn this procedure easily with minimal additional training. However, the relatively high incidence of FBs in the conjunctival sac (33% in the irrigation group vs. 26% in the nonirrigation group) suggested that some of the dislodged corneal FBs might have ended up in the fornix. Compared with removal of embedded corneal FBs, removal of conjunctival FBs is associated with a lower risk and required skill level.15. Studies have attempted to quantify subjective eye discomfort in dry eye disease. However, such discomfort is affected by conditions including ocular surface diseases16, inflammation17, neuropathic factors18, and nonocular discomfort19. The purely mechanical stress encountered by patients with ocular FBs differs from the multifactorial dry eye disease. Therefore, instead of using dry eye disease evaluation scales, we used a combination of general pain assessment scales including 11-point Box Scale20, 5-category scale21, and Wong–Baker FACES Pain Rating Scale22 as our ocular discomfort measurement tool. These scales have been widely validated and are the gold standards for pain evaluation23. Nevertheless, the perceived magnitude of discomfort greatly varies between individuals and is affected by factors such as sex and antidepressant use25. In the present study, we initially tried to use the absolute mean pain score to predict FBs. Unsurprisingly, the mean score had a low discriminatory power (AUC = 47.6%). Instead, we used the changes in pain score after irrigation to minimize the interindividual differences and achieved a much higher AUC of 71%. Additionally, a cutoff of 5 points for the change in ocular pain score resulted in a high sensitivity (100%) in detecting retained FBs. Thus, the irrigation-related change in the ocular pain score is a simple and acquirable factor for predicting ocular FB retention.The cornea is densely innervated and among the most sensitive tissues27. In a rural setting with nearly 300 participants, prophylactic chloramphenicol ointment prescribed within 18 h after corneal abrasion resulted in no corneal ulcers28. In addition, after noncomplicated corneal FB removal, only 1.7% of eyes exhibited infectious keratitis after treatment with prophylactic fourth-generation fluoroquinolone eye drops, and the development of an infection could be alarmed by the subjective worsening of ocular symptoms29. In the present study, we prescribed chloramphenicol for noncomplicated cases and levofloxacin drops for large abrasions, patients who wore contact lenses, and FBs retained after irrigation. None of the patients in the irrigation group who returned to the clinic developed infectious complications, and their ocular surface injuries all resolved. The above studies and our results suggest that the chances of developing infection under prophylactic antibiotics in abrasion-related ocular surface injuries are low and that external eye irrigation did not compromise outcomes.Although studies have reported that 14–33% of the FBs removed from corneas exhibited positive cultures, 95% and 90% of the isolated microorganisms were sensitive to chloramphenicol and ciprofloxacin, respectivelyThe present study has several limitations. Two patients who complained of bilateral eye discomfort were included, and although we enrolled only the subjectively more painful eye, the sensation in the excluded eye might have affected the pain score of the study eye. Our use of the changes in each patient’s own pain score as the diagnostic factor could have minimized such an impact, but the results may nevertheless be inapplicable to patients affected bilaterally. Another two patients who underwent irrigation were diagnosed with intraocular FBs. They passed the initial open-globe screenings because their entry wounds were small, noncentralized, and self-sealed. Nonetheless, we used sterile saline for irrigation and cautiously avoided applying pressure to the globe. Because the entry wounds were sealed, the risks of intraocular infection and content protrusion should be low. In addition, the ocular pain score was unchanged after irrigation in these patients, which had warranted ophthalmologist consultation. Finally, the FBs were not confirmed by an ophthalmologist with a slit-lamp both before irrigation because the examination itself might affect the location of the FB, especially if the eyelid were to be everted, and this could alter the outcomes of irrigation.On the basis of our results, we propose a flowchart for patients with complaints of ocular FBs Fig. . After oSupplementary Figure S1.


Evidence indicates that inflammatory processes are involved in radicular pain as well as in resorption of herniated disc tissue. Furthermore there are indications that the presence of vertebral end plate pathology  is associated with a negative effect on inflammation. It is hypothesized that in patients with MC, the  inflammation will be accompanied by pro inflammatory cytokines that worsen the outcome, and that in patients without MC, the inflammation is accompanied by cytokines that induce a resorption process to accelerate recovery.This prospective cohort study will include 160 lumbar and 160 cervical patients , which are scheduled for surgery for either a lumbar or cervical herniated disc with ages between 18 and 75. The main and interaction effects of local bacterial infection (culture), inflammatory cells in disc material (immunohistology), MC (MRI), and blood biomarkers indicating inflammation or infection  will be evaluated. Clinical parameters to be evaluated are leg pain on the 11 point NRS pain scale, Oswestry (lumbar spine) or Neck  Disability Index, Global Perceived Recovery, Womac Questionnaire, and medication status, at baseline, and after 6, 16, 26 and 52 weeks.Gaining insight in the aetiology of pain and discomfort in radiculopathy caused by a herniated disc could lead to more effective management of patients. If the type of inflammatory cells shows to be of major influence on the rate of recovery, new immunomodulating treatment strategies can be developed to decrease the duration and intensity of symptoms. Moreover, identifying a beneficial inflammatory response in the disc through a biomarker in blood could lead to early identification of patients whose herniations will resorb spontaneously versus those that require surgery.NL8464.prospectively enrolled at trialregister.nl, ID:The online version contains supplementary material available at 10.1186/s12883-021-02377-4. Radiculopathy is a clinical symptom that has its origin in irritation of the spinal nerve. In patients with a bulging or herniating disc, compression of the nerve is considered the main cause. In more recent studies on radiculopathy, inflammatory processes appear to have a bigger role than originally thought. It is hypothesized that the disruptive process in the area of the spinal nerve starts with micro traumata in the vertebral endplate or disruption of the annulus fibrosus. Disruption of the annulus or micro breakage of the endplate at the location where the annulus is attached, leads to exposure of the nucleus pulposus to the epidural space . In the In our previous work, we found that the impact of the presence of macrophages on clinical outcomes was dependent on the presence of Modic changes (MC), which are considered inflammatory vertebral endplate signal changes that occur frequently on cervical and lumbar endplates , 11. We Propionibacterium acnes or Staphylococcus epidermidis, both of which are opportunistic bacteria that were demonstrated in lumbar and cervical herniated disc material [A different possible scenario is that the exposure to the systemic circulation is accompanied by infiltration of material , and havmaterial . In the material , 15.For future perspectives, it is important to understand the interconnectivity and clinical relevance of inflammation, infection and MC. Until now, no studies have sought to explore the relationship of these three together and how their interconnectivity affects clinical outcomes. Therefore, we would like to investigate the interactions between MC, bacterial infection, inflammation, and their impact on the clinical symptoms of both sciatica and cervical radiculopathy patients. Explicating these mechanisms may lead to characterization of certain subgroups, of which some may benefit from antibiotic treatment, some from anti-inflammatory treatment, some from a conservative approach and some from (early) surgery. Hence, identifying these subgroups will allow future studies to focus on specific treatments for each subgroup. If this is accomplished, we could significantly decrease the disease burden of patients that suffer from herniated discs.In a group of lumbar and cervical radiculopathy patients undergoing disc surgery, this study will determine the impact of bacterial infiltration of the disc on patient reported pain scores, in the presence or absence of MC on MRI and histological defined disc inflammation.A secondary aim of this study is to assess whether patients that suffer from disc inflammation benefit more from anti-inflammatory drugs than those without inflammation.Another secondary aim of this study is to further explore the inflammation process by characterizing different types of macrophages (M1 and M2).At last this study aims to associate the presence of bacterial infection to the presence and type of MC.Figure After the disc is herniated, neovascularisation can be formed, which could lead to a couple of scenario’s. Firstly, in healthy discs, macrophages can enter and likely predominantly differentiate towards M2, which will help with disc resorption and reduce radicular pain. Secondly, likely in a degenerated disc, neovascularisation can be accompanied by infiltrating bacteria. By itself, this may irritate the nerve and cause pain symptoms, but it can also stimulate the disc to excrete pro inflammatory factors which worsen pain and may stimulate macrophages to differentiate towards M1. This could result in more M1 and less M2 macrophages and lead to more radicular pain symptoms. In addition, the adjacent endplate might also get involved, which could lead to more irritation of the adjacent nerve. Animations in the figure originate from cliparts.zone and are free to use, MRI picture is our own.This prospective- observational cohort study is an imaging, histological, immunological and clinical study. Both the MRI scan and surgery are part of the usual care, in addition to these procedures, this study will draw 3 blood samples, use the rest material from surgery and ask the patient to fill in short pain related questionnaires.The total duration of the study is approximately 2.5 years, of which 1.5 years for inclusion and 1 additional year for the follow up. Because Lumbar disc herniations occur more often than cervical ones, the inclusion of lumbar patients might be finished after 1 year, while the inclusion of the cervical patients will likely take 1.5 years. Patients will be recruited from one of the three inclusion centers in which they are planned for surgery: the Spaarne Gasthuis Haarlem Zuid, Alrijne Hospital Leiderdorp, HMC the Hague and Haga Hospital the Hague. The analyses and coordination of the study will be done from the Leiden University Medical Center (LUMC).Patient recruitment will take place during the first (pre-operative) visit with the neurosurgeon, where the patient will be informed about the study. Patients that want to participate will be asked to sign an Informed Consent Form (ICF) in the week prior to the surgery. Afterwards, the participant will fill in a set of online questionnaires in Castor EDC. This set will contain questionnaires that assess demographic data, pain scores , disability scores , Osteoarthritis (Womac) and medication status. Furthermore, the patient will receive an MRI scan in the weeks before surgery which is part of the usual care. In addition, during surgery, the herniated part of the disc will be dissected and transferred to the LUMC for further analyses. The dissected material will be used for three different purposes: One part of the dissected material will be used for bacterial culture, one part for histological analyses, and one part will be snap frozen for later defined analyses.. In addition to the frozen disc samples, this study will also collect blood samples for two purposes: the first is to assess the general inflammation  and vascular status (lipid and apolipoprotein profile) and the second purpose is for future analysis, for which a sample will be stored in the freezer. Only if our hypotheses turn out to be true, the stored blood samples will be used to search for a predictive biomarker for a bacterial infection and/or inflammation of the disc. The exact analysis that will be used to identify the biomarker will be defined in a later stage and will be based on our results from the histological analysis and bacterial cultures. Blood will be drawn in the waiting room for surgery from the canula that is placed for the purpose of the surgery. This means that only the donated blood is an additional aspect of the study, injecting the canula is part of the usual care.All participants will be asked to co-operate during the entire follow-up. During follow-up patients will be asked to fill in questionnaires regarding clinical outcome  and medication status at 8 weeks, 16 weeks, 26 weeks and 52 weeks post-surgery. Patients will receive emails with a link to the follow-up questionnaires at the above mentioned time points. A timeline of the study is provided in Fig. For this study, all patients (18–75 yr.) with 8 or more weeks of radicular pain symptoms, that are eligible for surgery according to a neurosurgeon in the participating hospital, will be asked to participate. Eligibility criteria for surgery in participating hospitals are persisting pain symptoms after 8–12 weeks of conservative therapy with an MRI verified HNP that compresses the nerve root corresponding to the radicular pain symptoms. Patients are eligible for the study if they already planned to undergo surgery for herniated disc and meet the following in and exclusion criteria:Age 18–75o Radicular incitement: radiating pain from (a part of the) dermatome L4, L5 and/or S1o Present for at least 8 weeksa unilateral lumbosacral radicular syndrome, with at least the following criteria:MRI verified lumbosacral disc herniation that is corresponding to the side of the symptomsIndication for surgeryInformed consentAge 18–75o Radicular incitement: radiating pain from (a part of the) dermatome C45, C56, C67 and/or C7T1o Present for at least 8 weeksa unilateral cervical radicular syndrome, with at least the following criteria:MRI verified cervical disc herniation that is corresponding to the side of the symptomsIndication for surgeryInformed consentPrevious lumbar spinal surgery or chemonucleolysisParesis of MRC < 4History of spinal inflammatory diseaseInstability that requires surgical fixationActive infection at the time of surgeryUsage of Anti-biotics in the past six monthsEpidural steroid injection in the past six monthsPregnancyInadequate knowledge of the Dutch languagePrevious cervical spinal surgery chemonucleolysisParesis of MRC < 4Myelopathy as major complaintHistory of spinal inflammatory diseaseInstability that requires surgical fixationActive infection at the time of surgeryUsage of Anti-biotics in the past six monthsEpidural steroid injection in the past six monthsPregnancyInadequate knowledge of the Dutch languageThe main study parameter will be the NRS leg pain for lumbar patients and NRS arm pain for cervical patients. A description of these endpoints and all other parameters used during the study are described below.The pain experienced by the patients will be measured by questionnaires that assess leg pain for lumbar patients and arm pain for cervical patients: NRS leg pain, and NRS arm pain. In these validated questionnaires, the patients will display the amount of pain they have experienced in respective locations during the week previously to the visit. The pain intensity will be determined on a scale of 0–10. 0 represents ‘no pain’ and 10 represents ‘worst pain imaginable’ . NRS wilFunctionalityRecoveryFor estimating functionality of the lumbar patient, the Oswestry Disability index (ODI) will be used. This validated questionnaire contains 10 topics related to the impact of the pain on the patient’s life, with 5 grading’s for each topic. The total will give a score between 0 (no disability) and 50 (maximum disability possible), which will be calculated to a 1–100% score . For estIn order to estimate the perceived recovery of the patients, the Global Perceived Effect (GPE) questionnaire will be used. The GPE is a widely validated questionnaire in which patients can express their perceived recovery on a 7 point Likert scale. On this scale the numbers 1–7 are accompanied by an expression of a state such as ‘Fully recovered’ = 7, ‘Same as before’= 4 or ‘Very bad’ = 1. All recovery scores will be measured at every follow-up moment . Previous test results will not be visible for the patient.Bacterial infection of the discDisc inflammationBacterial infection in the disc will be verified by a bacterial culture protocol. Tissue necessary for the bacterial culture will be harvested from herniated disc tissue that was taken out during surgery. The bacterial culture will be accompanied by a gram stain and methyl blue stain. Infection can be distinguished from a contamination by the quantity of colonies on the culture (0–10 is considered as contamination). Nevertheless, since it cannot be ruled out that the presence of 0–10 colonies is an infection instead of contamination, additional analysis with 0–10 regarded as infection will also be performed.Modic ChangesDisc material harvested during surgery will be stained for the presence of macrophages, for M1 and M2 macrophages separately. Evaluation will be done through counting cells and subsequently categorizing them.Type  and severity (< 50% & > 50%) of MC will be scored at baseline on MRI. Type 1 shows an hypointense endplate on T1 MRI and a hyperintense endplate on T2 MRI, Type 2 shows an hyperintense endplate on both T1 and T2 MRI and Type 3 shows a hypointense endplate on both T1 and T2 MRI.A possible mediator in this study is the amount and type of pain medication that patients take, either in self-care or on prescription from the neurosurgeon or GP as part of the usual care. This could potentially alter the inflammation profile (in the case of NSAID’s) or could lead to lower perceived pain scores. In addition, it could be that patients with severe inflammation benefit more from anti-inflammatory drugs. Therefore this study will measure participants usage of pain medication as follows:participants will be asked to fill in a form regarding the frequency, type and dosage of pain medication and anti-inflammatory drug usage. This form will be given to the participant at baseline (in week before surgery) and will also be given during the one-year follow-up at 8, 16, 26 and 52 weeks.In order to investigate to what extent MC are related to clinical features of osteoarthritis, participants will be asked to fill in the Womac questionnaire. The Western Ontario and McMaster Universities Osteoarthritis (Womac) index questionnaire evaluates pain and physical function, containing 24 questions about daily functioning and stiffness. The questionnaire will be given to participants at baseline and after 1 year follow-up.Furthermore, some additional study parameters that may cause confounding will be measured:From all patients, general information will be collected: age, sex, BMI, ASA, smoking habits, duration of radiating pain symptoms and comorbidity including: hypercholesteremia, hypertension, chronic heart failure, myocardial infarction, angina pectoris, COPD, stroke and diabetes . Furthermore, work-related risk factors will be assessed .nerve root compression  will be scored on MRI (compression is believed to lead to more severe pain symptoms)A unilateral transflaval discectomy will be performed according to usual care. Patients are placed in the knee-elbow position. Using anatomical landmarks and fluoroscopy the level of incision is determined. A small midline incision in the lumbosacral region is made. Muscles are unilateral detached from the spinous process. After spreading the wound a very small partial resection of the rostral lamen is executed, followed by a flavectomy with unilateral opening of the lateral recess. The nerve root is identified as well as the bulging disc. A discectomy is performed and the tissue taken out is assembled in a jar, identified with patient name and study number. If the nerve root is compressed by a sequester, only a sequesterectomy is performed if deemed necessary by the surgeon. After decompressing the nerve and performing a discectomy, the wound is closed in layers.Surgery will be performed by a qualified neurosurgeon. Postoperative care will consist of an admission period of 2 days (day of surgery and day after) and one postoperative visit to the physiotherapist. From there on, the general practitioner will take care of the postoperative care.For anterior discectomy, the level of surgery is verified by fluoroscopy. The operation will be carried out by a qualified neurosurgeon. Most surgeons operate using loupe magnification. The platysma muscle is separated or cleaved at the right side of the midline (less frequently on the left side), and the prevertebral space is reached by an approach medial to the sternocleidomastoid muscle and the carotid artery, and lateral to the trachea and oesophagus. The disc is incised and the corpora are distracted. Discectomy is performed as thorough as possible. Regularly the posterior ligament is cut and the spinal root is decompressed. If necessary, spondylarthrotic rims are removed. To the preference of the surgeon bone graft or an intervertebral fusion device is left behind.Sagittal T1SE (turbo spin echo)Sagittal T2TSETransversal T1-TSETransversal T2-TSEThe MRI imaging process, which are part of the usual care, will be done according to the standard protocol of each participating hospital. Every patient will receive a series of images performed by a 9.0 Tesla scanner:Evaluation of the MRI’s will be done by two independent researchers, both experienced in evaluating spine MRI scans, by using two evaluators, this study can perform a intra agreement analyses and provide a kappa value to put the accuracy of the evaluators in perspective. The evaluators will describe the disc characteristics  and the severity of nerve root compression. In addition, the images will be scored on the presence, severity and type of MC. The Type will be scored according to criteria from Modic et al. , 18. TypDuring surgery, the neurosurgeon will collect a sample of the herniated disc tissue that was removed during the procedure, which will be used for further histological analysis.All harvested discs will be fixed in a 4% formaldehyde solution for 3–7 days. Tissue will subsequently embedded in paraffin blocks and 5-μm thick slices shall be taken from the middle of the block for haematoxylin staining. Stained coupes will be evaluated under the microscope for clear signs of infiltrating inflammatory cells, if tissue from one sample exceeded the capacity of 1 paraffin block, multiple blocks will be formed and a slide of each block will be evaluated. One slide of each disc that contained inflammatory cells was submitted to further analysis using immunohistochemistry:Presence of M1 macrophages will be characterized by the co-presence of CD68 , with CD192  [For the staining procedure, 5-μm paraffin slices will be rinsed in ethanol and methanol solutions and prepared for the expression of CD68, CD192, CD163. Immunohistochemistry will be performed using a three-step indirect method. Antibodies will be cooked in EDTA pH 9.0 buffer as a pre-treatment. Subsequently, an avidin-biotin complex technique will be performed with the Vectastain ABC-Elite Kit (Vector Lab. USA) and the appropriate biotinylated antibodies. Visualization of the peroxidase reaction will be done with DAB solution (Sigma). Moreover, samples will be counterstained with Harris haematoxylin. All of these samples will be accompanied by a positive control. In control samples, primary antibodies will be omitted, which results in the expected absence of any cellular labelling. In order to standardize the evaluation of the samples, all samples were photographed under the microscope before they were evaluated. Since our pilot study showed that CD68 and CD192 was also expressed by nucleus pulposus cells/chondrocytes, cells were analysed based on morphological features and only macrophages were photographed and evaluated. The same approach was used for CD163.In order to assess and characterize the bacterial infiltration of the herniated discs, additional samples will be extracted from the resected tissues. Disc samples will be used for anaerobic and aerobic bacterial cultivation, gram staining and methyl blue staining, to verify and characterize a bacterial infection according to standard clinical protocol. Samples with > 10 colonies per species per culture will be scored as infection, In contrast, samples with 0–10 colonies per species will be scored as contamination. At last, a third disc sample will be collected from the herniated excised tissue, and will be snap frozen for future analysis.Blood samples will be collected from the canula directly after it has been inserted on the holding (OR preparation room). By doing so, the blood sample for the study will be drawn before the patient receives prophylactic antibiotic treatment according to the usual care. A total of 3 blood samples will be collected: the first sample (4 ml EDTA) will be used for a general blood count, the second (3 ml Heparin) for lipid and apolipoprotein profiling, these samples will be send directly to the laboratory in respective hospitals, the 3th and 4th samples will be collected in a 4 ml EDTA for future purposes and will be transferred to the LUMC at the end of the day. At the LUMC, the 3th sample will be deposited at the microbiology department where the plasma will be subtracted according to standard protocol and stored in the freezer. Since the plasma samples will only be analyzed if the hypotheses turn out to be true, the exact analysis protocol will be defined at a later stage.any effect of bacterial infection by comparing the full factorial model to a model without bacterial infection by means of an F-test on 4 degrees of freedom. We implemented a Monte-Carlo simulation in the statistical software R to compute the appropriate sample size. We found that a total of 160 patients suffices to have about 90% power to detect any effect of bacterial infection , bacterial infection (yes/no) and inflammation (yes/no) we have 2x2x2 = 8 groups. We expect the mean during follow-up of the primary outcome (NRS pain score) and the distribution of patients among the 8 groups to be as in Fig. For the statistical analysis, a linear mixed model will be used in which bacterial infection, Modic Changes and disc inflammation are used as a fixed factor and the NRS-scores of all time points  are used as an outcome measure. The model will be full factorial . In addition, age, sex, nerve root compression and pain medication will be considered as a covariate.All secondary study parameters will be analysed by multiple tests including a Pearson/Spearman correlation test, linear mixed model and a Chi-square test for categorical variables.At present, the guideline for radiculopathy is the same for all patients: a wait and see approach, and surgery is only offered to those with persevering symptoms. Even after surgery, for some patients the symptoms persist or return after a short period of relief. The great variety in how radiculopathy patients recover indicates that our ‘one size fits all’ model for treating radiculopathy requires refinement. Previous research has already indicated that inflammatory cells such as macrophages play a crucial role in recovery and that the extend of this inflammation response varies from patient to patient . MoreoveThe design of the present study is aimed at reducing the amount of time and effort that is required from the participants and surgeons as much as possible. At the same time we focus on saving unnecessary costs by postponing additional analyses until our initial hypothesis is confirmed and additional analysis are more likely to reveal critical information. Unfortunately, this design comes with some practical issues that have to be dealt with. For instance, transferring the samples to the LUMC takes time and if surgery is scheduled late in the afternoon, it could mean that the samples cannot be processed in the LUMC the same day which may impact the quality of the data. Therefore it is crucial for the quality of our data that the inclusions are tailored to the OR schedules.Moreover, as participants fill in the follow-up questionnaires through an email link, it makes it harder to control if they fill in the questionnaires, which may lead to missing data. In order to manage this issue, the status of the questionnaire will be monitored frequently and participants that forgot to fill in the questionnaires will be reminded to do so by email and phone.Additional file 1: Figure S1. Monte Carlo simulation for sample size calculation.