Chronic post-surgical pain (CPSP) after hysterectomy has been recognized as a major clinical problem in the Western World. Reports on post-hysterectomy pain are relatively scarce in China. The aim of the current study was to prospectively investigate the incidence and the potential risk factors of CPSP at 3 months following hysterectomy in Chinese population.We assessed and collected data on preoperative socio-demographic characteristics, preexisting pain, anxiety and depression, sexual satisfaction, intra-operative variables, and acute postoperative pain intensity in a cohort of 870 women undergoing hysterectomy. The participants were interviewed to determine their suitability to diagnostic criteria of CPSP 3 months later. Logistic regression analyses were subsequently performed to identify predictors for CPSP.The incidence of CPSP at 3 months after hysterectomy was 27.7%. Most of the women with CPSP suffered from mild pain and had a slight impact on daily life with sleep and emotion functional limitation. Risk factors for CPSP after hysterectomy were preoperative anxiety, depression, pelvic pain, preexisting pain, very-moderate sexual dissatisfaction, and acute postoperative pain at movement. Intra-operative dexmedetomidine infusion with 0.5 μg/kg/h was associated with a decreased incidence rate of chronic post-hysterectomy pain.Twenty-eight percent of patients after hysterectomy in southern Jiangsu china had CPSP with 92% of those women describing it as mild with sleep and emotion functional limitation. Patients with preoperative anxiety and depression, poor sexual satisfaction, preexisting pain, and acute postoperative pain on movement have been identified to be at risk to develop CPSP. Preoperative anxiety and depression, poor sex satisfaction, presence of pre-surgical pain elsewhere, and acute postoperative pain on movement are risk factors for CPSP in a Chinese population.Chronic post-surgical pain (CPSP) is a major clinical problem which could lead to impaired physical function and reduced quality of life. Several studies have been published on development of CPSP following hysterectomy in western population, with the incidence being to be between 5 and 50% , 2. The This prospective observational cohort study was approved by the ethics committee of the affiliated Yixing Hospital of Jiangsu University, China. Patients admitted for hysterectomy for benign indications from March 2014 to March 2016 in the affiliated Yixing Hospital of Jiangsu University were invited to participate in this study. Inclusion criteria: (1) age between 18 and 75 years, (2) able to understand consent procedures and questionnaire materials, (3) total or subtotal hysterectomy with or without oophorectomy. Patients who agreed to participate were explained about the procedures, and they signed the consent form. All participants were interviewed in person both preoperatively and 48 h postoperatively by a trained anesthetist. The follow-up interviews were completed 3 months after surgery. Exclusion criteria were cognitive impairment, a history of cancer, malignant uterine tumors, surgery-related infection.Study-specific questionnaires were given to the patients for self-administration during the preoperative screening visit before surgery. The questionnaire consisted of questions on patients’ age, education, employment, body mass index (BMI), smoking, alcohol abuse, indications for hysterectomy, co-morbidities, and a history of caesarean section, laparotomy or laparoscopy.Hospital Anxiety and Depression Scale (HADS) in a Chinese version was used for screening anxiety disorders and depression, considering the influence of psychological factors on chronic pain. HADS performed well in assessing symptom severity and in diagnosing anxiety disorders and depression in various populations, with significant internal consistency and concurrent validity . A systeThe Female Sexual Function Index (FSFI) is the most widely used instrument for female sexual health, comprising six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain . We asseAssessment of pain and its consequences were performed by a trained anesthetist, in face-to-face interviews, before surgery, 48 h after surgery, and at 3 months after surgery. The Chinese version of brief pain inventory-short form (BPI-SF) was used to estimate the pain severity and the impact on daily life at every interview. The BPI-SF contained 11 items which references pain existed during the past 24 h. It was consisted of 2 subscales: pain severity (NRS: 4 items) and pain interference (7 items). Scores of NRS ranged from 0 to 10 .A variety of methods including median lower abdominal approach, Pfannenstiel, vaginal, laparoscopic hysterectomy (LH), or laparoscopic assisted vaginal hysterectomy (LAVH), total or subtotal hysterectomy with or without oophorectomy have been used for removing the uterus and/or ovaries. Anesthetists determined the anesthesia protocol according to the surgery and custom, involving total intravenous anesthesia (TIVA), inhalation anesthesia (IA), epidural anesthesia. Intra-operative sedative and analgesic drugs, duration of operation, blood loss were collected. Postoperative analgesia and complications were also recorded from the hospital database.An experienced anesthetist, who was in charge of pain questionnaire, visited patients within 48 h after hysterectomy. Pain related data were collected using BPI-SF, including the NRS value at rest and at movement.BPI-SF was completed, when patients return to hospital at 3 months after hysterectomy. If diagnosed of CPSP, a douleur neuropathic 4-questionnaire (DN-4) was followed to ascertain whether the pain was a neuropathic Pain (NP). DN-4 is an instrument evaluating pain characteristics through 10 items, total score being 10 , 10. If We defined CPSP following hysterectomy based on the diagnosis criteria from the International Association for the Study of Pain (IASP)  and prop2) were used to analyse socio-demographic, clinical, and psychological measures. Univariate logistic regression analysis was performed to test the influence of possible risk factors on CPSP at 3 months after surgery, and candidate covariates were chosen based on statistical significance or possible clinical importance. Only covariates with P-values less than 0.25 in the univariate analysis were entered in the multivariate model. Then, multiple logistic regression analyses were used to determine risk factors for CPSP. Two-sided P-values of 0.05 were considered statistically significant.SPSS  was used to analyse all data. Categorical data were presented as numbers and percentages. Chi-square tests  were excluded after surgery for the following reasons: (1) surgery cancelled, (2) inability to complete the questionnaire because of postoperative complications or intensive care unit admission, and (3) refusal to continue the whole interview; and another 41(13 + 8 + 20) were deleted because of: (1) Malignancy outcome, (2) postoperative infection, and (3) follow-up interview 3 months after surgery uncompleted. A total of 870 patients were finally enrolled in the analysis. According to the study definition, of 870 patients, 241 (27.7%) have been found to have CPSP and the remaining patients (629/870 -72.3%) were free of CPSP 3 months after hysterectomy. Patient inclusion is illustrated in the flow chart in Fig. Table Table P < 0.25 for the comparisons between patients who did and did not develop chronic persistent pain. The independent predictors for CPSP following hysterectomy were indentified with preoperative pain, anxiety, depression, sexual dissatisfaction, postoperative acute pain intensity NRS ≥ 3 with 24 h at movement. Meanwhile, Intra-operative dexmedetomidine infusion with 0.5 μg/kg/h was associated with a decreased incidence rate of chronic post-hysterectomy pain.As Table In our prospective cohort study conducted on 870 women who underwent hysterectomy, the incidence of CPSP was 27.7% at 3 months after surgery. Bransborg et al.  reportedThe incidence of neuropathic pain ranged widely after various types of surgery. The prevalence of probable or definite neuropathic pain among patients with chronic pain was 52-66% after thoracic surgery, 68-74% after breast surgery, 31-45% after hernia repair, and 6-9% after total hip and knee arthroplasty . A multiWe found most of patients with CPSP experienced mild pain with a low frequency. A few women reported moderate to severe pain. Pain is localized to the area of surgical incision and pelvis. Our study also found that CPSP had a slight negative impact on daily life of patients undergoing hysterectomy, particularly in mood and sleep.Previous research has identified multiple risk factor for CPSP in different surgeries, including age, employment, BMI, education, smoking, preoperative co-morbidities , 18–20. Previous surgery has been recognized as a risk factor for development of chronic pain after hysterectomy. In present study, prior surgery including cesarean section, laparoscopy, and laparotomy were associated with chronic pain in univariate but not in multiple logistic regression analyses.A large body of evidence suggests that the presence of preoperative pain in patients may be related to CPSP –24. Pre-Psychological factors including anxiety and depression, play a critical role in the development of CPSP . A serieThe effect of hysterectomy on female sexual function has been well studied , 30. On Surgical approach associated with nerve damage has been considered as risk factor for CPSP in many operations. Laparoscopy may minimize the trauma and reduce the risk of nerve injury, leading to a decreased incidence of CPSP, which had been verified in laparoscopic hernia repair . Pinto ePostoperative epidural analgesia was showed to be related to a reduced incidence of CPSP after abdominal surgery . In our Substantial evidence indicates that intensity of acute postoperative pain was associated with the development of CPSP following hysterectomy , 19, 26.The effect of anesthetics on development of CPSP is still debatable. Ketamine, an NMDA receptor antagonist, usually used as an adjunct peri-operative analgesic, could reduce the rate of CPSP via a mechanism of preventing peripheral and central sensitizations . AdminisOur study has some limitations that need to be addressed. First of all, the study relied on the subjective self-report, which might be influenced by the psychological and mental status of patients. Second limitation was the data excluded, which could impact the accuracy of the results. Another defect was that most of patients were local residents, therefore, the results of the current study cannot be generalized to women population in China. Lastly, in some cases, economic factors may influence the choice of surgical approach.Despite these limitations, one advantage of this study was the prospective design. Patients in our study were asked to report pain at interviews, rather than recalling previous pain experiences in retrospective studies. Another merit of this study was the diversity of the treatments, which allows investigating multiple variables.In summary, 28 % of patients after hysterectomy in southern Jiangsu china had CPSP with 92% of those women describing it as mild. Preoperative anxiety and depression, poor sexual satisfaction, presence of pre-surgical pain, and acute postoperative pain on movement are risk factors for development of CPSP in women in China. Intra-operative dexmedetomidine infusion with 0.5 μg/kg/h is associated with a decreased incidence of chronic post-hysterectomy pain. These results suggest that preventive strategies should be targeted at preoperative psychosocial care and postoperative pain management. A further controlled prospective randomized trial on dexmedetomidine is needed.


The aim of this study was to compare post-operative pain following one-visit pulpectomy and placing stainless steel crown (SSC), with two-visit treatment (performing pulpectomy at the first visit followed by placing SSC at the next visit one week later) in vital pulp of primary molars with carious involvement. In this randomized clinical trial, 100 children aged 6-12 years with a carious primary molar tooth in need of pulpectomy were randomly divided into two groups of 50 each. In one-visit group, pulpectomy and placement of SSC were carried out at the same appointment. In two-visit group, pulpectomy of root canals was carried out at the first visit and placement of SSC was performed at the second visit one week after the first appointment. Post-operative pain was recorded using visual analogue scale (VAS) during one week after each treatment visit. P˃0.05 for both comparisons). Findings revealed that in the two-visit (pulpectomy) group during first three days and 4-7 days after the first treatment appointment, pain felt by the children was significantly lower than that felt by the one-visit group at the same time period (P˂0.0001 for both comparisons). Moreover, children in two-visit (pulpectomy) group consumed significantly lower amount of analgesics than those in the one-visit group (P<0.0001). No significant difference was found in the mean age and gender distribution between the two groups (No significant difference was found between pain felt by children during the first three days following one-visit pulpectomy and placement of SSC at the same appointment. Therefore, one-visit treatment of vital primary tooth is recommended. Pain is an unpleasant multidimensional experience which comprises strong sensory and cognitive components . The preFear of pain following dental treatment can cause parents to prevent their children from visiting dentists for dental care . ChildreThe main purpose of pulp treatment in primary teeth is to maintain and preserve them as the important parts of the dental arch to provide the ability to chew and speak, to maintain required space for the permanent teeth to replace the primary teeth and to effectively prevent damages caused by tooth decay . To achiThis randomized clinical trial was approved by the Ethics Committee of Kerman University of Medical Sciences and was recorded at Iranian Registry of Clinical Trials (IRCT) center (IRCT2016122231473N1). Moreover, given α=5% and power of 80%, each group required a sample size of 50 patients.A total 0f 100 participants met the qualifications required to enter this prospective, randomized and single-blind study. All the participating patients received treatment at the postgraduate clinic of the Endodontic Department of Kerman Dental School, Iran (from August 2016 to February 2017). To randomize the patients, each patient was assigned a number. The numbers in each group were written on paper, and each one was kept in a separate sealed opaque envelope. Each patient was required to select one of the envelopes and was assigned to one of the groups according to the number. It should be noted that after the nature of the procedure and the possible risks and benefits was explained, written informed consent was obtained from all participants. To assess pain levels, a visual analogue pain scale (VAS) was utilized. Furthermore, the other form was applied to record analgesic consumption after they felt pain. The VAS was explained to the parents and children, instructing them how to use it. They were asked to fill the VAS before local anesthesia was administered to rate their preoperative pain. The following inclusion and exclusion criteria were used. Inclusion criteria were as follows: 1- Vital primary molar teeth with active bleeding at the time of access cavity preparation. 2- The teeth should not have any sign of clinical and radiographic evidence indicating pulp necrosis. 3- Root resorption should be less than two-third of the root. 4- The restorable tooth should be curable. 5- The children should be cooperative. 6- There must be at least one molar with irreversible pulpitis signs such as sensitivity to coldness or heat. 7- The patients should require pulpectomy treatment. On the other hand, exclusion criteria were: 1- Suffering from a systematic disease. 2- There must be a follicular or dentigerous cyst beneath the primary molar teeth. 3- There must be at least one-third of pathological decay in the root caused by fistulous sinus track. 4- There must be more than two-thirds decay of the root length. 5- Lack of tooth isolation. 6- Advanced internal resorption. 7- Periapical radiolucency covering permanent tooth bud. 8- Inability to complete questionnaire by the child and parents within one week after the treatment. 9- Existence of cases like internal resorption, widening of the PDL, radiolucency, degeneration and calcification before beginning the study .Patients were randomly divided into two one-visit (a combination of pulpectomy and placing stainless steel crown (SSC) in one-visit) and two-visit treatment (performing pulpectomy at the first visit followed by placing SSC at the next visit one week later) groups. One-visit treatment was performed as follows: Teeth were anesthetized using 2% lidocaine 1:80000  followed by isolation under rubber dam. Tooth caries were removed using round fine finishing bur .After removing the pulp tissue, if the bleeding did not stop, then under certain circumstances for pulpectomy, barbed broach was utilized to remove pulp tissue from root canals. A H-file  was used to remove the remaining pulp tissue. After removing the pulp from the root, the canals were irrigated with 2% chlorhexidine using syringes. This was an important step in decreasing microbial contamination. Then canals were dried using paper cone. When the bleeding was stopped and the canals got dried, the root canal walls were covered using paper cones dipped with a mixture of diluted zinc oxide-eugenol (ZEO) pulp. Then a thick mixture of medical paste in the form of small granules was compressed into the canals. Root canal pluggers were used to press the materials in the root canals. Radiography was used to assess the internal structure of the obturation. Eventually, the tooth was restored using SSC. Pain and analgesic consumption questionnaire was completed by the children and their parents within a week after the treatment. Two-visit treatment was conducted as follows: in the first visit, pulpectomy treatment was performed entirely by specialized assistant and the questionnaire was completed by the children and their parents within a week after the treatment. In the second visit, the tooth was restored using a SSC by a pediatric dentist (Blinded) and when the treatment was completed; the children and their parents recompleted the questionnaire within a week. So, the process of pulpectomy treatment was carried out entirely by a specialized pediatric assistant and SSC was bonded to the tooth by the plan executor (pediatrician). In order to control the pain at home, the parents were instructed to administer 325 mg of acetaminophen  to their children every six hours and record the numbers of pills taken by the children in the questionnaire. Participants were given two forms to complete. The first one was VAS form to record the severity of pain from 0 to 9 during a week after the first treatment appointment, and the other form was used to record analgesic consumption after they felt pain -19. VAS Statistical analysis:P<0.05 were considered statistically significant. Statistical analysis was performed using SPSS version 21 for windows .Continuous variables were displayed as mean ± standard error of mean (SEM), and qualitative variables as numbers (percentage). Chi-square test was used to compare the qualitative variables. Independent Sample t-test was used to compare the mean of pain between groups. The Having met the qualifications for participating in the study, none of the selected one-hundred patients was excluded from the research, thereby continuing the course of steady as demonstrated in n=26) and boys (n=24) accounted for 52% and 45%, respectively, of the 50 participants in the one-visit group. In the two-visit group, girls (n=24) and boys (n=26) constitute 45% and 52%, respectively, of the all participants. No significant difference was found in the mean age and gender distribution between the two groups.P<0.0001 for both comparisons). However, no significant pain difference felt by children was observed between the two-visit (SSC) and one-visit groups at both the first three days after the first appointment and the rest of the study period . Children in two-visit (pulpectomy) group consumed significantly lower amount of analgesics than those in the one-visit group (P<0.0001). However, no significant difference was found in the mean number of analgesics between two-visit (SSC) and one-visit groups (P=0.172).Linearity graph of pain score divided by days after treatment within each three groups is shown in n=42, 84%) and two-visit group  require analgesics (P˃0.05). However, children in the two-visit (pulpectomy) group (28 (56%)) had significantly lower need to analgesics need than those in the one-visit and two-visit (SSC) groups (P˂0.05 for both comparison).There was no significant difference regarding the extended to which the one-visit group (P<0.05). Nowadays, studies related to pain are of particular importance in the field of healthcare around the globe. Despite the great progress that has been made in dentistry, post-treatment pain in tooth root is still an important complication after the treatment. Preventing or minimizing post-treatment pain is an important issue which has been investigated in different studies [Based on the present findings, pulpectomy of primary teeth showed significantly lower pain compared to placement of SSC  children was significantly lower than one-visit and two-visit (SSC) groups during first three days after the first appointment. However, pain felt by children during the first three days following one-visit pulpectomy and placement of SSC at the same appointment was almost the same. Therefore, one-visit treatment of vital primary tooth is recommended. Due to the complex etiology of pain and limited experience of aggressive treatment among children in this age range, predicting and healing the pediatric pain during the process of treatment and also after dental treatments, should be an integral part of child care.


Our objective was to describe dosing, duration, and pre- and post-infusion analgesic administration of continuous intravenous sub-dissociative dose ketamine (SDK) infusion for managing a variety of painful conditions in the emergency department (ED).We conducted a retrospective chart review of patients aged 18 and older presenting to the ED with acute and chronic painful conditions who received continuous SDK infusion in the ED for a period over six years (2010–2016). Primary data analyses included dosing and duration of infusion, rates of pre- and post-infusion analgesic administration, and final diagnoses. Secondary data included pre- and post-infusion pain scores and rates of side effects.A total of 104 patients were enrolled in the study. Average dosing of SDK infusion was 11.26 mg/hr, and the mean duration of infusion was 135.87 minutes. There was a 38% increase in patients not requiring post-infusion analgesia. The average decrease in pain score was 5.04. There were 12 reported adverse effects, with nausea being the most prevalent.Continuous intravenous SDK infusion has a role in controlling pain of various etiologies in the ED with a potential to reduce the need for co-analgesics or rescue analgesic administration. There is a need for more robust, prospective, randomized trials that will further evaluate the analgesic efficacy and safety of this modality across a wide range of pain syndromes and different age groups in the ED. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA)/glutamate receptor complex antagonist that reduces pain by diminishing central sensitization, hyperalgesia, and “wind-up” phenomenon at the level of the spinal cord  and central nervous system.4A large body of evidence supports the use of SDK analgesia administered either as an adjunct to opioids or as a single agent in the ED and in the prehospital setting that leads to significant pain relief and opioid sparing.5The goal of our investigation was to evaluate feasibility , analgesic efficacy, and side-effects profile of continuous SDK infusion in order to manage various acute and chronic painful conditions in the ED. We hypothesized that this analgesic modality can be used in the ED and its administration might result in adequate pain relief with minimal risk for adverse effects.We retrospectively reviewed medical charts of patients who were admitted to our ED and received continuous SDK infusion over a six-year period (2010–2016). The study was conducted at a 711-bed urban community teaching hospital with an annual ED census of greater than 120,000 visits. In our ED, ketamine infusions are prepared by the ED pharmacists and administered by nursing staff via infusion pump. The continuous, weight-based SDK infusion order sets are built into our electronic medical record (EMR) system (Allscripts™) with a starting dose of 0.15mg/kg/hr that is titrated upward every 30 minutes by 2.5–5mg as determined by the treating physician. We defined pre-infusion analgesia as an administration of any analgesics deemed necessary by a treating ED clinician prior to initiation of continuous ketamine infusion. Post-infusion analgesia was defined as an administration of opioid and/or non-opioid analgesic from the end of the infusion until patient’s final disposition from the ED. All data with respect to doses and types of analgesics administered to each patient enrolled in the study  was aggregated and described as a percentage of total amount of analgesics given pre- and post-infusion. All patients underwent continuous cardiac monitoring and pulse oximetry. This study was approved by the hospital’s institutional review board.What do we already know about this issue?SDK analgesia administered either as an adjunct to opioids or as a single agent in the ED and in prehospital settings leads to significant pain relief and opioid sparing.What was the research question?We sought to evaluate the feasibility, analgesic efficacy and side-effects profile of continuous intravenous SDK infusion in the ED.What was the major finding of the study?The mean SDK dose was 11 mg/hr with mean duration of 136 minutes, and mean pain scores (NRS) were 7.6 and 2.6 pre-/post-infusion.How does this improve population health?Continuous SDK infusion can be used in the ED for a wide range of acute and chronic painful conditions and age groups either as an adjunct to opioid and non-opioid analgesics or as a single agent.Patients 18 and older presenting to the ED with a variety of acute and chronic painful conditions and receiving a continuous SDK infusion in the ED were eligible for the study. We excluded patients if they received a ketamine infusion for the purpose of sedation, end-of-life care, or received only a bolus dose of ketamine.We performed data collection by querying the ED EMR database. Extracted data included age, sex, chief complaint, final diagnoses, pre- and post-infusion NRS pain score, duration of infusion, analgesics given before and after infusion, and adverse effects.The primary outcomes of the study were the following: 1) mean dose and duration of the continuous ketamine infusion, 2) percentage of patients receiving analgesics before and after ketamine infusion, and 3) percentage of patients receiving SDK bolus dose prior to continuous ketamine infusion. Secondary outcomes consisted of 1) change in pain score before and after infusion administration via standard 11-point NRS score, and 2) overall rates of adverse effects.The data analyses consisted primarily of descriptive statistics. We described baseline characteristics of patients in each treatment group in terms of mean ± standard deviation for continuous variables and frequency (percent) for categorical variables. A student’s t-test was used to compare simple group differences in terms of means , while we used the chi-square test to look at differences in terms of percent rates . We carried out all statistical analyses using SPSS® version 24.We reviewed 2,781 medical records containing orders for ketamine dosing, which occurred between January 2010 and December 2016. Of those, we excluded 2,677 patient records due to ketamine use other than a continuous infusion for analgesia. The remaining 104 subjects receiving a continuous SDK infusion for pain control were enrolled into our study .The mean age was 49.5 years old respectively, with 43% male patients. Mean baseline NRS pain score was 7.63. Most patients presented with chief complaints related to musculoskeletal pain (40.4%) and abdominal pain (36.6%), which roughly correlated with final diagnoses  and 2.The overall mean dose for SDK infusion was 11.26 mg/hr (6.0–22.50 mg/hr) with an overall mean duration of treatment of 135.87 minutes (20–480 minutes). When we compared dose and duration of infusion in four different age groups , we found that patients in the 30–49 age group received the highest mean dose of continuous SDK infusion of 12.17 mg/hr, as well as the longest mean duration of infusion of 140.6 minutes. There was a trend towards lower dosing and shorter duration of infusion in patients 50 years of age and older .Non-opioid analgesics had the highest rates of pre-infusion administration (38.4% of patients). In addition, 11.5% of patients received no analgesics prior to infusion. Post-infusion, opioids constituted the largest class of analgesics administered (23.1% of patients) with 50% of patients receiving no additional analgesics. Furthermore, 59.6% of patients received an SDK bolus before the continuous infusion, and 11.5% of patients received the continuous SDK infusion alone.Furthermore, upon comparing the dose and duration of continuous SDK infusion across the nine final diagnoses, we found that patients with a clinical diagnoses of headache, renal colic, and chronic non-cancer pain received the highest doses of continuous ketamine infusion. Patients with a clinical diagnoses of soft tissue, chronic non-cancer, and abdominal pain on average had the longest duration of ketamine infusion .. Patients with cancer pain also showed a significant difference of not receiving any analgesic from 9.1% pre-infusion to 63.6% post-infusion (p<0.05). These findings were noted despite the fact that abdominal-pain and cancer-pain patients received relatively lower doses of ketamine. While no definitive conclusion can be drawn from this observation, it may suggest a higher rate of analgesic efficacy in the two patient populations. Furthermore, patients with abdominal and cancer pain had reduced requirements for non-opioid analgesics post-continuous ketamine infusion (p<0.05) . Patient.Complete NRS data was not available for all 104 patients. For 53.8% of patients with available pain scores, the mean NRS pain scores were 7.63 (±2.3) pre-infusion and 2.65 (±3.3) post-infusion, resulting in an average pain score decrease of 5.04 . Furthermore, for patients with one of the top three diagnoses of abdominal, musculoskeletal, and neuropathic pain with available pre- and post-pain scores, the mean decrease in pain score was 4.95  for abdominal pain, 4.78  for musculoskeletal pain, and 3.69  for neuropathic pain. Five adverse effects were documented in a total of 12 patients: nausea (5.8%), headache (1.9%), dizziness (1.9%), rash (1.0%), and confusion (1.0%). Ninety-two (88.4%) patients had no documentation of any adverse effects. Two (1.9%) patients presenting with abdominal and renal colic pain required discontinuation of SDK infusion due to severe nausea. Thirty-six (34.6%) patients were admitted to the hospital for further pain control after infusion was completed, which included 13 (12.5%) with abdominal pain, six (5.8%) with cancer pain, five (4.8%) with musculoskeletal pain, five (4.8%) with neuropathic pain, three (2.9%) with sickle cell pain, three (2.9%) with chronic pain, and one (0.9%) with flank pain.The retrospective nature of our study, relatively small sample size, and lack of documented pain scores in 46.2% of patients were the major limitations. As a result, we could not fully evaluate and compare the analgesic efficacy of continuous SDK infusion between different age groups and between different pain syndromes; thus, we could not assert any recommendation with respect to overall pain relief. Furthermore, due to the fact that only 53.8% of patients had documented pre- and post-infusion pain scores and only 59.6% of patients received a ketamine bolus prior to the infusion we could not accurately and reliably compare the difference in improvement of pain scores between patients receiving a bolus dose followed by infusion to infusion only. Additionally, since the primary outcome of the study was the dosing regimen for continuous ketamine infusion, dosages for analgesics given to patients before and after infusion were not abstracted. Lastly, due to the retrospective nature of the study we cannot make any statements regarding the safety of continuous SDK infusion in our ED. Future prospective studies are needed to evaluate the safety and efficacy of SDK infusion in the ED.SDK administration in the form of IV push or short infusion is becoming increasingly popular as a viable adjunct to or even a substitute for opioid analgesics in managing a variety of acute and chronic painful conditions in the ED.5A growing body of literature advocates for use of continuous SDK infusion either as an adjunct to opioids or as a single agent for pediatric and adult patients with predominantly chronic painful conditions. A recent cohort study that included 230 hospitalized patients receiving continuous ketamine infusion demonstrated a 34% decrease in pain score after one day of treatment. In addition 58% of patients achieved equal or greater than 20% overall reduction in pain scores without psychotomimetic side effects requiring therapy. Furthermore, patients with cancer pain and patients with pancreatitis and Crohn’s disease had greater reductions in pain scores.13A retrospective chart review of five pediatric patients with sickle cell disease and acute vaso-occlusive crisis who received continuous ketamine infusion with a dosing range of 0.06 mg/kg/hr to 0.1 mg/kg/hr and duration of treatment from 19 to 90 hours, demonstrated a clinically significant pain reduction in two children and reduction in opioid consumption in one child. Two patients experienced side effects (mainly dysphoria) that resulted in treatment termination in one patient.16Our retrospective chart review demonstrates that continuous SDK infusion has the potential to be used in the ED across a wide range of acute and chronic painful conditions and age groups either as an adjunct to opioid and non-opioid analgesics or as a single agent. The fact that continuous SDK infusion alleviated the need for additional post-infusion analgesia in 60% and 55% of patients with abdominal pain and cancer pain is very encouraging even though we could not fully evaluate the analgesic efficacy of this analgesic modality due to the retrospective nature of this study. In addition, our chart review showed that patients with neuropathic pain and chronic non-cancer pain required higher rates of post-infusion opioid rescue analgesia and a longer duration of ketamine infusion, thus demonstrating that management of such painful conditions in the ED can be very challenging.Lastly, our data showed that continuous SDK infusion can be employed for geriatric patients with a broad range of painful syndromes in the ED, thus adding an additional analgesic modality when opioids and non-steroidal anti-inflammatory drugs are contraindicated.One of the possible barriers to use of continuous SDK infusion are potential administrative concerns regarding an off-label use of an anesthetic agent such as ketamine for managing pain in the ED and on the hospital wards. Departmental and interdisciplinary protocols with clearly specified, patient eligibility criteria as well as indications for and contraindications to SDK infusion should be in place before widespread use of this analgesic modality is considered for implementation.Continuous intravenous SDK infusion does have a role in controlling pain of various etiologies in the ED with the potential added benefit of decreased need for additional analgesia. There is a need for more robust, prospective, randomized trials that will further evaluate the analgesic efficacy and safety of this analgesic modality across a wide range of pain syndromes and different age groups.


The use of tranexamic acid (TXA) in total knee arthroplasty (TKA) has shown good results. Bleeding may cause local complications consequently greater pain and reduced function postoperatively. No study has related the use of TXA to these facts.The aim was to evaluate the effects of TXA haemoglobin, Western Ontario and McMaster Universities Index (WOMAC), pain intensity and flexion gain after TKA.43 patients were randomized and then underwent TKA. TXA was applied to 22 of these patients before closure of the joint capsule. Haemoglobin measurements (mg/dL) were taken preoperatively and 24 and 48 hours after surgery. The WOMAC questionnaire and pain visual analogue scale (VAS) were applied, and flexion gain was measured up to the second postoperative month. Statistical analysis compared the results to determine whether there were differences between the groups for each of the evaluated times.There were differences in favour of the drug 48 hours postoperatively for the haemoglobin variable (p = 0.01), in pain evaluation, 24 and 48 hours, postoperatively (p < 0.01) and in flexion gain, 24 hours after surgery (p = 0.03). There were no significant differences between the groups in the haemoglobin evaluation 24 hours postoperatively, in pain assessment 7 days, 21 days and 2 months, postoperatively, in flexion gain 48 hours, 7 days, 21 days and 2 months, postoperatively and in WOMAC after 2 months.In addition to reducing bleeding, topical TXA improved pain and increased flexion gain in the first hours after TKA.RBR-9b4qgq Accordi1). TXA is a synthetic product that is inexpensive and easily accessible [Intraoperative homeostatic control is important and can avoid possible procedural and transfusion complications in patients with anaemia in the postoperative period , 4. It icessible , 10-12, cessible .Orthopaedics initially hesitated to use this substance, as there was a lack of information regarding the safety of TXA use in relation to thromboembolic events , 21, 22.Intra-articular administration of TXA in TKA has shown good results, effectively reducing the decrease in haemoglobin, the blood loss through drainage and the need for transfusion for up 48 hours, postoperatively , 16. It Therefore, the hypothesis of this study was that, in addition to reducing bleeding, the topical application of TXA at the end of surgery before closure of the joint capsule and surgical incision would be effective in controlling pain and improving functional recovery and flexion gain in the postoperative period of TKA.2The objective was to evaluate the effects of TXA on serum haemoglobin, the Western Ontario and McMaster Universities Index (WOMAC), pain intensity and flexion gain after TKA.3The study was conducted in the city of Londrina-PR, at the Brotherhood of Santa Casa de Londrina, Philanthropic Hospital , a reference in high-complexity orthopaedics and traumatology services within the Unified Health System (Sistema Único de Saúde - SUS). This study was undertaken after approval by the Research Ethics Committee of the institution, which is linked to the National Research Ethics Commission . This study was approved under protocol number 634815 on 05/05/2014. Trial Registration: RBR-9b4qgq.A total of 43 patients with indications for TKA, treated at the outpatient clinic of the institution, were selected between June 2014 and October 2015. The selected patients were duly informed about the project and signed terms of free and informed consent. Inclusion criteria were patients of either gender with the presence of tricompartmental knee osteoarthritis with varus deformity, with indications for TKA. Exclusion criteria were patients with major deformities that would lead to bone cuts or release of a more extensive area of soft tissue; presence of inflammatory diseases; patients who had undergone previous surgeries of the same knee; use of anticoagulation medication up to seven days before surgery; and patients with history of atrial fibrillation, deep vein thrombosis or prior pulmonary embolism.2): those using TXA and a control group (no applied substance). Allocation was randomized by the surgeon, and the subjects were monitored for 2 months. The groups were named “Control”  and TXA . The dose chosen for topical treatment followed the existing literature data on the use of TXA in total knee prosthesis and was 1.0 g (4 x 5 ml ampoules with a concentration of 50 mg/ml) [The subjects were divided into 2 groups  , 27. Pat1):The following data on the pre- and postoperative periods were recorded (Table Haemoglobin (Hb) levels preoperatively and 24 and 48 hours after surgery.Reports of clinical flexion gain examination using a goniometer for evaluations 24 hours, 48 hours, 7 days, 21 days and 2 months after surgery.Pain evaluation using a visual analogue scale (VAS), which consists of a 1-dimensional instrument containing an 11-point scale (0-10), where zero is rated as no pain and 10 the worst pain one has ever felt. Patients selected a single number that best represented the intensity of their pain at the following postoperative time intervals: 24 and 48 hours, 7 days, 21 days and 2 months after surgery. Evaluations of knee function, preoperatively and 2 months after surgery, using the “WOMAC” instrument, were translated and validated for the Portuguese language .3) and maintained for 5 minutes. After this period, the joint capsule and incision were closed without drain . All procedures were performed by the same surgeon and with the same instrument and implant .The surgical technique was used documented within the current literature, with subarachnoid anesthesia, patellar medial access and application of TXA all over the exposed joint in the selected cases using a syringe  . The ort51).The mean age of the participants was 68.74 (55-86) years. The mean ages were 68.36 (55-81) years in the TXA group and 69.14 (55-81) years in the control group. The average operating time was 92.9 (80-105) minutes; 94.3 (80-105) minutes in the TXA group and 91.5 (85-95) minutes in the control group. There were 11 male patients; 4 in the TXA group and 7 in the control group Table  shows that there were statistically significant differences in favour of the group using TXA 48 hours postoperatively for the haemoglobin variable (p = 0.01), 24 and 48 hours postoperatively for pain evaluation (p <0.01) and 24 hours postoperatively for flexion gain (p = 0.03). There were no significant differences between the groups in the haemoglobin evaluation 24 hours postoperatively, in pain assessment 7 days, 21 days and 2 months postoperatively, in flexion gain 48 hours, 7 days, 21 days and 2 months postoperatively and in the WOMAC questionnaire 2 months postoperatively.Tables  from 24 to 48 hours postoperatively in the group using TXA. The flexion range of motion analysis showed a statistically significant difference in the group that used TXA (p = 0.03). Pain control and range of motion gain are important goals after the knee arthroplasty procedure. Immediate postoperative pain impairs mobility and reduces the patient's ability to cooperate with rehabilitation treatment . When exThe result obtained in the first 48 hours after the procedure, with advantages in relation to pain and gain in range of motion, was not maintained in the outpatient evaluations in the first months. Knee function, analysed using the WOMAC questionnaire, did not show a better gain in that period than that of the control group.We believe that the surgeon's and the researcher's knowledge regarding which subjects were cases and which were controls during the procedure and the short follow-up time may be considered weaknesses of the study. A multicentre study with a greater number of individuals may provide better evidence on the subject.In the manner in which it was used, in addition to reducing bleeding, TXA improved pain and increased flexion gain in the first hours after TKA. There were no differences between groups in terms of pain evaluation, flexion gain and knee function beyond the first 48 hours after the procedure.


This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain.μg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints , and safety was evaluated using standard measures. Eligible patients were randomized to receive TTX (30 p = 0.0460). The p value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient. 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis “intent-to-treat” population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (NCT00725114). Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov ( Pain related to cancer is highly prevalent. However, existing analgesic treatments do not always alleviate the pain; moreover, medications such as opioids may be inadequately tolerated , 2. AddiTetrodotoxin (TTX) is a small molecule that blocks voltage-gated sodium channels on neurons. It exerts its analgesic properties by inhibiting the initiation and conduction of impulses in the peripheral nervous system , 4. ClinV 1.7, found predominantly on nociceptive neurons in the periphery  during the EPIP or LPIP period.(3) A ≥30% improvement of QoL in at least 1 descriptor of emotional functioning [BPI Q#9B (mood) or BPI Q#9E (relations with other people) or BPI Q#9G (enjoyment of life)] during the EPIP or LPIP period.The secondary endpoints were the proportion of responders during the injection period, time to overall response, duration of overall response, time to peak analgesic response, duration of peak analgesic response, pain intensity difference (PID) for worst pain, average pain and most bothersome pain, opioid use , and overall or global impression of change (GIC).The efficacy was evaluated as the proportion of responders who satisfied specified criteria. A responder for the pain endpoint  had to satisfy the following criterion:The study was also designed to compare the safety of subcutaneous TTX with that of placebo. Safety was evaluated using standard approaches to monitor for and record adverse events (AEs), plus 12-lead ECG, neurological examinations, and routine clinical tests. Patients were screened for the study and then entered a 4- to 7-day baseline period within 28 days of screening. Following the baseline period, patients were randomized on Day 1 to receive study drug twice daily for 4 consecutive days. Drug administration from Days 1 to 4 was done either in a full-service hospital setting or at a private clinic, depending on the investigator. After the treatment period, all patients were seen again at the facility on Days 5, 8 (EPIP), and 15 (LPIP) for further safety and efficacy evaluations and then every week by telephone or at the clinic, until pain returned to baseline level. The Brief Pain Inventory form and Patient Diary were completed weekly after day 15.Patients with continued pain relief were assessed beyond 10 weeks. Patients receiving at least 1 but less than 8 doses of study medication  were expected to undergo all study procedures per protocol until Day 15 (or until pain returned to baseline level if after Day 15).The inclusion criteria included ≥18 years of age, a diagnosis of cancer, and stable baseline pain intensity score of ≥4/10 as assessed by numeric rating scale (worst pain in the past 24 hours on the Brief Pain Inventory). Pain stability was defined as a no greater than a 3-point difference between the highest and lowest pain intensity scores (as assessed by BPI Q#5) during the baseline period, and a no more than 50% increase or decrease in opioid analgesic use during the same baseline period without introduction of a new analgesic. Opioid consumption was expressed in MEDD. Patients were allowed one outlier day  if, in the opinion of the qualified investigator, there was unusual life circumstance that likely affected the pain experience.All patients had a history of treatment with analgesics. Patients were maintained on their existing analgesic regimens that included opioids and coanalgesics .2 retention or clinically relevant hypoxia, severe renal impairment, prolonged QTc interval, planned initiation of any new anticancer treatment, and female patients with a positive pregnancy test.The key exclusion criteria included a history of CODuring the conduct of the trial, two interim analyses were undertaken by an arms-length, unblinded Data Monitoring Committee in order to adjust the sample size and make recommendations on early termination. A first interim analysis was conducted after 60 evaluable patients were enrolled and a second after 110 evaluable patients. The statistical analysis included penalties for this approach .The Data Monitoring Committee indicated that the first interim analysis showed that the composite endpoint would be futile; however, based on one or more of the single components  the results may not be futile. The trial conduct remained unchanged, but following discussion with Canada's drug regulatory agency the decision was made to elevate the importance of the pain intensity reduction portion as a coprimary endpoint, with statistical adjustment to account for possible success on either endpoint.Assuming a proportion of responders (for each coprimary endpoint) for the placebo group of 20% versus 40% for TTX and adjusting for the 2 coprimary endpoints (using Bonferroni methods), 220 evaluable patients (110 per arm) were required for 80% power and a two-sided test. To obtain 220 evaluable  patients, a total of 254 patients would need to be randomized.Efficacy and safety analyses were performed on an “intent-to-treat (ITT)” population defined as all randomized patients who had at least 1 injection of study medication and at least 1 postbaseline efficacy assessment. A per-protocol (PP) population of patients without major protocol violations was also prespecified for secondary analyses.The proportion of responders observed in each treatment arm for the composite endpoint (coprimary #1) and for reduction in pain intensity endpoint (coprimary #2) was summarized and compared using the Wald chi-square test on the (above defined) ITT and per-protocol populations, the ITT population being of primary interest. The Holm-Bonferroni and O'Brien-Fleming methods were used to control for type I error arising from multiple treatment comparisons and for the (multiple) two coprimary endpoints. In addition, trends for differences between treatments were individually tabulated for impact of treatment on pain and QoL . All hypotheses other than the primary hypothesis tests for the two coprimary endpoints were based on 2-sided tests using a 5% level of significance.Covariate-adjusted analyses were specified to explore the impact of possible confounders and effect modifiers on the primary results to examine the robustness of the treatment effect across subgroups and for unbiased estimation of treatment effect. The clinically relevant covariables used to assess the robustness of the treatment effect were age, sex, baseline daily opioid use, pain , metastases, and site type (outpatient clinic versus inpatient facility).To address the issue of missing data, for patients who terminated the study prematurely or data missing for other reasons, sensitivity analyses including all 165 randomized patients were conducted using three imputation methods.The trial protocol underwent formal scientific and ethical review and was approved at each of the participating sites. Full written, informed consent was obtained from each participating subject.Patients were enrolled at 19 of 21 participating sites in Canada, Australia, and New Zealand. The study opened in April 2008 and last data was collected in November 2012. 165 patients were randomized, 77 patients (46.7%) in the TTX arm and 88 (53.3%) in the placebo arm. The intent-to-treat (ITT) population consisted of 149 patients, 65 (84.4%) in the TTX group and 84 (95.5%) in placebo. The per-protocol population included 50 patients (64.9%) in the TTX group and 77 patients (87.5%) in placebo. While the intent was to enroll 254 patients, because of associated costs, the sponsor decided to halt the study enrollment at 165 patients. The primary analysis included the 149 completed patients who fulfilled criteria for ITT inclusion (defined above).All patients had a cancer diagnosis, including a wide range of solid and other tumors. The cohort ranged in age from 25 to 84. Demographic elements were similarly distributed between treatment groups except gender .p = 0.0460 one-sided t test) and a number-needed-to-treat (NNT) value of 6.2. The p value of 0.0460 was nominally statistically significant but not at the prespecified two-sided 5% level after the prespecified (Bonferroni Holm) adjustment for the two primary endpoints.Thirty-three (50.8%) patients who received TTX and 29 (34.5%) patients who received placebo were responders on the pain coprimary endpoint. The primary analysis of the efficacy data from this study supports a clinically relevant benefit of TTX over placebo on the prespecified pain intensity endpoint with an effect size of 16.2% in favour of TTX  were the only cofactors remaining in a standard forward selection logistic regression using an entry threshold of 0.2. The resulting model (primary model) fit for the pain intensity model was very good (Hosmer-Lemeshow p = 0.8336).Upon adjustment for the baseline factors of age, opioid level, and pain level , the analysis of the pain intensity endpoint showed a greater effect size and nominal statistical significance with an estimated response difference of 23.1% , nominal p value increased by 0.11 (0.16–0.05).Conservative sensitivity analyses were conducted to address the issue of potential bias due to dropouts. In the most conservative analysis conducted, upon imputation for the missing data, response for the pain intensity endpoint was decreased by 5.0%, (16.2% versus 11.2%), with All imputation sensitivity analyses supported efficacy results in the same direction, with somewhat attenuated effect sizes as expected.p = 0.2035) with a NNT value of 11.1. The impact of pain on QoL was physical functioning, difference of 4.6%, and p = 0.5651 and emotional functioning, difference of 6.9%, and p = 0.4011.Nineteen (29.2%) patients who received TTX and 17 (20.2%) patients who received placebo were responders. However, the proportion of responders to treatment with TTX during EPIP or LPIP was not statistically significant  versus 8 days (placebo). The means were 56.7 days (TTX) and 9.9 days (placebo) . This mex-axis) during the late postinjection period. Similar graphs were obtained for the early postinjection period as well as for worst pain, most bothersome pain, and opioid use at both early and late postinjection periods (data not shown)  .While the primary endpoints use a fall in pain from baseline by at least 30% in the definition of an analgesic response, the cumulative proportion of responders analysis allows a broader comparison of the active and placebo treatment arms by comparing the proportion of patients in both groups who have a reduction by any specific percentage change from baseline of pain . The CumGIC results at LPIP are presented in very much improved and much improved), at EPIP 30.8% of patients in the TTX group and 8.3% in the placebo group  reported improvement; at LPIP 32.3% versus 11.9% for placebo  . These differences in GIC strong response translated into clinically significant calculated NNT estimates of 4.4, 4.9, and 3.6 at EPIP, LPIP, and EPIP or LPIP, respectively.When considering a GIC strong response (-square) ; and at  minimally improved response category, the proportion of patients reporting an improvement in the TTX group was 55.4% and in placebo 23.8% at LPIP. The NNT estimates for TTX were also clinically significant: 2.6 for EPIP, 3.2 for LPIP, and 2.7 for EPIP or LPIP. Similar results were obtained in the low baseline opioids subgroup (data not shown).When considering thep value of 0.0044 (chi-square test). Sensitivity analyses similar to those conducted on the predefined ITT population provided results consistent with these analyses. In the sensitivity analysis for the coprimary pain intensity endpoint in the low baseline opioid subgroup, there was a 20.0% treatment difference in proportion of responders between TTX and placebo .After the completion of the study, it was found that a modest number of patients of the study population, 23 patients, were receiving very high doses of opioids, 500 mg or greater MEDD. These patients had not been a priori excluded from participation in the trial. Of the 126 patients who received less than 500 mg MEDD, 31 (50.8%) in the active treatment arm and 17 (26.2%) in the placebo arm were pain (coprimary endpoint) responders. The difference between the two treatment arms was 24.6%, with a nominal p = 0.0196).For the composite coprimary endpoint, the results for patients receiving less than 500 mg MEDD were similar. The number of responders was significantly higher in the TTX group, 19 (31.1%), compared with the placebo group, 9 (13.8%), for the composite endpoint  injection and multiple i.m. doses for 4 or 7 days. Administration of TTX by subcutaneous injection elicits a pharmacological effect similar to that achieved when it is administered by intramuscular injection [The study drug is an injectable formulation of highly purified TTX extracted from the puffer fish (Fugu). Data from our group involving dose tolerance studies in healthy human patients have demonstrated that single doses up to 45 μg b.i.d. dose of TTX administered intramuscularly for 4 days appeared to be safe and efficacious in cancer patients whose pain was not relieved with standard therapy that included strong opioids and adjuvant analgesics [A Phase IIa open-label study found that 30 algesics . The rolalgesics . The desIn that Phase IIa study, 82 patients were randomized, and results for 77 patients were used for analysis. A futility interim analysis was conducted and the results showed that there was a nonstatistically significant trend toward more responders in the active treatment arm based on the primary endpoint (pain intensity difference) and the DMC recommended to stop the study for futility. However, analysis of secondary endpoints and an exploratory post hoc analysis suggested that a robust analgesic effect might have been shown if a composite endpoint had been used, for example, an evaluation that combines pain outcome (pain intensity) and QoL. This retrospective analysis suggested that TTX may potentially relieve moderate or severe, treatment resistant cancer pain in a large proportion of patients, and for prolonged periods following treatment, but further study was recommended using a primary composite endpoint.The current study, TEC-006, adds to these earlier, smaller trials and provides further evidence for the safety and efficacy of TTX at the prescribed dose and schedule. The TEC-006 study was intended to be a pivotal trial that is to bring the drug to market in Canada. Firm statistical conclusions are however difficult since the TEC-006 study was stopped prematurely well before the planned sample size was reached; it is an underpowered study. The study demonstrates a treatment difference across endpoints and, adjusting for baseline imbalances, the treatment difference was consistent with a clinically meaningful analgesic signal but not reaching statistical significance in the prespecified primary analyses. We interpret these results to be most consistent with the study being underpowered  as the main cause. Even with this smaller patient cohort, in a group of heavily pretreated patients and with advanced disease, the pain coprimary endpoint fell just short of statistical significance, with a clinically meaningful NNT between 4 and 6. All secondary analyses showed a similar analgesic effect: duration of analgesia, patient global impression of change, the cumulative proportion of responders, and the low opioid subgroup analysis. Strikingly, a large group of patients experienced a prolonged analgesic effect lasting weeks or even months. There was no underlying mechanism of pain – somatic, visceral, neuropathic, or mixed pain – which showed a greater or lesser likelihood of such a response.The study design did not exclude patients receiving very high dose opioids (500 mg or greater MEDD) from enrollment in the trial. The literature shows that patients on very high doses of opioid are likely to represent a group of patients who are difficult to manage and have unpredictable treatment outcomes . Some anWhile underpowered, this multicentre, randomized, double-blind, placebo-controlled, parallel-design trial suggests a clinically important analgesic effect (NNT about 4–6) in a cohort of heavily pretreated patients with advanced illness and otherwise with poorly controlled moderate to severe cancer pain. The pain reduction primary endpoint was nominally statistically significant; however, because of the statistical penalties for multiplicity, the study could not be considered statistically positive. There was further indication of an analgesic signal: with a convergence of positive findings within the secondary and post hoc exploratory analyses. Finally, the results of this trial support the hypothesis that patients requiring high dosages of opioids, for example, 500 mg MEDD or greater, are poor candidates for TTX pain therapy.We conclude that TTX demonstrates a favourable benefit-risk profile in the treatment of uncontrolled moderate to severe cancer-related pain and may play an important role in addressing a major unmet medical and societal need. The promising results suggesting prolonged analgesia lasting weeks or even months following four days of administration need to be confirmed, for example, through a sufficiently powered Phase III clinical trial.


Chronic pain enhances sensory sensitivity and induces the biased development of psychological traits such as depression and pain catastrophizing, leading to the formation of heterogeneous conditions. Fluctuations in the sensory-related thresholds of non-injured sites  in patients with chronic pain are thought to be related to central sensitization. The objectives of this study were to analyze the association between pain tolerance thresholds (PTTs) in non-injured sites and the psychological traits of patients with chronic pain and to evaluate the usefulness of PTT measures in assessments of pathological conditions related to chronic pain.This study included 57 patients with chronic pain. The PTTs were measured in non-injured sites with quantitative sensory testing (QST) with electrical stimulation and then classified with cluster analysis. The Short-Form McGill Pain Questionnaire was used to subjectively assess pain in the injured sites. The Minnesota Multiphasic Personality Inventory (MMPI) was used to assess the patients’ psychological traits.Based on the cluster analysis of PTTs, the patients were classified into a High-Sensitivity group and an Others group consisting of the remaining patients. The results of the MMPI profiles showed that the High-Sensitivity group included significantly more patients with the Neurotic Triad pattern and no patients with the Conversion V pattern. The scores of the hypochondriasis and hysteria scales were significantly lower in the High-Sensitivity group than in the Others group.This study indicated that patients with chronic pain can be classified according to PTTs in non-injured sites and suggests that patients with High-Sensitivity have characteristic psychological traits. Assessment of PTTs in non-injured sites would be useful for evaluating the psychological condition of patients with chronic pain. Pain is defined as an unpleasant sensory and emotional experience that is associated with actual or potential tissue damage or that is described in terms of such damage . While aChronic pain refers to pain of no fixed duration extending beyond the expected period of healing or to pain related to progressive non-cancer diseases . As pathThe following three in vivo mechanisms transform acute pain into chronic pain: peripheral sensitization at the peripheral level, dysfunction of the descending pain inhibitory system, and central sensitization at the central level –13. ThesQuantitative sensory testing (QST) is a noninvasive method used to objectively assess subjective pain. Specifically, QST assesses neural function by quantifying the sensory-related thresholds of the responses of the examinees to various experimental stimuli, such as thermal, pressure, electrical, and ischemic stimuli –20. The Many studies have referred to the psychological traits of patients with chronic pain. These traits include alexithymia, catastrophizing, anxiety, and depression –7, 26–28Factors that have been reported to be associated with low pain thresholds include physical variables, such as the severity and duration of the pain and decreased autonomic function , 36. On Some patients with chronic pain are, however, resistant to psychological intervention , 39. In The participants were selected from 81 patients with chronic pain who had been admitted to the department of Psychosomatic Medicine of Kansai Medical University. Based on previous studies –42, the In this study, the QST was performed with a Neurometer CPT . With this device, an electrical stimulus of either 250 or 5 Hz was selectively applied to Aδ primary afferent fibers, which transmit sharp pain, and C primary afferent fibers, which transmit dull pain. The QST was performed in a quiet room at a comfortable temperature. The participants sat on a chair and a stimulating electrode was attached around the distal interphalangeal joint of the fourth finger of the non-dominant hand. The electrical stimulation current was increased from 0 to 9.99 mA at a set rate while the button on the device was pressed, and the current stopped when the button was released. After the patients were informed that stimulation with the highest electrical current would not cause tissue or other damage to the body, the participants then operated the device by themselves. They were instructed to release the button when the stimulus reached an unbearable level of pain, and this was defined as the PTT. The QST was performed once for each level of stimulation, and measurements were taken every 30 s. Previous studies have shown only a small level of variation among measurements –45.Subjective assessments of the pain were performed with the Short-Form McGill Pain Questionnaire (SF-MPQ). The participants evaluated the pain with 15 expressions that described the sensations and the emotions of pain, which were rated on a 4-point scale, while the severity of the pain was evaluated with both a visual analog scale (VAS) and the Present Pain Intensity 6-point scale. The reliability of the Japanese version of the SF-MPQ has been confirmed .The MMPI questionnaires were distributed to the participants before the experiment and then collected at the time of the PTT measurement. The MMPI, which is a self-reported questionnaire on personality, is highly reliable for less invasively evaluating psychological traits from various perspectives. The MMPI consists of four validity scales  and ten clinical scales: Hypochondriasis (Hs), Depression (D), Hysteria (Hy), Psychopathic deviate, Masculinity/femininity, Paranoia, Psychasthenia, Schizophrenia, Hypomania, and Social introversion that are assessed with 550 questions that are answered on a 3 point scale . The scores are calculated by assigning two points to agree and one point to neither. Higher scores indicate a greater tendency for that trait. The results are expressed as numerical values and profile forms , 30.In Japan, the MMPI has been widely used in the clinical and academic fields –49. In tt-test, one-way analysis of variance (ANOVA), χ2 test, or residual analysis. The SPSS software program  was used for the analyses.All values are presented as mean ± standard deviation (SD). The statistical analyses were performed on the data of the 57 participants . According to the scatter diagrams of the PTTs to the 250-Hz and 5-Hz stimuli Fig. , the PTTOf the participants, 61.4% were female. The mean age was 47.7 years, with a SD of 17.5 years. The mean pain duration was 59.3 months, with a SD of 75.0 months Table . The SF-The PTTs to 250-Hz stimulus ranged from 0.80 mA to 9.99 mA, with a mean ± SD of 4.59 ± 3.00 mA. The PTTs to 5-Hz stimulus ranged from 0.75 mA to 9.99 mA, with a mean ± SD of 4.23 ± 2.93 mA.p < 0.05; 5 Hz, p < 0.01).The mean ± SD PTTs to 250-Hz stimulus were 5.74 ± 3.19 mA for male and 3.87 ± 2.67 mA for female participants, while those to 5-Hz stimulus were 5.53 ± 3.19 mA and 3.41 ± 2.47 mA, respectively. The PTTs to both stimuli were significantly lower for female participants  .The cluster analysis done to create the High-Sensitivity group selected 23 participants with decreased PTTs (23) Fig. . The PTT2 test showed that the male-to-female ratio did not differ between the groups. The mean ± SD ages were 56.30 ± 15.83 years in the High-Sensitivity group and 41.94 ± 16.35 years in the Others group. The mean ± SD pain durations were 40.60 ± 76.42 months in the High-Sensitivity group and 73.23 ± 81.90 months in the Others group. The t-tests showed that neither age nor pain duration differed between the groups. In addition, t-tests showed that the scores on the sensitive and affective components of the SF-MPQ, VAS scores, and current pain ratings did not differ between the groups  showed that the distribution of these patterns differed significantly between the groups. The residual analyses showed that the proportion of participants with the Conversion V pattern was significantly lower in the High-Sensitivity group, while the Neurotic Triad pattern was significantly higher (p < 0.01 for both). No significant difference in the proportions of the participants with the other patterns was observed.In the MMPI profiles, both groups showed high values on the Hs, D, and Hy, scales (t ≥ 70), which are typical profiles for patients with chronic pain Fig. . Patientp < 0.05 for both) (Table Moreover, the scores on the MMPI clinical scales were compared with a one-way ANOVA. The scores on the Hs and Hy scales were significantly lower in the High-Sensitivity group than in the Others group p < 0.0 for bothThis study aimed to examine the relationship between the PTTs and psychological traits of patients with chronic pain in order to evaluate the usefulness of pain thresholds for assessing the pathological conditions of patients with chronic pain.In this study, the PTT, which is an indicator of central sensitization, was measured in non-injured sites in patients with chronic pain. This study had two important findings: these measurements differentiated a High-Sensitivity group of patients who showed substantial decreases in their PTTs, and assessment with the MMPI revealed psychological traits that were characteristic of the patients with chronic pain, some of which have been reported by previous studies.In this study, the PTT was significantly lower in female participants. Several previous studies on sex difference have shown that pain sensitivity differs between males and females. For instance, Fernández-Carnero et al. studied hyperalgesia in patients with unilateral epicondylalgia and reported that the pain threshold for experimental pain was lower in female than in male patients , and KinAge was significantly higher in the High-Sensitivity group compared to that in the Others group. Previous studies have shown that aging is associated with an increase in pain perception threshold and a decrease in PTT, and this has been attributed to aging-induced impairments in both the excitatory and inhibitory functions in the mechanisms underlying pain perception . The resAlthough the pain duration of the participants did not differ between the High-Sensitivity and the Others groups, the pain duration varied widely, from 3 months to 240 months. While pain duration has been reported to be longer in patients with the Conversion V pattern , our resIn this study, patients with chronic pain were classified using cluster analysis of the PTT at non-injured sites and their psychological traits were evaluated. As a result, we identified a characteristic High-Sensitivity group. Several previous studies done to classify patients with chronic pain have suggested a relationship between pain and psychological traits. Murphy et al. showed that there were multiple detectable subgroups of patients with chronic pain by cluster analysis of clinical pain intensity and psychological variables . In addiPrevious studies were classified according to psychological variables. In this study, we classified patients with chronic pain by cluster analysis with only reproducible PTT as a physical variable to assess the relationship between psychological factors and PTTs. The results strongly supported the study of Cruz-Almedia et al., which showed close relationship among psychological traits, somatosensory sensations, and central sensitization to chronic pain . This shThis study yielded results indicating an association between classifications based on PTTs and psychological traits. Previous studies that used MMPI for patients with chronic pain found that their participants could be classified into three to six types –56, and In this study, analysis of the MMPI showed that the High-Sensitivity group contained significantly more participants with the Neurotic Triad pattern, but none with the Conversion V pattern. Moreover, the scores on the Hs and Hy scales were significantly lower than those of the Others group. The Conversion V pattern relates to a characteristic profile of patients with chronic pain. It shows the tendency to replace psychological problems with physical complaints, and its socially incompatible personality is also known to cause difficulties in treatment. On the other hand, the Neurotic Triad pattern is characterized by depressive tendency and hypochondriac concerns . While pIn this study, data on income, social status, and working conditions of the participants were not collected, and further studies with such data will be necessary. As ethnic differences have been suggested to affect assessment of psychological traits when using the MMPI, further studies with multiple ethnic groups are needed. Since several reports have indicated that pain thresholds are affected by hormonal levels during the cycle phases , 59 the In this study, we were able to differentiate the patients into a High-Sensitivity group by performing a cluster analysis of PTTs to two types of pain stimuli that were applied to unaffected tissue in patients with chronic pain. This High-Sensitivity group showed a significant difference in the pattern and level of neurosis scales, which is a characteristic MMPI profile of patients with chronic pain, different than the Others group. These results suggest that PTT would be a useful tool for understanding the psychological traits of patients with chronic pain.


Electrophysiological correlates of empathy processing are reduced in BD depending on manic symptom severity.Bipolar disorder (BD) patients often demonstrate poor socialization that may stem from a lower capacity for empathy. We examined the associated neurophysiological abnormalities by comparing event-related potentials (ERP) between 30 BD patients in different states and 23 healthy controls  during a pain empathy task. Subjects were presented pictures depicting pain or neutral images and asked to judge whether the person shown felt pain (pain task) and to identify the affected side  during ERP recording. Amplitude of pain-empathy related P3 (450–550 ms) of patients versus HCs was reduced in painful but not neutral conditions in occipital areas  only in pain task. Similarly, P3 (550–650 ms) was reduced in central areas [4.305  vs. 6.611 ]. Current source density in anterior cingulate cortex differed between pain-depicting and neutral conditions in HCs but not patients. Manic severity was negatively correlated with P3 difference waves  in frontal and central areas (Pearson  Bipolar disorder (BD) is a severe mood disorder characterized by alternating manic or hypomanic and depressive episodes. Manic or hypomanic episodes are characterized by elevated mood, irritable mood, or both, which are variable in severity and length, while depressive episodes are states of low mood1Bipolar disorder is one of the major causes of disability worldwide and afflicts not only individual patients but also family and society by placing a heavy burden on mental health and other social services463810Empathy is defined as the ability to imagine oneself in another’s situation and to share their mental state121719The neural mechanisms of empathy have also been explored in large scale studies, most focused on pain empathy due to the robustness of pain in inducing empathy. Functional magnetic resonance studies have reported that watching others in pain consistently activates regions of the anterior insula and anterior cingulate cortex (ACC)132323To the best of our knowledge, there have been no studies investigating the neural activation patterns underlying pain empathy in BD. In previous studies, BD patients showed dysfunction in emotional processing and emotional regulation that were associated with abnormalities in the fronto-limbic neuroanatomical network26The ERP components N1 and P3 are always induced by pain empathy tasks. Previous studies of BD showed abnormalities in N1, indicating a deficit in the early stage of sensory processing2931The aim of the present study is to compare the neural processing of pain empathy between BD patients and HCs as manifested by ERPs. Both BD patients and HCs were asked to complete a pain empathy task involving images of individuals in pain and neutral conditions during ERP recording. Based on previous studies, we expected reduced N1 and P3 ERP amplitudes induced by the pain depictions relative to neutral images in BD patients compared to HCs. We also expected decreased activation in pain empathy-related brain areas, such as anterior insula and ACC, according to electrophysiological source analysis when perceiving others in painful situations. In order to identify whether a potential deficit of pain empathy is trait-related or state-related, we also investigated correlations with current symptom severity.There were no differences in age, sex ratio, and years of education between BD patients and HCs. Both groups performed similarly in Verbal Fluency, Digit Span Forward, Digit Span Backward, and Stroop tests, but patients performed worse on the Montreal Cognitive Assessment. In the Chinese IRI, patients and HCs performed similarly on fantasy and personal distress items, while patients scored lower on perspective taking and empathy concern .t32 = 30.21, P < 0.01). There was a significant stimulus  × task  interaction for accuracy . Pairwise comparison showed higher task accuracy for neutral images compared to pain depictions in both tasks  ] .F1, 51 = 18.513, P < 0.001, η2 = 0.266), with patients responding slower than HCs in all conditions. The interaction of stimulus × task also reached significance . Pairwise comparison showed that RTs were longer for neutral stimuli compared to pain depictions for the laterality task  but not for the pain task  in reaction time for correct answers (RTs) . Pairwise comparison showed that the difference between N1 amplitudes induced by pain depictions and neutral images reached significance , with BD patients showing less positive amplitudes during pain depictions than during neutral images. The difference was not significant in the HCs (P = 0.181)  showed no main effect of stimulus. The interaction of stimulus, task, and group (BD vs. HCs) reached significance for the frontal area (= 0.181) .F1, 50 = 5.042, P = 0.029, η2 = 0.092). Amplitudes of P3 (450–550 ms) evoked by pain depictions were larger than those evoked by neutral images. Furthermore, the interaction of stimulus, task, and group reached significance for the frontal area  and central area , and marginal significance for the occipital area . Pairwise comparisons showed that pain depictions evoked P3 (450–550 ms) responses of greater positive amplitude compared to neutral images in the HCs group on the pain task for the frontal , central , and occipital areas , while positive P3 (450–550 ms) amplitudes did not differ significantly between stimuli for BD patients in any area (Pmin = 0.284). Moreover, the group difference reached marginal significance for the pain depiction condition in the central area  and significance for the occipital area , but not in the neutral condition for any area (Pmin = 0.319), with larger amplitudes in HCs than BD patients (For the early phase of P3 (450–550 ms), RM-ANCOVA revealed main effects of stimulus as measured from the central area  and central area  and a main effect of group in the occipital area . Amplitudes in response to pain depictions were larger than in response to neutral images, and pain-associated P3 (550–650 ms) amplitudes were larger in HCs than BD patients. Furthermore, the interaction of stimulus, task, and group reached significance in the frontal area  and marginal significance in the central area ]. Pairwise comparisons showed that painful depictions evoked P3 (550–650 ms) responses of greater positive amplitude compared to neutral images during the pain task in HCs for the frontal area  and central area , but not in BD patients (Pmin = 0.172). Moreover, the group difference reached significance in the pain depiction condition for the central area  but in no brain region on the neutral image condition (Pmin = 0.520), with larger amplitudes in HCs than BD patients (For the later phase P3 (550–650 ms), RM-ANCOVA revealed main effects of stimulus in the frontal , while the activation pattern was similar in both conditions for BD patients . During pain judgment, current source density in the ACC  was larger in the pain depiction condition than in the neutral image condition for HCs  were analysed in pain depiction and neutral image conditions during the later P3 phase (550 to 650 ms post-stimulus presentation) using non-parametric randomisation tests. As hypothesized, activation of brain regions involved in pain judgment was higher in HCs for the pain depiction condition than the neutral image condition ; antidepressants ; benzodiazepines ; mood stabilizers ]. Pairwise comparison showed that pain depictions in the pain task evoked less positive N1 amplitudes compared to neutral images in patients receiving antidepressants , benzodiazepines , and mood stabilizers . Response amplitudes induced by pain depictions were less positive compared to neutral images in the pain task for patients not taking antipsychotics .To investigate effects of medication on ERP results, we conducted RM-ANCOVA to compare the differences among medicated patients, un-medicated patients, and HCs. All four types of medication received by patients  showed interactions with stimulus condition and task for N1 measured from the frontal area . Scores on the Hamilton Depression Scale (HAMD) did not show any significant correlation with either early or late difference waves, but the scores were positively correlated with personal distress (r (30) = 0.544, P = 0.002).Pearson correlation analysis showed significant negative correlations between scores on the Young Mania Rating Scale (YMRS) and P3 (550–650 ms) difference waves in the pain task for the frontal area , strongly suggesting that the aberrant neural processing of pain empathy in BD is dependent on current disease state.We detected an N1 component of the ERP response corresponding to early processing of pain empathy, with a trend showing more positive-amplitude N1 waves in response to depictions of other’s pain compared to neutral images in HCs, consistent with previous studies232423We also detected later ERP components P3 (450–550 ms) and P3 (550–650 ms) that differed in amplitude between groups. Consistent with previous studies, the positive P3 signal was larger in response to pain depiction than neutral images during the pain judgment task232489101118Bipolar disease patients also exhibit P3 deficits in other cognitive tasks using a variety of target stimuliWe also found significant region-specific negative correlations between P3 difference waves and manic symptoms. That is, patients with manic symptoms had lower empathy for other people’s pain compared to non-manic patients due to specific processing deficits. This is consistent with previous findings that patients with more severe manic symptoms or patients in manic states were less able to identify the negative emotions of others39Using sLORETA source localization analysis during a late ERP time window, we found that BD patients exhibited little difference in ACC current source density between pain and neutral judgment conditions. Previous research demonstrated that the ACC plays an important role in the processing of pain empathy1343Medications also influence ERP amplitudesThe present investigation had some limitations. First, our sample size was relatively small, increasing the likelihood of type II errors. Second, the sample included patients with varying courses of illness so we could not distinguish whether the neural processing abnormalities in BD patients are state- or trait-dependent. Further studies involving larger numbers of subjects in varying states of illness are required to confirm these preliminary findings and clarify the relationship between symptom severity and the neural mechanisms of pain empathy. Third, all patients participating in the present study were currently taking medications, which proved to be an important confound on the ERP results. Although we made efforts to analyse the effects of each medication, some patients were taking combinations. Future studies should therefore be conducted with stricter control of concomitant medication. Finally, the spatial resolution of the ERP technique was comparatively low, providing only limited evidence for differences in neural activation pattern between patients and controls. However, the main goal of this study was to investigate differences in the temporal dynamics of empathic processing between BD patients and HCs, which was achieved. Further studies using high-resolution neuroimaging techniques such as functional MRI are needed to reveal the neural activation patterns associated with pain empathy in BD.In conclusion, our study provides preliminary but compelling evidence for a pain empathy deficit in BD patients at the neurophysiological level using ERP recordings during a well validated empathy paradigm. The results showed that late (conscious) and potentially also early (automatic) neural processing stages of pain empathy were impaired and that ACC activity while judging pain in others was reduced in BD patients. In addition, self-reported empathy scores were lower in BD patients than HCs. Taken together, the present results demonstrate impaired empathy at the neurophysiological level in patients with BD. YMRS scores were negatively correlated with difference waves, providing the first indication that altered pain empathy in BD may be state-dependent. This deficit in empathy may explain the poor interpersonal interactions observed in many BD patients and suggests that BD patients may benefit from psychotherapy targeting empathy.Twenty-two outpatients and eight inpatients diagnosed with BD using the 10th version of the International Classification of Diseases (ICD-10) were recruited from the Anhui Mental Health Centre. Twenty-three HCs were recruited by advertisements from the community and matched to the patients for age, sex ratio, and education. The HCs had no personal or family history of psychosis. Exclusion criteria for patients and HCs were: i) history of electroconvulsive therapy in the previous six months, ii) substance abuse based on ICD-10 criteria in the previous six months, iii) current or history of nervous system disease, iv) history of brain injury.Patients were currently treated with medications. All patients were taking mood stabilizers (n = 21), antipsychotics (n = 18), and/or antidepressants (n = 19), either individually or in combinations of two or three of these medications. Some patients were also taking benzodiazepines (n = 11) in addition to these other drugs. Patients were in different disease states, including depressed, manic, and remitted. We used the 17-item HAMDAll subjects signed an informed consent form for the study. All study procedures were approved by the Anhui Medical University Ethics Committee and conducted according to the Helsinki Declaration (1975 and subsequent revisions).As previously reportedBefore electroencephalograph (EEG) recordings, subjects were assessed empathy with the Chinese IRI5254A block design task consisting of two blocks was administered in the pain empathy task, as described in previous studies23EEG data were recorded from 64 tin electrodes placed on the scalp according to the extended International 10/20 system using a Neuroscan recording system . Four electrodes were used to measure electrooculogram (EOG), with vertical EOG recorded above and below the left eye and horizontal EOG on the outer canthus of the left and right eye. EEG signals were recorded using a left mastoid electrode as the online reference. All electrode impedances were maintained below 10 kΩ. EEG and EOG activities were amplified with 0.01–100 Hz band-pass filtering and continuously sampled at 500 Hz/channel.https://github.com/bigdelys/pre_ICA_cleaning). Continuous data of every channel were cut into 1-s segments. Segments were considered artefactual when the correlation coefficient with others channels was lower than 0.4. If the proportion of artefactual segments from a channel was higher than 1%, all data from that channel were rejected. The preprocessed data were segmented into 3000 ms epochs covering 1000 ms before to 2000 ms after onset of image presentation.Offline processing was implemented in EEGLABt47 = 0.65, P = 0.52).Artefactual epochs were identified and removed based on a) abnormal spectral characteristics of high frequency noise , b) abnormal trends , c) abnormal amplitude (threshold −300 μV or +300 μV), d) improbable data using joint probability  for single channel and 4 SD for all channels), or e) abnormal distributions . Data from electrodes responsible for more than 10% of rejected epochs were rejected. Then, independent component analysis (infomax) was conducted on 1 Hz high-pass filtered data and the resulting weight matrices were applied to the 0.02 Hz high-passed data. Independent components corresponding to EOG, electromyogram and electrocardiogram were removed. On average, 58 (SD 3) channels and 55 (SD 4) independent components were retained per subject. The mean fraction of excluded trials was 4.11% (SD 2.1%) in the patient group and 5.06% (SD 3.5%) in HCs. Rejection rate did not differ significantly between groups  centred around peak P3 ground average waveforms. Statistical analyses were conducted on frontal , central , and parietal  electrode sites.Standard low-resolution electromagnetic tomography  analysis was applied to calculate the cerebral generators of pain empathy processing based on a subject-specific boundary element model applied to the Montreal Neurological Institute 152 template5758To detect the neural generators of pain empathy processing in the HCs and BD groups, voxel-based whole brain sLORETA images were compared between pain and neutral image conditions. The sLORETA built-in voxel-wise randomisation tests (5000 permutations) based on statistical non-parametric mapping methodology were used to yield a whole-brain statistical correctiont-test were used to assess group differences in age, years of education, neurocognitive test scores, pain ratings and Chinese IRI subscale scores. Chi-square tests were used to assess the difference in sex ratio between groups. Repeated measures analysis of variance tests were conducted on RTs, accuracy of task response  and stimulus  as within-subject factors, and group (BD patients and HCs) as a between-subject factor. RM-ANCOVA tests were conducted on the average amplitude of each ERP component measured from frontal, central, and occipital areas, with task and stimulus as within-subject factors, group as a between-subject factor, and pain ratings as a covariate.All data were analysed using IBM SPSS 16.0 . One sample K-S tests were conducted on all continuous data. Independent samples A potential confounding factor is the different types of medications currently used by the patients. Medications were coded as ‘on’ or ‘off’ for each patient. RM-ANCOVA tests were conducted with task, stimulus as within-subject factors, group  as a between-subjects factor and pain ratings as a covariate.P values, and the Bonferroni method was used for multiple comparisons. Bivariate Pearson correlations were calculated to examine the association strengths among difference waves, Chinese IRI and symptom severity as measured by YMRS and HAMD scores. A two-tailed P < 0.05 was considered significant.Greenhouse-Geisser correction was used to correct How to cite this article: Yang, J. et al. Decreased empathy response to other people’s pain in bipolar disorder: evidence from an event-related potential study. Sci. Rep.7, 39903; doi: 10.1038/srep39903 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.