One of the major issues in thoracic surgery is adequate post-operative pain management. Inadequate management leads to complications, such as atelectasis, pneumonia, respiratory failure, and the development of chronic pain. Paravertebral block (PVB) has now become the first-line locoregional technique for video-assisted thoracic surgery (VATS) or robot-assisted thoracic surgery (RATS). New chest wall blocks, such as the erector spinae plane block (ESPB) have been described in recent years to facilitate analgesia and limit the risk of puncturing adjacent structures . The ESPB is more superficial than the PVB and some studies suggest that the anesthetic could spread into the thoracic paravertebral space. Therefore, the ESPB may have fewer complications and be more effective than PVB. We hypothesize that the ESPB could decrease post-operative pain compared to PVB block after VATS or RATS for lung cancer.p = 0.0181, with PSA; ESPB −0.80 , p = 0.0255, and at cough . There were no differences between groups concerning post-operative morphine consumption at 24 h and respiratory complications. Conclusions: Our results suggest that ESPB is associated with less post-operative pain at 24 h than PVB after VATS or RATS for lung cancer. Furthermore, ESPB is an acceptable and safe alternative compared to PVB.Introduction: The prevention of respiratory complications is a major issue after thoracic surgery for lung cancer, and requires adequate post-operative pain management. The erector spinae plane block (ESPB) may decrease post-operative pain. The objective of this study was to evaluate the impact of ESPB on pain after video or robot-assisted thoracic surgery (VATS or RATS). Methods: The main outcome of this retrospective study with a propensity score analysis (PSA) was to compare the post-operative pain at 24 h at rest and at cough between a group that received ESPB and a group that received paravertebral block (PVB). Post-operative morphine consumption at 24 h and complications were also assessed. Results: One hundred and seven patients were included: 54 in the ESPB group and 53 in the PVB group. The post-operative median pain score at rest and cough was lower in the ESPB group compared to the PVB group at 24 h (respectively, at rest 2  vs. 2 ,  One of the major issues in thoracic surgery is adequate post-operative pain management. Inadequate management leads to complications, such as atelectasis, pneumonia, respiratory failure, and the development of chronic pain . In lungHowever, the studies performed are heterogeneous and the randomized studies conducted are non-inferiority studies with a limited number of patients ,9,10. ThWe conducted an observational retrospective study in a tertiary care hospital in Rouen, France. Patients undergoing VATS or RATS for lobectomy or segmentectomy with ESPB or PVB between May 2020 and May 2021 were included. ESPB or PVB was provided by 7 different anesthesiologists and was left to the appreciation of the anesthesiologist based on the locoregional anesthesia risks and patients’ comorbidities. The study was approved by the Ethics and Evaluation Committee for Non-Interventional Research of Rouen University Hospital (CERNI E2021-87). According to the current French law, this retrospective study dispensed with the requirement for written informed consent for each patient . The lisExclusion criteria were patients with intraoperative thoracotomy conversion, patients with chronic pain (>3 months), patients with active or past drug addiction (cocaine or heroin), chronic analgesic consumption (>3 months), and age < 18 y/o. A specific identification number for each patient was attributed and the data were collected and analyzed confidentially.The anesthetic procedure for thoracic surgery was protocolized. Prior to surgery, no oral premedication was delivered. All patients were monitored with electrocardiogram, pulse oximetry, and non-invasive blood pressure. The induction was realized with an intravenous (IV) bolus of ketamine (0.25 mg/kg), target-controlled anesthesia (TCI) of remifentanil  and propofol (2 to 3 mg/kg). Maintenance of hypnosis and analgesia was realized with sevoflurane with a mixture of air and oxygen  and TCI of remifentanil (target between 2 and 4 ng/mL)). Neuromuscular blockade agents were provided during all interventions (left to the appreciation of the anesthesiologist). Post-operative nausea and vomiting (PONV) were prevented according to Apfel’s score with IV droperidol (1.25 mg) and IV dexamethasone (4 mg) if the patient presented with two or more risk factors.2O, tidal volume 6 mL/kg). The adequate position of the double lumen tube was controlled by fiberoptic bronchoscopy after intubation and in the lateral decubitus position. The IV fluid administration was limited to 6 mL/kg/h of crystalloids.A double-lumen tube was used for all intubations and the same parameters were used to ventilate the patients , IV nefopam (20 mg), IV ketoprofen (100 mg), and IV morphine (0.15 mg/kg). Following intubation, locoregional chest wall block, ESPB, or PVB was realized. In the ESPB group, ultrasound-guided ESPB was performed in a lateral decubitus position on the thoracoscopic side, out-of-plane technique under aseptic precautions. The tip of the T6 transverse process was identified by progressively downgrading from C7. When the T6 transverse process was in the middle of the image and the pleura were visualized, A 22-gauge block needle was inserted out-plane and guided the middle of the transverse process of T6. The confirmation of the correct location of the needle tip in the fascial deep to the erector spinae muscle was realized by injecting 1 to 2 mL of saline to view the elevation of the erector spinae muscle from the transverse process without distending the muscle. Forty mL of ropivacaine 0.2% (80 mg) was injected into the erector spinae plane. In the PVB group, the ultrasound-guided PVB was performed in a lateral decubitus position on the thoracoscopic side, on the T6 intervertebral level, under ultrasound guidance with 20 mL of ropivacaine 0.2% (40 mg). Following the procedure and after neuromuscular blocking reversal, patients were extubated in the operating room and transferred to the post-anesthesia care unit (PACU). The pain was assessed using a numerical rating scale (NRS), scored from 0 to 10, and was treated if the pain was ≥3/10 in PACU with IV morphine titration. Then, 90 min later, patients returned to the thoracic surgery service if the Aldrete score was adequate. In the service, analgesia prescriptions were protocolized. Patients were administered systematically paracetamol (1 g) every 6 h, ketoprofen (100 mg) every 12 h in the absence of individual contraindications and nefopam (20 mg) every 6 h. If the pain remained and was >6/10, patients also administered morphine sulfate per os, every 6 h (10 mg). If the pain was not managed, the physician could prescribe IV opioids administered through a programmable intravenous patient-controlled analgesia system.The primary outcome was to compare the level of post-operative pain at rest and at cough at 24 h (H24) between the ESPB group and the PVB group. The pain was assessed using NRS, ranging from 0 to 10.The level of post-operative pain at rest and cough at the arrival (H0) and the leaving from PACU (H′), and at 6 h (H6). The pain was assessed using NRS, ranging from 0 to 10;The post-operative consumption of morphine within the first 24 h. The cumulative consumption of morphine was calculated from PACU until 24 h post-operatively. Results are expressed in IV equivalent;Rehabilitation parameters within the first 24 h . Rehabilitation parameters were assessed by a physiotherapist in the surgical department;Impact of VATS and RATS on post-operative pain and post-operative consumption of morphine in the ESPB and PVB groups.The secondary outcomes were:Demographic data, surgical procedure, anesthetic, and post-operative data were collected and are available in The sample size was determined from a preliminary retrospective analysis including 20 patients receiving PVB. In these patients, the mean post-operative pain at 24 h was 2 ± 1.8. Considering that a decrease in pain score of 1.2 was clinically relevant with ESPB, a sample size of 48 patients (+15% for non-parametric tests) per group was necessary to show a statistical difference with a power of 90% and a two-sided type I error of 0.05 ,13,14.http://www.r-project.org (accessed on 2 March 2022)) and Graph Pad v9 . Using the Shapiro–Wilk test, the Gaussian distribution of the data was explored. Following these explorations, the quantitative variables were compared with a Student t-test if the distribution was normal. A nonparametric Mann–Whitney test was used if the distribution was not normal. For the qualitative variables, depending on the group size, the two samples were compared with a Chi2 test or Fisher’s exact test. For continuous measurements, data are presented as the mean ± standard deviation, or median with interquartile ranges [IQR: 25th and 75th percentiles] depending on the distribution of the data. Qualitative parameters are presented as the number of cases n (percentage (%) of patients). As previously described, we used generalized boosted models or a multivariate nonparametric regression technique to estimate the inverse probability weighting (IPTW) in order to control confounding factors in the case of an unknown relationship between the groups (ESPB and PVB) and covariates ) [Statistical analyses were performed with R 4.1.0 ) ,17,18,19p < 0.05.Furthermore, to estimate the regression coefficients , we used weighted IPTW with generalized linear models (GLM) adjusted for imbalanced covariates. Variables included in the final GLM model were selected using a step-down procedure. Statistical significance was indicated by a value of One hundred and eleven consecutive patients were identified for eligibility between May 2020 and May 2021. Four patients were excluded. There was 54 patients in the ESPB group and 53 in the PVB group . There wp = 0.0181 and at cough  and at cough at 24 h   .p = 0.0099 and at cough 4 (2.7–6) vs. 5 (4–6), p = 0.0155) (p = 0.012) and found a tendency at cough at H6   vs. 3 (1–4),  0.0155) . A weigh 0.0524) . There w 0.0524) .There was no difference between the two groups concerning post-operative morphine consumption .p = 0.04) (p = 0.13) (p = 0.01) (p = 0.008) ) compared to the PVB group (40 patients (75%)) at 24 h ( = 0.04) . A weigh = 0.13) . Effecti = 0.01) . A weigh= 0.008) .p = 0.99), post-operative bleeding (p = 0.99), persistent air leak (p = 0.30) and pneumothorax (p = 0.99)), and morphine-related complications (bradypnea (p = 0.06) acute urine retention (p = 0.99). No patient died during hospitalization and no patient developed acute respiratory distress syndrome.There was no difference between groups concerning the surgical complications (pneumonia p = 0.84) or cough (p = 0.63), at 24 h at rest (p = 0.39) or cough (p = 0.59), and for post-operative morphine consumption at 24 h (p = 0.76). Furthermore, we did not find any difference in the PVB group for post-operative median pain at 6 h at rest (p = 0.29) or cough (p = 0.77), at 24 h at rest (p = 0.80) or cough (p = 0.35), and for post-operative morphine consumption at 24 h (p = 0.92).Considering the type of surgery (VATS or RATS), we did not find any difference in the ESPB group for post-operative median pain at 6 h at rest  even if echo-guided, ultrasound decreased the complication rate. In this context, other blocks, such as the ESPB were explored .The mechanism of action of ESPB is still discussed in the literature with many contradictory studies. The diffusion of the anesthetic solution would be at the thoracolumbar fascia space providing a significant craniocaudal and lateral extension analgesia by blocking the posterior branch of the thoracic spinal nerve, but also at the paravertebral space by blocking the anterior branch of the thoracic spinal nerve and the intercostal nerve. Several cadaveric and imaging studies have supported this hypothesis . The effThe efficacy of the ESPB compared to the PVB remains controversial in the literature, but the analysis suggests a comparable efficacy between the two blocks. However, to our knowledge, our study is the first to compare the efficacy between the two blocks with a single injection of a local anesthetic after VATS or RATS.The clinical efficacy with the ESPB can be attributed to several factors in our study. First, in the ESPB, the diffusion of the anesthetic solution would be in the thoraco-lumbar fascia allowing for a cranio-caudal and lateral extension by blocking the posterior branch of the spinal nerve, but also the anterior branch of the paravertebral space and the intercostal nerve providing a visceral analgesia ,6,7,23. Randomized-controlled superiority trials are needed to legitimize the routine use of the ESPB. However, the efficiency, ease of use, and safety of the ESPB can be attractive as a replacement for the PVB for some clinical situations, and should be kept in mind. Indeed, the PVB can be hazardous when there is a poor visual quality of ultrasound, when the BMI is high, when the patient is taking treatments, such as vitamin K antagonists, direct oral anticoagulants, or heparin, or when there is no chest drain after a surgical procedure (such as a lung wedge resection in ambulatory surgery) or after a block for neuropathic chest pain. The advantages and inconveniences of the ESPB and PVB are summarized in This work has limitations. First, although propensity scores reinforced our results in this retrospective study, they did not reveal unobserved differences between the ESPB and PVB groups. Second, this study was a monocentric experience with a restricted number of patients and based on our local practices, and this does not permit us to generalize our results to all thoracic surgery centers widely. Third, the volume of injection of local anesthetics was greater in the ESPB group (40 mL) compared to PVB (20 mL) to obtain a sufficient diffusion, and can explain the difference between groups for post-operative pain. Fourth, the retrospective nature of our study did not allow us to compare the dermatomal distribution of the sensory blockade between the groups. Finally, we were not able to evaluate the impact of ESPB on chronic pain at 3 months, a topic of particular interest in thoracic surgery.ESPB was associated with lower pain scores at 24 h compared to PVB. However, the clinical relevance of the results is less clear. Although, this study suggests that ESPB is an acceptable and safe alternative compared to PVB, ESPB should be kept in mind by the anesthesiologist when the PVB is difficult or hazardous. A regional procedure, such as ESPB or PVB should be used whenever possible in VATS or RATS for lung resection.


As post-endodontic pain control is one of the main targeted addressed in endodontics, our aim was delignated to compare two different methods for low-level laser application utilizing diode laser: low-level laser therapy (LLLT) and laser-activated irrigation (LAI) in the control of post-endodontic pain.A total of 180 patients received single-visit root canal treatment; they were randomly allocated into 3 equal groups. Group I received LAI, group II received LLLT, and group III served as control with normal root canal treatment and mock laser intervention (ML group). Postoperative pain was recorded using visual analogue scale (VAS) after 24, 48, and 72 h. Data were tabulated and statistically analyzed.P value < 0.001) with ML group scored highest score followed by LAI and then LLLT group. At 48 h, there was a statistically significant difference between the three groups , with ML group scoring highest median pain scores while LLLT and LAI showed statistical insignificant scores. At 72 h, there was no statistically significant difference between the 3 groups .At 24 h, there was a statistically significant difference between median pain scores in the three groups (LLLT is superior to LAI and ML group in the control of immediate postoperative pain after 24 h while after 48 h both LAI and LLLT were equally effective, but they still showed significant differences when compared to ML group.Diode laser can be used by clinicians as it decreases the post-endodontic pain in patients with symptomatic apical periodontitis undergoing endodontic treatment. The control of postoperative pain is a golden target with miscellaneous tactics to achieve as it is a frequent sequalae after endodontic treatment and is accredited to either mechanical, chemical, or microbial aspects . The usaLaser therapy has been employed in dentistry widely since its development by Maiman in 1960 . Its usaLLLT reacts with cells through light, a phenomenon called photo-biomodulation , 10. It Laser-activated irrigation (LAI) generate optical cavitation in the irrigant, causing the formation of vapor bubbles . The labAs no comparison was found in literatures between these laser applications, this randomized controlled trial study aims to compare two different methods for low-level laser application: LLLT and LAI in terms of post-endodontic pain control in patients with symptomatic apical periodontitis undergoing primary root canal treatment. The null hypothesis assumes that there is no significant difference in postoperative pain after root canal treatment using LAI or LLLT.www.clinicaltrials.gov database with identifier number NCT04315259. It was assessed then approved by the Ethics committee, Faculty of Dentistry, Ain Shams University .This study is a single blinded, three-arm, randomized, placebo-controlled, clinical trial that was designed and reported by adhering to the Consolidated Standards of Reporting Trials statement CONSORT . A flow The study population was recruited from the outpatient Endodontic clinic at Faculty of Dentistry, Ain Shams University, between July 2017 and January 2020. All applicants signed a consent after a detailed description of the study’s aim, methods, advantages, and possible hazards.Sample size calculation was done using one-way analysis of variance power calculation for more than two groups in R statistical package, version 3.3.1, copyright (C) 2016, considering the pain described with the visual analogue scale (VAS) as the primary outcome. The expected effect size was calculated according to Yoo et al. [Medically free male patients aged between 18 and 50 years, suffering from acute or chronic infection with symptomatic apical periodontitis related to mandibular permanent molars with sensitivity to percussion and radiographic apical rarefaction, were enrolled in our study. Patients were rejected if they suffered from any medical problem or took any medication that could modify pain assessment  within 12 h before the visit.An experienced endodontist (IH)  handles every aspect of dental treatment. After detailed medical and dental history, clinical and radiographic assessment was done to establish accurate diagnosis. Every participant was questioned to record the degree of preoperative pain by drawing a line on a VAS (0–10 cm), with 0 meaning “no pain” and 10 “intolerable pain.”Local anesthetic  was administered, and endodontic access was achieved under rubber dam isolation. A periapical radiograph was used to confirm the working length that had been determined using an apex locator . Following the manufacturer’s specifications, canals were mechanically prepared using an engine-driven rotary nickel titanium Protaper Next system  with finishing files ranging from F1 to F5, depending on the canal’s original diameter. Using a torque-controlled endodontic motor  and the SX tool , the coronal section of the canals was enlarged. Each canal’s final apical preparation size was selected three sizes larger than the first binding file at the WL with a minimum apical diameter of size 25. Irrigation was accomplished using a 27-gauge needle attached to a 3-mL syringe  with 2 mL of 2.5% NaOCl in between files. The needle was advanced to a depth of 2–3 mm short of WL. The final irrigation was done using 2-mL EDTA 17%  followed by 3 mL of normal saline.After that, patients were randomly assigned to one of the three groups based on the mode of use of diode laser: group 1 (LLLT), group 2 (LAI), and group 3 (mock laser (ML)). The investigator created 18 envelopes containing concealed group codes to be assigned sequentially to the eligible patients. The operator opened the envelopes and recorded the codes with respective patient details on a computer to have adequate randomization using an equal proportion randomization allocation ratio.For patients in low-level laser therapy (LLLT) group, laser applicator was positioned 3 mm away from the oral mucosa with beam focused on apical location. Briefly, after the application of the final flush and with the aid of a dental applicator, a 200-mm fiber optic laser tip was placed perpendicular to soft tissue mucosa at the level of the apices of the targeted tooth based on the tooth length taken by the apex locator and confirmed by the working length periapical X-ray. Diode laser exposure  was carried out using a continuous-mode with 10 Hz frequency, 980 nm wavelength, and max power 15 WCW. The tip was applied both at the buccal and the lingual side for 30 s each .For patient in laser-activated irrigation (LAI) group, at the step final step of irrigation, the irrigant was activated with diode laser  . The optical fiber was introduced 2–3 mm short of the working length and was withdrawn from apical to coronal direction . Each caFor mock laser (ML) group: the diode laser tip was positioned similarly as in group 1 without activation (mock laser).After root canal preparation, the root canals were dried with paper points and filled using matched single cones (Meta Biomed Korea) and AD seal sealer (Meta Biomed Korea) was used. Obturation was done using warm vertical compaction.All participants had a chart to record their pain after 24, 48, and 72 h of treatment. A visual analogue scale (VAS) (0–10 cm) was used to indicate the pain intensity where 0 = no pain and 10 = unbearable pain in Arabic. It was fully described to the participants, and they were instructed to return the reports at their next visit to the faculty. Additionally, participants were questioned orally about their use of antibiotics and analgesics over the previous 72 h when they turned in their VAS questionnaire and were excluded and replaced if they took medications. All data were collected and statistically analyzed. Recall rate of patients was 100% as any patient who failed to give feedback or took any analgesics was replaced by new cases.P ≤ 0.05).All data were gathered and organized in Excel sheets . Demographic data in the three groups were compared utilizing one-way ANOVA test and Chi-square test. Various time interval within each group were analyzed using Friedman’s test and the comparison between groups was done utilizing Kruskal–Wallis test . In pairwise comparisons, statistically there was no significant change between median pain score after 24-to-48-h time intervals, but a statistically significant change recorded after 72 h. Results showed a decrease in median of pain score from 24  to 48 h  and the least recorded was after 72 h .All data are presented in Table P value < 0.001, effect size = 0.959). In pairwise comparisons, statistically there was a significant change in pain scores from 24 to 48 h interval as well as from 48 to 72 h. Results showed a decrease in the median of pain scores from 24  to 48 h  and the least was recorded at 72 h .In LAI group, there was a statistically significant change in pain scores by time . In pairwise comparisons, statistically there was a significant change in pain scores recorded from 24 to 48 h’ time interval as well as from 48 to 72 h. Results showed a decrease in median pain scores from 24 , P value < 0.001) to 48 h , P value < 0.001)) and the least recorded was after 72 h , P value < 0.001).In placebo group, there was a statistically significant change in pain scores by time . Pairwise comparisons between the groups revealed that ML group showed the statistically significantly highest median pain score , P value < 0.001) followed by LAI group , P value < 0.001), and the lowest pain score was in LLLT group , P value < 0.001).After 24 h, there was a statistically significant difference between median pain scores in the three groups . Pairwise comparisons between the groups revealed that ML group has statistically significantly highest median pain score . There was no statistically significant difference between LAI group and LLLT group; both showed the statistically significant lower median pain scores.After 48 h, there was a statistically significant difference between median pain scores in the three groups .After 72 h, there was no statistically significant difference between median pain scores in the three groups (Varying levels of pain and discomfort may persist even after removal of the inflammation source by cleaning and shaping procedures  and sincThe use of laser in low level had a notable effect on the outcomes of endodontic treatment; our point of search focused to investigate the optimum low-level laser intervention methodology that may affect the postoperative pain level. Thus, our aim was to compare two different methods for low-level laser applications: LLLT and LAI in terms of post-endodontic pain control.Our study is a single blinded, three-arm, randomized, placebo-controlled, clinical trial with patient-reported outcome procedures for the greatest possible chance to minimize bias and in which the patient, who is the outcome reporter, was blinded to the interventions done, consequently decreasing act and find bias .Only persons who did not take any pain modulating medications 12 h before the visit were allowed to participate in the study to abolish the influence of pre-treatment analgesics on pain analysis. The impact of gender on postoperative pain has been conflicting ; thus, oA single-visit root canal treatment was selected in this study to remove any positive or negative influence of using intracanal medication on our outcome . To avoiAs studies reported elevated levels of post-endodontic pain after 48–72 h , 31, ourRegarding the choice of the wavelength and the power of the diode laser in our study, we used wavelength of 980 because as it showed more bactericidal with signs of changes in the bacterial surface . The useProper positioning of the fiber optic probe in LAI was mastered to be 2–3 mm short of the WL. This was to ensure adequate irrigant flow through the root canal  and to aIn LLLT group, the laser beam was targeted directly over the alveolar mucosa at a location corresponding to the apices of each tooth, although the beam was targeted in other studies  10 mm awOur results showed that there was statistically significant difference in pain score after 24 h where lowest pain score was related to LLLT group. After 48 h, there was no statistically significant difference between LAI and LLLT groups, but both differ statistically significantly lower than ML group.The results of our study agree with the findings of Arsalan A et al.  and ÇakiLAI showed favorable responses in pain control in several studies , 40–42. Considering that both LAI and LLLT are clinically viable options, using LAI would be the more clinically useful and effective option given the similar results. This is because LAI has been shown to have antibacterial effects, is reasonably priced, and is increasingly used in general practice.A limitation of this research may be the unenrolment of female patients; thus, wider range of patients may enhance the generalizability of the clinical trial outcomes. Upcoming studies are advised to assess the effects of other lasers on the short- and long-term results.LLLT is superior to LAI and ML group in the control of immediate postoperative pain after 24 h while after 48 h both LAI and LLLT were equally effective, but they still showed significant difference when compared to ML group. After 72 h LAI, LLLT and conventional root canal treatment had similar results in the control of post-endodontic pain.


Prehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury.A two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes.The PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia.Trial registration: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474 At least 70% of Ambulance calls involve patients experiencing pain . NHS ParEffective management of acute pain is important for humanitarian reasons, for improving patient experience and reducing adverse long-term outcomes. In 2004 the World Health Organisation declared that effective management of pain is a universal human right. Poorly managed acute pain is associated with increased chronic pain. Studies indicate chronic pain is common following trauma with a reported incidence of 15–30%, increasing to 62% in patients suffering major trauma –9. PoorlThe Joint Royal Colleges Ambulance Liaison Committee (JRCALC) produce national clinical guidelines for NHS Ambulance Services. These guidelines suggest a stepwise approach to pain management according to the pain severity and availability of pre-hospital treatments for pain. The strongest parenteral analgesia routinely available for use by paramedics when treating patients with severe pain is morphine. Ketamine may be an ideal prehospital analgesic agent due to its rapid onset of action, superior analgesic properties and haemodynamic profile. The National Institute for Health and Care Excellence (NICE) has identified the need for a pragmatic, randomised trial to determine the clinical and cost effectiveness of ketamine against standard care (morphine) .A barrier to effective pain treatment is the limited formulary available to paramedics. The most frequently used drug for moderate to severe pain outside a hospital is morphine . UnfortuKetamine has a wide margin of safety. Serious adverse outcomes have not been reported even though overdoses of 5 to 100 times the intended dose have been inadvertently administered . Due to The primary aim of this trial is to determine whether paramedic administered ketamine (intervention) or morphine (comparator) provides more effective pain relief for patients reporting severe pain following trauma, as measured by the Sum of Pain Intensity Difference (SPID), assessed using a 0–10 numeric rating scale.Core trial information is presented in Table This is a multi-centre, randomised controlled, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury. It is a pragmatic, phase III trial working with two large NHS ambulance trusts with an internal pilot, aimed at mirroring existing practice of dealing with severe pain following acute traumatic injury. Participants will be followed up for 6 months. Adult patients (> = 16 years old) will be eligible for recruitment if they report severe pain following acute injury, in the pre-hospital environment and are determined by a paramedic to require parenteral morphine or equivalent.The trial has been designed to determine if ketamine is superior to morphine as a prehospital analgesic. The prehospital phase ends once the patient arrives at hospital.Randomisation will occur when the trial drug-pack is opened. The trial drug pack includes three ampoules of trial drug containing either ketamine of morphine. The ampoules of ketamine and morphine appear identical. The treating paramedic will not know which drug they are administering, hence the double blinding.Inclusion criteriaAge ≥ 16Patient reports a pain score ≥ 7/10 on a 0–10 NRS following acute traumatic injuryIntravenous or intraosseous access obtainedDetermined by a paramedic to require IV morphine or equivalentExclusion criteriaKnown or suspected pregnancyUnable to articulate severity of pain using the 0–10 NRSLack of capacity due to a reason other than painIntravenous (IV) or intraosseous (IO) ketamine or opioid analgesia immediately prior to randomisation*Known contraindication to either ketamine or morphine as per the published Summary of Product Characteristics (SmPC)Patient declines participationKnown prisoner*The trial is a pragmatic one and mirrors real life practice, hence why some analgesics e.g. paracetamol are not a justification for exclusion. Administration of ketamine or morphine is likely to significantly bias results hence why these two analgesics are excluded. Immediately before, here, refers to administration by a by a clinician responder who has arrived on scene prior to the arrival of the trial trained paramedic.The study aims to recruit 446 participants. Potential participants will be identified by the attending paramedic and if eligible will be enrolled into the trial.Acute severe pain disrupts cognitive function and may impair mental capacity. Furthermore, patients with severe pain require urgent treatment to relieve pain for humanitarian reasons as well as to reduce the physiological stress caused by severe pain. It may therefore be impractical to obtain written informed consent prior to treatment from either the patient or a personal legal representative as to do so would delay treating the patient’s pain.Before recruiting any patient to the trial, the paramedic will provide the patient with brief verbal information about the trial by reading predefined text from an aide memoire and advising the patient of their intention to enrol the patient into the trial. At this time, the paramedic will not be seeking informed written consent, but will provide the patient the opportunity to decline participation in the trial. Written informed consent will be obtained from the patient, or their legal representative, by research paramedics at the earliest opportunity, once the initial emergency has passed.Ethics approval was granted on 01/09/2020 by West of Scotland REC 1.The randomisation sequence will be provided by the Programming Team at the Warwick CTU. Randomisation will be achieved by way of specially prepared, sequentially numbered treatment packs containing identical ampoules of either ketamine (intervention) or morphine (comparator). The content of the drug packs will be determined from a randomisation list prepared by the study programmer. The blinded block randomisation system will look to ensure a ratio of 1:1 control: intervention. The balance between arms at each site is handled by the ordering system that ensures a pre specified number of paired packs are delivered to each site. The block size is determined by the number of drugs in any given site batch order. Distribution of trial drug packs by the trial drug manufacturer will ensure equal proportions of ketamine (intervention) and morphine (comparator) are distributed to each participating site. Allocation will be concealed from study personnel, ambulance staff and patients.Numbered study drug packs in a pre-randomised sequence, will be carried by participating ambulance paramedics. Randomisation will be achieved by opening the pack. This avoids the need for any randomisation procedures before recruitment which could delay patient treatment.The packaging and the labelling of the IMP packs will conceal which trial drug is being used therefore the patient, attending clinicians, research paramedics and trial administration team will be blinded. Only the statistician and the programming team will be able to link the trial drug pack number to the allocation of ketamine or morphine.Ketamine will be supplied in 2 ml glass ampoules containing 15 mg in 1 ml and supplied in numbered treatment packs containing 3 ampoules (up to 2 for administration and 1 in case of breakage).Morphine will be supplied in 2 ml glass ampoules containing 10 mg in 1 ml and supplied in numbered treatment packs containing 3 ampoules (up to 2 for administration and 1 in case of breakage).Trial IMP was manufactured and supplied by ModePharma Ltd, an MHRA licenced company who specialise in producing medications for clinical trials. The IMP is supplied in a standard white cardboard ampoule box.The trial drug is prepared by diluting one ampoule of trial drug (either ketamine or morphine) with 9 ml of 0.9% sodium chloride in a 10 ml syringe. The trial drug is then administered by slow IV or IO injection, titrated to effect over five minutes , aiming to give the minimal effective dose.If the patient still reports pain 5 min after receiving the first full syringe, the paramedic will prepare a second syringe of trial drug in the same manner. Further trial analgesia will be administered in 2 ml aliquots every 5 min until adequate pain relief is achieved, or all 10 ml of the second syringe has been administered.The maximum volume of trial drug that can be administered is 20 ml (2 syringes), while the maximum dose that can be administered is 30 mg (two ampoules) of ketamine or 20 mg (two ampoules) of morphine. In standard practice, paramedics carry 2 × 10 mg in 1 ml ampoules of morphine. The maximum dose of morphine that a paramedic can administer is 20 mg (or two syringes). The rate of administration in the trial mirrors standard practice. Consequently, if a trial paramedic happened to open a drug pack containing morphine, then the patient would receive morphine in the exact same manner as standard practice.The study is intended to compare morphine and sub-dissociative ketamine. Unfortunately, no morphine equivalent dose for ketamine has been published. Bredmose et al.  publisheWe wanted to minimise the likelihood of dissociative effects. Based upon mean UK adult weights  we estimated that an average male would receive approximately 0.18 mg/kg from one syringe containing 15 mg ketamine, with the potential for further analgesia up to 0.36 mg/kg by administering the second syringe. Our approach of titration to effect (standard practice) should minimise the risk of larger dissociative doses being administered. More recent reviews by Riccardi et al.  and SandTable Effectiveness of pain relief from randomisation to arrival at hospital as measured by Sum of Pain Intensity Difference (SPID) score . As this is a pragmatic trial, no fixed time interval was specified to record pain scores, however we did request that pain scores were documented regularly from the point of initial IMP administration to arrival at the hospital.Effectiveness of pain relief and overall patient experience from randomisation to arrival at hospitalTotal Pain Relief (TOTPAR) scoreTime to perceptible analgesiaTime to meaningful analgesiaTime to peak analgesiaDuration of analgesiaRequirement for rescue analgesiaProportion of patients with a pain intensity score below 4/10 ) on arrival at hospitalVital signs Patient Global Impression of Change on arrival at hospitalIncidence of side effects and adverse eventsAirway: vomiting, aspiration, advanced airway managementRespiratory: desaturation, need for ventilatory supportCardiovascular: arrhythmia, hypotension and hypertensionNeurologic: sedation, excitatory movements, adverse behavioural reactionsOther: nausea, allergic reactionResource useAmbulance job cycle time Number of ambulance resources  in attendanceCumulative IMP doses administeredCT scan useHospital or ICU admissionLength of stay ED, ICU, HospitalLonger term outcomesChronic pain using Brief pain inventory-short form (BPI-SF) at 3 & 6 months from randomisationHealth-related quality of life measured using the EQ-5D-5L at 3 and 6 months from randomisationCost-effectiveness expressed in terms of incremental cost per quality-adjusted life year (QALY) gainedIn line with IMMPACT recommendations, our primary outcome reports Sum of Pain Intensity Difference (SPID). Reductions in pain severity can be reported as either change in NRS, the pain intensity difference (PID), or as a percentage change PID (%PID). The International Association for the Study of Pain has quantified clinically meaningful improvements in pain intensity. Depending on how severe the initial pain is, clinically important improvements in PID range from 1.3 to 5.2. Those with severe pain will need to experience a greater reduction in pain than those with mild pain to experience a clinically important reduction in pain. Similarly, improvements in %PID range from 20.1 to 56.1% depending on severity of pain. Previous studies have established that improvement in PID is equivalent to improvement in SPID .The study has been powered to identify change in SPID calculated using the change in PID. To ensure our study is able to detect at least a 20% improvement in %SPID, regardless of baseline pain intensity, our sample size calculation is powered to detect 20% improvement in %PID, which in turn is equivalent to a 1 point difference (0–10 NRS) in effectiveness between morphine and ketamine.Previous randomised controlled trials comparing ketamine and morphine have adopted a standard deviation of 3.0 , 40, 41.Based on these estimates we calculate our trial will require a sample of 446 subjects, recruiting 223 to each arm of the study, to detect a 1 point difference on the NRS (range 0–10) in primary outcome between morphine and ketamine.The statistical analysis will follow the estimand framework . PrimaryVarious intercurrent events have been identified for this trial, in line with the estimand framework , and appItem missingness is expected for the primary outcome due to the method of recording data used in the trial, however the primary outcome is a measure of the area under a curve, therefore if two pain measurements are recorded the primary outcome can still be measured. Imputation methods have been considered for missingness, but methods such as last observation carried forward are not reliable due to the variability of pain scores, and we cannot assume that pain scores are missing at random therefore multiple imputation is also not feasible. Analyses and template tables will be reported in a detailed statistical analysis plan for review and approval by the Data Monitoring Committee (DMC), prior to final statistical analysis of the data.We have selected the following subgroups to explore interactions relating to age, gender and the administration of intravenous paracetamol prior to randomisation. The primary outcome will be used as the dependent variable, interaction between the subgroup variable and treatment will be included as an independent variable. Linear regression models will be used to assess the subgroup effect, using interaction terms, subgroup by treatment, to measure the effect of each subgroup.Participant data are being stored on a secure database in accordance with the Data Protection Act (1998). A unique trial identification number is used on all follow-up questionnaires. Warwick clinical trials unit does not receive nor process any personal identifiable data for this trial.. Patient eligibility and ambulance data will be collected from electronic patient records, whereas patient hospital data will be obtained from retrospectively from medical records. Follow up data is obtained from questionnaire packs posted out to participants that have consented to receive them.Source documents are where data are first recorded, and from which participants’ case report form (CRF) data are obtained. These include, but are not limited to, ambulance service records and hospital records (from which secondary outcome data will be collected from)On all trial-specific documents, other than the signed consent form, the participant will be referred to by the trial participant number/code, not by name. Data will be entered on to the trial database by the research team.A health economic evaluation has been embedded into the PACKMaN trial. The economic evaluation will take the form of a within-trial cost-effectiveness analysis, conducted from the perspective of the UK NHS and personal social services . EstimatThe primary trial-based analysis will focus on the costs and QALYs accrued during the trial period. There is however potential for costs and benefits to accrue beyond the trial period. If outcomes have not converged by the 6 month timepoint we will consider extrapolating the results over a longer time horizon using a decision analytic model. This would involve combining the trial data with external sources to estimate the long-term cost-effectiveness of the intervention. Any costs and benefits accruing after the first year would be discounted at a rate of 3.5% per year and full probabilistic sensitivity analysis would be conducted in line with the NICE reference case . A decisThe trial is enrolling patients with acute traumatic injuries which may be immediately life threatening, or result in hospitalisation, persistent or significant disability/incapacity and or death. Potential adverse events are captured on the case report form and investigated by the research paramedic in the first instance. The research paramedic passes the results of their investigation to the PI to determine if the event is an adverse event or not. The trial team are then informed of the outcome as required. In addition, hospital clinicians are able to report clinical concerns to the research paramedic for review that will similarly be reported via the PI to the CI and onward as necessary.Clinically predictable side effects will be captured but may not be classified as adverse events. For example, morphine is known to cause respiratory depression. A reduction in respiratory rate will be captured on case report forms. If no intervention is required, this will not be classified as an adverse event. However, if the treating paramedic has to assist ventilations of administer naloxone, then this would be classified as an adverse event.Airway: vomiting, aspiration, advanced airway managementRespiratory: desaturation, need for ventilatory supportCardiovascular: arrhythmia, hypotension and hypertensionNeurologic: sedation, excitatory movements, adverse behavioural reactionsOther: nausea, allergic reactionThe following adverse events are captured on the case report form as secondary outcomes. If deemed serious they will also be recorded and reported using the SAE form.Serious adverse events which are not related to the acute traumatic injury, or are complications resulting from the IMP administration to 30 days post trial drug will be reported to the PACKMaN Trial team as soon as possible and within 24 h of the research staff becoming aware of the event.Results from the PACKMaN trial will be reported to a trial registry within 12 months of a database lock.The trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines Fig.  51].Fig.Fig51].FOur dissemination strategy will target policy makers, commissioners, trauma networks, ambulance services, healthcare providers, academic audiences, patients and the public, charities and advocacy groups. It will include presentations at national and international conferences. We will submit publications to open access peer reviewed journals, develop a lay summary and infographic of the research findings. We will work with our patient and public partners to develop patient stories which effectively communicate key messages from the study. We will publicise via press releases to established media contacts and use our website, blog, Facebook page and Twitter feed to communicate our findings. Our research will support the development of an evidence-based pain management guideline for paramedics by NHS ambulance services. It will improve healthcare quality for patients with severe pain following trauma by engaging clinicians, patients, ambulance services and policy makers to provide better care, by reducing variation in practice and optimising the use of limited health resources.Professor Siobhan Creanor (Chair), Professor Julia Williams, Dr Charlotte Small.Dr Fionna Moore (Chair), Tim Edwards, Andy Collen, Caroline Leech, Jonathan Bishop, Claire Hulme, Maria Devlin.PACKMaN Study Group: chief investigator: Professor Gavin Perkins. Co-chief investigator: Dr Michael Smyth. Co-investigators (Grant holders): Dr Joyce Yeung, Professor Ranjit Lall, Dr Gordon Fuller, Professor Stavros Petrou, Dr Allison Walker, Dr Julian Mark, Duncan Buckley. Senior project manager: Kath Starr. Trial co-ordination/administration: Dr Hannah Noordali. Research fellows/assistants: Felix Michelet , Kamran Khan . Patient representative: Duncan Buckley. Trial statistician: Professor Ranjit Lall. Health economist: Professor Stavros Petrou. Intervention development: MODEPHARMA Limited. Data programming team: Ade Willis, Chockalingam Muthiah.The trial statisticians and DMEC will have access to the dataset for the analysis of trial outcomes. Once the main analyses have been undertaken, deidentified individual participant data will be available to principal and other investigators subject to approval of data analysis plans by the TSC and compliance with the University of Warwick SOPs on Data Management and Sharing. We will comply with Data Sharing Policies that may be instituted by the NIHR during the lifetime of the project.West of Scotland REC 1 approved 01/09/2020.The study was independently peer reviewed as part of the funding application to the NIHR.


Haemophilia is an X-linked recessive genetic disorder characterised by bleeding within soft tissue and joints. The ankle is disproportionally affected by haemarthropathy when compared to the elbows and knees; reported as the most affected joints in patients with haemophilia. Despite advances in treatment, patients still report ongoing pain and disability, however, the impact has not been evaluated, nor has the effect on health-related quality of life (HRQoL) or foot and ankle patient-reported outcome measures (PROMs). The primary aim of this study was to establish the impact of ankle haemarthropathy in patients with severe and moderate haemophilia A and B. Secondly to identify the clinical outcomes associated with a decline in HRQoL and foot and ankle PROMs.A cross-sectional multi-centre questionnaire study was conducted across 18 haemophilia centres in England, Scotland and Wales with a recruitment target of 245 participants. The HAEMO-QoL-A and Manchester-Oxford Foot Questionnaire (MOXFQ) (foot and ankle) with total and domain scores measured impact on HRQOL and foot and ankle outcomes. Demographics, clinical characteristics, ankle haemophilia joint health scores, multi-joint haemarthropathy and Numerical Pain Rating Scales (NPRS) of “ankle pain over the past six months” were collected as a measure of chronic ankle pain.. HAEMO-QoL-A and MOXFQ (foot and ankle) total and index scores indicated worse HRQoL with total scores ranging from a mean of 35.3 to 35.8  and 50.5 to 45.8  respectively. NPRS (mean (SD)) ranged from 5.0 (2.6) to 5.5 (2.5), with median (IQR) ankle haemophilia joint health score of 4.5 (1 to 12.5) to 6.0 (3.0 to 10.0) indicating moderate to severe levels of ankle haemarthropathy. Ankle NPRS over six months and inhibitor status were associated with decline in outcome.A total of 243 of 250 participants provided complete dataHRQoL and foot and ankle PROMs were poor in participants with moderate to severe levels of ankle haemarthropathy. Pain was a major driver for decline in HRQoL and foot and ankle PROMs and use of NPRS has the potential to predict worsening HRQoL and PROMs at the ankle and other affected joints. Haemophilia is an X-linked recessive genetic disorder characterised by bleeding in soft-tissue and joints caused by an absence or reduction in circulation clotting factor needed to maintain haemostasis . The twoMulti-joint haemarthropathy is an inherent clinical feature of severe haemophilia and moderate haemophilia with a more severe phenotype , 4. SeveDespite improvement in primary and secondary prophylaxis treatment with novel factor and non-factor treatment regimes, musculoskeletal complications of repeated and historical haemarthrosis remain a long-term health issue resulting in significant levels of impairment and pain , 9. The The physical and mental burden of haemophilia is great when compared to the general population ; changesThe ankle joint is often cited as the main site of pain and haemarthropathy however, little has been reported on how ankle haemarthropathy contributes to overall musculoskeletal health, HRQoL and foot and ankle specific patient-reported outcome measures (PROMs) –26. SimiTo report the impact of ankle haemarthropathy on HRQoL and foot and ankle PROMs in UK patients with moderate and severe haemophilia. The study also aims to identify clinical associations of decline in this cohort.th April 2017 and ended on 31st August 2019. Recruitment was undertaken at 18 sites across England, Scotland and Wales, with support from the NIHR clinical research network .Ethical approval was obtained on 24th January 2017 . Recruitment commenced on 13A cross-sectional multi-centre questionnaire consisting of two sections was distributed to participating haemophilia comprehensive care centres and haemophilia treatment centres (Appendix A). Section A contained the validated HRQoL measure the HAEMO-QoL-A and the foot and ankle specific outcome measure the MOXFQ (foot and ankle). Participants provided demographic information, detail of disease characteristics , and treatment . Ankle pain status over the past six months was capture using a numerical pain rating scale (NPRS). Participants were asked “how painful has your ankle been over the past six months?”, 0 = No pain to 10 = Pain as bad as you can imagine . SectionA recruitment target of 245 was set to allow the mean HAEM-QoL-A to be estimated to be within ± 2.5 units of the measurement scale, assuming a between the patient standard deviation of 16.96 . Inclusith and 75th percentiles).To report associations between participant disease status and HEAMO-QoL-A and MOXFQ (foot and ankle) total score and domain data, the outcomes were entered into a linear regression model where the effect of haemophilia type, severity and treatment regime were entered separately as predictors of decline. Sensitivity analysis was undertaken using stepwise regression models to determine whether clinical measures of pain, inhibitor status, and ankle haemophilia joint health score were associated with decline in HRQoL and foot and ankle PROMs subscale and total scores. Data are reported as mean and standard deviation, non-parametric data are presented and median and interquartile range , leaving 243 for analysis.n = 184) of the cohort. Age, height and weight were similar across haemophilia type and severity. Body mass index (BMI) was similar across haemophilia types, with the majority of patients classed as over-weight. Patients receiving standard half-life (SHL) clotting factor concentrate treatment were exclusive to haemophilia A, with 107 (45.3%) patients using SHL products. Extended half-life products were used by 88 (37.38%) and 32 (13.55%) patients with haemophilia A and B respectively. Nine (3.8%) patients used a bispecific monoclonal antibody, which at the time of this study, were used exclusively in the management of haemophilia A with a current inhibitor.Patient demographics and disease characteristics are presented in Table Patient questionnaire data and clinical measures are presented in Table n = 131) indicating they did not use regular pain medication. In the remaining 43.7% (n = 102) patients paracetamol and COX2 inhibitors were the most commonly used pain medications.Ankle pain severity experienced over six months Table  were conRegression analysis of haemophilia disease and treatment characteristics were not independently associated with the decline in total or domain scores of the HEAMO-QoL-A and MOXFQ. Stepwise regression analysis of the clinical variables associated with the HEAMO-QoL-A and MOXFQ total scores excluded ankle haemophilia joint health score (left and right), treatment IU/kg and treatment product from the final model. Ankle NRPS and inhibitor status accounted for 52% of the R-Square for HAEMO-QoL-A total scores. NPRS and inhibitor status accounted for 53.7% of the R-Square for Total MOXFQ. Sensitivity analysis of the total and subscales of the HEAMO-QoL-A and MOXFQ are presented in Table The primary aim of this study was to identify the impact of ankle haemarthrosis and haemarthropathy in patients with moderate and severe haemophilia. This large multicentre study has identified that across the UK, patients with moderate and severe haemophilia experience poor HRQoL and foot and ankle PROM.n = 34 and n = 29 respectively) the findings are similar to that of De Juili et al. (2014) who in a much larger sample of patients (n = 75) found that despite few complications of bleeding, a proportion of moderate haemophilia patients was more severely affected by haemarthropathy [The impact of multi-joint haemarthropathy has previously been associated with severity. Patients with severe haemophilia report worse outcomes than moderate and mild disease , 22. Highropathy . HaemophThe clinically detectable levels of haemarthropathy, measured using the haemophilia joint health score indicate advancing haemarthropathy across both disease severities. There is no consensus as to the level of haemarthropathy indicated by the haemophilia joint health score, however radiological compassions using the Pettersson score a radiological measure of joint damage in haemophilia suggests haemophilia joint health score of 5.0 to 6.0 correlates with moderate to severe levels of haemarthropathy . The levAnkle pain was the most impactful feature across all haemophilia disease characteristics. NPRS ankle pain ranged from 4.9 to 5.5 across the cohort with similar levels reported in studies of severe haemophilia. A large US survey of pain reported NPRS average mean (SD) persistent pain of 4.32/10  in moderate and 4.25/10  in severe haemophilia; patient-reported pain was also the most significant association with decline in HRQoL . AlthougThe NRPS “average pain in your ankle over the past six months” has been based on the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials chronic pain guidance and appears to be associated with decline for both HRQoL and foot and ankle PROMs . This clPain management, despite high levels of patient-reported chronic pain, was poor with less than half the cohort using regular pain medication, with 56% of patients not use pain medication . The comThe development of inhibitors is a major complication of haemophilia management both physically and physiologically , 40, 41.The findings of this study and the associations with decline in HRQoL and foot and ankle PROMs need to be replicated in another sample such as patients changing to novel factor and non-factor treatment therapies to confirm whether ankle haemarthropathy is a major contributor to decline in the haemophilia population. The small sample size of moderate and haemophilia B patients is acknowledged as a limitation of this study and their results should be interpreted with caution. The small sample size highlights the difficulties in undertaking research in rare diseases and obtaining an adequate sample size of subgroups within the selected population. Whilst these samples are small, this study provides focus to the emerging issue of the impact of ankle haemarthropathy outside of severe haemophilia A.In the presence of ankle haemarthropathy HRQoL is poor and foot and ankle PROMs are significantly affected. Pain appears to be a major driver of the decline in outcomes, with patients with ankle haemarthropathy having high levels of chronic pain. The use of an NPRS for average pain over six months is associated with decline in HRQoL and identify the non-physical burden of the patient’s disease at the ankle and other commonly affected joints. Use of a NPRS of average ankle pain over six month period may be used to assess current pain status in clinical practice and direct the use of HRQoL and foot and ankle PROMs. Further research is needed to provide robust evidence in clinical practice for the use of pharmacological and non-pharmacological interventions that may improve pain and prevent the decline in ankle joint health across haemophilia.


The United States FDA has approved daprodustat (DPD) as the first oral treatment option for anemia due to chronic kidney disease (CKD) in dialysis patients. Clinical trials have demonstrated DPD’s efficacy and safety, showing non-inferiority to darbepoetin and suggesting reduced IV iron usage. DPD also holds potential for treating chronic kidney disease anemia in non-dialysis patients and may have benefits for patients with coexisting renal anemia and heart failure, pending further research and trials. The United States Food and Drug Administration (FDA) has approved daprodustat (DPD) for treating anemia due to chronic kidney disease (CKD) for patients undergoing dialysis for at least 4 months . This isAnother Randomized, Double-Blind, Phase 3 Study was carried out in Japanese hemodialysis patients with anemia to compare the effects of DPD and darbepoetin. With most participants obtaining and maintaining hemoglobin levels within the target range, the results showed DPD’s non-inferiority to darbepoetin. Also, it was strongly advised to continuously check the hemoglobin response following the start of the DPD treatment. This study also suggested using less IV iron to regulate hemoglobin in individuals receiving DPD . AnotherDPD has not yet been approved for patients with CKD anemia without dialysis, but ASCEND-ND  trial has demonstrated safety and efficacy of DPD in treating anemia due to CKD in patients not undergoing dialysis. . DPD wouData from the FDA’s adverse event reporting system (FAERS) may indicate an elevated risk of GI bleeding when HIF-PHIs are used to treat renal anaemia. DPD treatment may also raise the risk of vascular calcification in CKD patients with hyperphosphatemia. Serum copper excess may also be noted in some patients in the treatment.Anemia in Heart Failure is a poor prognostic factor in both acute and chronic heart failure. Although anemia in heart failure is multifactorial, renal anaemia is one of the major causes. Coexisting renal and heart failure is reported to be associated with increased mortality . The StuProvenance and peer review: Not Commissioned, externally peer-reviewed.


Posterior chamber phakic intraocular implantable collamer lens (ICL) implantation is an effective surgical option for the management of myopia. Over the past few years, the number of ICL surgeries has significantly increased. Postoperative inflammation and endophthalmitis are among the most serious complications after successful ICL surgery. Sometimes, when the blepharospasm is removed at the end of surgery, a small amount of the ocular surface fluid will flow into the anterior chamber, which can lead to an increased risk of infection and inflammation. However, little attention has been paid to this phenomenon.We conducted a retrospective study to compare the incidence of extraocular fluid inflow into the eye through the clear corneal incision (CCI) at two different positions .n = 58) or temporal CCI ICL implantation (n = 58) at our hospital from October to December 2021. The incidence of conjunctival sac fluid entering the anterior chamber after eyelid fixative was removed was compared in both groups.A total of 116 patients with myopia underwent superior CCI ICL implantation (p < 0.05).Both groups were well matched in all parameters. Ocular surface fluid inflow into the anterior chamber was significantly higher in the superior CCI group  than in the temporal CCI group  (In the patients with ICL implantation, the temporal CCI was better than the superior CCI in avoiding the ocular surface fluid inflow into the anterior chamber, and the potential risk of infection and inflammation was lower. HowevWe hypothesized that the difference in the location of the CCI may be an important factor in conjunctival sac fluid inflow. In this study, we aimed to determine whether temporal CCIs have significantly better wound sealing ability than superior CCIs by comparing the occurrence of conjunctival sac fluid entering the anterior chamber when the eyelid fixing piece is removed at the end of the operation.2.2.1.Between October and December 2021, a total of 116 patients with myopia who underwent ICL implantation at our hospital were included in the study. The retrospective clinical study was approved by our hospital’s Biomedical Ethics Review Committee and adhered to the principles of the Helsinki Declaration. All participants were between the ages of 18 and 40 years and had an anterior chamber depth > 2.8 mm, anterior chamber angle 30° to 40°, and corneal diameter > 10.6 mm. Patients with keratopathy, history of previous eye surgery (including eyelid surgery), eyelid abnormality, and pupil displacement were excluded. Patients were divided into two groups based on the position of CCI. A total of 58 patients underwent temporal CCI and 58 underwent superior CCI.2.2.A complete ophthalmologic examination was performed the day before surgery. Preoperative assessments included best corrected visual acuity, intraocular pressure, slit lamp examination, fundus examination, ultrasound biomicroscopy, corneal topography, anterior segment optical coherence tomography, and B-scan ultrasonography. Topical antibiotic drops were administered prior to surgery and were continued for 1 week postoperatively. All surgeries were performed by the same surgeon with experience in phakic intraocular lens implantation. The surgeon was right-hand dominant. On the day of surgery, the patient underwent pupil dilation before surgery. After topical anesthesia by the Promecaine hydrochloride eye fluid, a standard two-plane 2.8-mm CCI(2.8 mm 45°Bevel Up(BVI Beaver) Xstar Safety Slit Knife) was created, and the incision tunnel was 2 to 3 mm long. Except for the incision site, all other surgical steps in the two groups were identified as follows: ICL was inserted into the anterior chamber, viscoelastic material (iviz MEDICAL SODIUM HYALURONATE GEL) was injected into the anterior chamber, and the ICL was adjusted to the posterior chamber. The viscoelastic agent was then completely replaced with a balanced salt solution. A watertight corneal incision was left unsutured. At the end of the operation, two ophthalmologists evaluated the self-sealing properties of CCI. When the lid retractor was removed, the same two ophthalmologists observed and recorded whether the ocular surface fluid flowed into the anterior chamber again under the microscope (Zeiss Lumera 700). All operations were videotaped for review. Post-operative follow-up was administered regularly, and any changes in ocular inflammation and visual acuity were recorded.2) test. The statistical significance was evaluated at 0.05 level, and all analyses were performed using SPSS 26.0 .The association between surgical incision location and the incidence of ocular surface fluid inflow into the anterior chamber was determined using the chi-square (χ3.p = 0.67), white-to-white distance (p = 0.506), central cornea thickness (p = 0.279), and keratometrics (p = 0.52). Conjunctival sac fluid flowing into the anterior chamber was observed in one of 58 (1.7%) in the horizontal CCI group and in 25 of 58 (47.1%) in the superior CCI group (p < 0.05).Our study population consisted of 116 patients of whom 58 eyes underwent temporal incision ICL and 58 eyes underwent superior incision ICL. Baseline demographic data  were similar between the groups . In the CI group . Figure ss p = 0.79, and k4.Our study showed that ocular surface fluid inflow in the anterior chamber after removing the lid retractors was more common with superior CCI than temporal CCI. Therefore, the self-sealing properties of unsutured temporal CCI were better than superior CCI. This is thus far the first study to report the differences between superior and temporal CCI with respect to the conjunctival sac fluid inflow the anterior chamber. Melvin et al.  demonstrStaphylococcus epidermidis, Staphylococcus aureus, and various Streptococcus spp.  for the publication of any potentially identifiable images or data included in this article.HW, YT, JD, LT, and LW contributed to the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The management of refractory occipital neuralgia (ON) can be challenging. Selection criteria for occipital nerve decompression surgery are not well defined in terms of clinical features and best preoperative medical management.In total, 15 patients diagnosed with ON by a board-certified, fellowship-trained headache specialist and referred to a plastic surgeon for nerve decompression surgery were prospectively enrolled. All subjects received trials of occipital nerve blocks (NB), at least three preventive medications, and onabotulinum toxin (BTX) prior to surgery before referral to a plastic surgeon. Treatment outcomes included headache frequency (headache days/month), intensity (0–10), duration (h), and response to medication/injectable therapies at 12 months postoperatively.p < 0.01), intensity was 4 (0–6) (p < 0.01), and duration was 10 (0–24) h (p < 0.01). Median patient-reported percent resolution of ON headaches was 80% (70–85%). All patients reported improvement of comorbid headache disorders, most commonly migraine, and a reduction, discontinuation, or increased effectiveness of medications, NB and BTX.Preoperatively, median headache days/month was 30 (20–30), intensity 8 (8–10), and duration 24 h (12–24). Patients trialed 10 (±5.8) NB and 11.7 (±9) BTX cycles. Postoperatively, headache frequency was 5 (0–16) days/month (All patients who underwent treatment for refractory ON by a headache specialist and plastic surgeon benefited from nerve decompression surgery in various degrees. The collaborative selection criteria employed in this study may be replicable in clinical practice. Occipital neuralgia (ON) is a disabling headache disorder that involves lancinating pain in the distribution of the greater occipital nerves (GON), lesser occipital nerves (LON), and/or third occipital nerves (TON). The GON is most frequently involved and presents with pain that originates in the neck or skull base and radiates superiorly toward the fronto-orbital regions . Less frAccording to the International Classification of Headache Disorders Third Edition ICHD-3) diagnostic criteria, ON involves pain of shooting, stabbing or sharp in quality, palpation tenderness in the distribution of the involved nerve(s), and improvement of symptoms with nerve blocks (NB) , neurostimulation, and surgical nerve decompression are therapeutic options. Although RFA has demonstrated efficacy for the treatment of ON, improvement of pain is often temporary and complications include permanent iatrogenic nerve injury, which can result in reduced effectiveness of subsequent peripheral nerve sparring decompression procedures , 16. ImpNerve decompression surgery is indicated in patients who have failed management with conservative therapies. The principles of occipital nerve decompression surgery include the release of affected occipital nerves at all possible compression points and cushioning of the nerve to avoid scarring –21. The Currently, nerve decompression surgery is underrecognized as a possible treatment option for patients with refractory ON. Education regarding the diagnosis of ON and the role of surgical treatment is necessary to broaden and improve treatment algorithms for ON. The objective of this study is to describe the clinical features, treatment path, selection process, and outcomes of occipital nerve decompression surgery in patients with refractory ON under the care of both neurologists and plastic surgeons.Institutional review board approval was obtained at the Massachusetts General Hospital in Boston, Massachusetts, with all patients providing informed consent. This prospective case series includes 15 consecutive patients who were managed and referred by a single-board certified, fellowship-trained headache specialist, and neurologist (PGM) to a board-certified plastic surgeon (WGA) for ON treatment occipital nerve decompression surgery between 2015 and 2022. Patient selection criteria for nerve decompression surgery candidacy were based on five internal selection criteria formulated by the neurologist and plastic surgeon:Diagnosis of ON based on the ICHD-3 criteria preferably by a headache specialist/neurologist.At least 15 headache days/month with failure of at least three different oral preventative medications , large volume occipital NB (6 cc of 0.75% bupivacaine without steroids), and at least three cycles of BTX injections.Investigation of other potential causes of ON-like headaches including cervical spine MRI and evaluation and management by a physical therapist who has expertise in cervical pathology including ON.An identifiable trigger/pain point along the course of the GON, LON, and/or TON using pain sketches, demarcation by the patient with an index finger, tenderness/Tinel sign, +/- a positive Doppler, suggesting the site of anatomic compression evaluated by the surgeon.A positive NB response was performed by the surgeon at the presumed site of compression. Nerve block response was defined as at least a 50% relative reduction of ON headache intensity with a duration of at least 24 h.Following occipital nerve decompression surgery, the treatment outcome was evaluated at 12 months postoperatively in terms of headache frequency (headache days per month), intensity , and duration (h), as well as changes in medications, NB and BTX injections. Patients were also questioned about the percent-resolution of ON headaches following surgery based on ON headache frequency, intensity, and duration. Although ON typically involves lancinating pain lasting for seconds to minutes, during a flare, some patients will have volleys of pain, and others will have a baseline steady pain in the same nerve distribution as the ON with superimposed lancinating pain, that is why duration was measured in hours to account for these two common presentations of ON. Patients were also questioned about the effect of nerve decompression surgery on reducing coexisting headaches. Data were collected prospectively using REDCap questionnaires preoperatively and at 12 months postoperatively. Data quantifying the number of preoperative treatments  were retrospectively collected from chart reviews.® software . Descriptive statistics of continuous variables were reported using means and standard deviations or median and interquartile range depending on normality. Frequencies and percentages were used for categorical variables. Paired t-tests were performed to compare preoperative and postoperative ON headache frequency, duration, and intensity. A p < 0.05 was considered statistically significant.Statistical analyses were conducted using SASAnonymized data will be shared by request from any qualified investigator.All 15 patients were included in the final analysis. Patients were predominantly female (80%). The average age of ON onset was 20 (±8) years. The time between the onset of ON headache and surgical decompression averaged at 19.9 ±13.6) years. Prior to nerve decompression surgery, median headache days per month was 30 (20–30), duration was 24 h (12–24), and intensity was 8 (8–10). ON was bilateral in 13 patients (86.7%) and unilateral in 2 patients (13.3%). All patients were diagnosed with at least one additional headache disorder. Most patients  had coexisting chronic migraine in the form of holocephalic throbbing pain, difficulty concentrating, photophobia, phonophobia, and nausea during attacks. Other headache diagnoses included persistent posttraumatic headache in three patients (20%), new daily persistent headache (NDPH) with migrainous features in two patients (13.3%), episodic migraine in one patient (6.7%), and trigeminal neuralgia in one patient (6.7%). Twelve patients (80%) reported a history of head or neck injury prior to ON onset. Patient demographics and ON headache characteristics are presented in .6 years.Preoperatively, all patients trialed at least three different pharmacologic classes of preventive medications, among which three patients (20%) were on no preventative medications prior to surgery due to lack of efficacy and/or side effects. An average of 11.7 (±9) BTX injection cycles were administered per patient. At the time of surgical screening, BTX had been discontinued in one (6.7%) patient and had reduced effectiveness over time in 6 patients (40%). An average of 10.2 (±5.8) NB injection cycles were performed per patient. Among the study patients, the maximum duration of relief after an NB was 3 months, but unfortunately that duration of benefit was not sustained with subsequent blocks, which prompted surgical evaluation. One (6.7%) patient had undergone previous radiofrequency ablation (RFA), which provided only temporary relief. Twelve (80%) patients reported having undergone physical therapy. Other treatment modalities included acupuncture, chiropractic therapy, and meditation with limited improvement. The average duration of medical management by the referring headache specialist before referral to the plastic surgeon for nerve decompression surgery was 3.9 (±2.8) years.Patients underwent bilateral  or unilateral  greater occipital nerve (GON) decompression. A thickened trapezius fascia overlying the GON was observed intraoperatively in 12 (80%) patients . Any conp < 0.01), intensity was 4 (0–6) (p < 0.01), and duration was 10 (0–24) h (p < 0.01). In terms of lancinating ON pain, the median patient-reported percent resolution was 80% (70%−85%). In 4 (26.7%) patients, 100% resolution was reported, in 5 (33.3%) patients, ≥80% resolution was reported in 4 (26.7%) patients, ≥50% resolution was reported, and in 2 (13.3%) patients, ≤ 20% resolution was reported. All patients reported a reduction or discontinuation of at least one class of medications. In 11 (73.3%) patients, medications were reported to be more effective after surgery as compared to preoperatively. All patients reported increased effectiveness and/or reduced frequency of needed occipital NB or BTX injections after surgery. One patient completely stopped all medications, BTX, and NB.At 12 months postoperatively, median lancinating ON headache frequency was 5 (0-16) days/month  for < 48 h at the time of surgical evaluation. After bilateral GON decompression, the patient initially reported 95% relief at 3 months postoperatively, but her ON headache returned predominantly on the right side, reporting an overall 0% resolution of her ON headaches at 12 months. The patient did, however, report discontinuing antiemetics and increased efficacy of NB. Reoperation was performed with GON transection and nerve end reconstruction on the side of the predominant ON headache and repeat GON decompression on the other side. At 12 months after reoperation, the patient reported a 95% resolution of her occipital pain.The second patient who reported < 50% resolution was diagnosed with ON, chronic migraine, and cervical radiculopathy status postmicrodiscectomy. The onset of ON was with no known initiating factor or history of head or neck injury. The patient reported intractable pain with multiple ED visits. At the time of surgical evaluation, NB provided significant relief (>50%) but for < 48 h. After 32 years since ON onset, the patient underwent unilateral GON, LON, and TON decompression. At 12 months postoperatively, she reported only a 20% resolution of ON headache with a reduction in the intensity of her ON headaches but not in frequency or duration. Postoperatively, she reported discontinuation of pregabalin, reductions in opioid and antiemetics, and better efficacy of medications. She did not endorse any changes in the use of BTX and NB. This patient did not undergo reoperation; however, given her diffuse body pain, she was seen in a peripheral nerve clinic and was diagnosed with small fiber neuropathy. During 2023 follow-up appointments, this patient's ON and migraine have been under relatively good control with 10 or fewer severe headache days per month as compared to her small fiber neuropathy pain, which has been daily and disabling.This case series (1) described the clinical features of patients with refractory ON amenable to surgical treatment, (2) demonstrated that all patients benefited from occipital nerve decompression surgery to varying degrees, and (3) suggests that the collaborative selection criteria employed by neurologist and surgeon may be replicable in clinical practice.The clinical diagnosis of ON is challenging, and its true prevalence is unknown. Although previous studies have reported on the clinical features of ON, few have described the features of chronic refractory cases potentially amenable to surgical decompression , 31–36. First, we observed a higher prevalence of bilateral ON headache compared to unilateral ON headache. While the ICDH-3 acknowledges that ON can manifest as both unilateral and bilateral, previous studies have reported a predominance of unilateral ON, which contrasts with the results from our series , 36, 37.Second, patients frequently presented with pain radiating from the occipital to the fronto-orbital regions, which can be clearly visualized with the use of pain drawings. Such distribution of pain has been documented by others and is thought to be due to either extracranial anastomoses of the occipital nerves with trigeminal nerves or due to referred pain mechanisms at the level of the trigeminocervical complex , 36. SinThird, in addition to experiencing short paroxysms of lancinating pain, shooting, stabbing, or sharp in quality and lasting from a few seconds to minutes, patients in our series presented with constant achy pain in the same distribution. In clinical practice, this is commonly seen with ON as well as in other paroxysmal pain disorders such as sciatica and trigeminal neuralgia. This is why the ICHD-3 diagnostic criteria for trigeminal neuralgia include subtypes of the purely lancinating form and the form that has a steady baseline pain in the same distribution as the superimposed lancinating pain . AlternaFurthermore, this study highlighted the high prevalence of coexisting headache disorders among patients with ON. The coexistence of ON with other primary headache diagnoses such as migraine may be an underrecognized phenomenon and has been reported to be seen in up to 25% of patients presenting to a headache specialty clinic . In our We found that all patients in our series benefited from nerve decompression surgery to varying degrees. Resolution of lancinating ON headache was evidenced by reductions in frequency, intensity, and duration of headaches, as well as significant reductions and/or increased effectiveness of medications, BTX, and NB at 12 months.Nerve decompression surgery has been previously shown to be an effective treatment option for refractory ON , 39–43. It could be posited that, given the substantial disease burden and the treatment-resistant nature of all patients in this series prior to surgery, this particular cohort of ON patients may exhibit a higher degree of surgical failure as compared to patients in other studies. However, our findings did not align with this expectation. Not only did patients experience resolution of ON  but patients also reported reductions in comorbid headache disorders, most frequently migraine.In our series, two patients reported < 50% resolution of ON headache at 12 months postoperatively. However, as illustrated in the first patient, revision surgery may be needed at times to achieve >50% resolution. Both cases prompt us to better understand risk factors associated with poor outcomes or reoperation.Risk factors have been previously described in the literature and include poor NB response, atypical pain drawings, RFA, and cervical spine disorders. While most patients in our series had days to weeks of ON headache relief with NB at the time of screening, both patients had the lowest duration lasting < 48 h. It has been reported that a NB response of < 24 h is associated with worse outcomes following nerve decompression surgery –51. SuboThe favorable outcomes observed following occipital nerve decompression surgery in our cohort suggest that the collaborative selection criteria employed in this study could be replicable in clinical practice. The listing of these criteria is not arranged in a temporal order and need not be considered in any particular order without overlap. For example, during the initial visit, the patient may receive a NB, a prescription for gabapentin that can be initiated by the patient depending on NB response, as well as a referral for physical therapy.The selection criteria for surgical candidacy, which involve assessments by both a headache specialist and a surgeon, highlight the importance of a multidisciplinary approach for optimal treatment of patients with refractory ON. While the headache specialist/neurologist plays a critical role in the diagnosis of refractory ON and in providing the best preoperative management before referral, the surgeon evaluates potential compression sites that can be surgically addressed to alleviate nerve compression symptoms. This relationship is bidirectional, as the surgeon is to refer patients, especially those who are self-referred or referred by their primary care physician, to a headache specialist/neurologist to confirm the diagnosis of ON and ensure that the patient has failed the best medical/interventional management before proceeding with surgery. These multidisciplinary selection criteria may guide the development of future treatment algorithms for patients with refractory ON.This study was limited by the lack of a control group, challenging the establishment of a cause-and-effect relationship between the surgical intervention and the observed outcomes. Although there are several studies in the literature highlighting the significant morbidity associated with ON as well as numerous studies reporting on the effectiveness of nerve decompression surgery, the risk of a placebo effect is particularly high in headache patients and should be acknowledged.In conclusion, ON can cause disabling headaches and may be highly underdiagnosed.The frequent coexistence of ON with other headache disorders likely contributes to its underdiagnosis. Therefore, screening for ON should be considered among other headache patients to improve ON diagnosis and treatment.Furthermore, we demonstrated that for patients with ON that is refractory to conservative therapies, occipital nerve decompression surgery can be an effective treatment, improving lancinating ON pain as well as the effectiveness of medications, NB and BTX. Additionally, surgical treatment of ON was able to improve coexisting headache disorders such as migraines.Therefore, the collaborative selection criteria employed in this study neurologist/headache specialist and surgeon may be replicable in clinical practice. Future efforts should be made to include and define occipital nerve decompression surgery within current and future ON treatment algorithms.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by Massachusetts General Hospital, Boston. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.WA: Conceptualization, Methodology, Project administration, Resources, Validation, Writing—review & editing. KR: Data curation, Formal analysis, Writing—original draft. KP: Data curation, Writing—original draft. MH: Data curation, Writing—original draft. LG: Conceptualization, Methodology, Project administration, Supervision, Validation, Writing—review & editing. PM: Conceptualization, Methodology, Project administration, Supervision, Validation, Writing—review & editing.