Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension.The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin  or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups . Secondary outcomes include percentage responders to treatment , number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life , and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis.We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose.2014-004897-40. Registered on 7 September 2017.EudractCT, NCT03275012. Registered on 7 September 2017.ClinicalTrials.gov, The online version of this article (10.1186/s13063-018-3169-3) contains supplementary material, which is available to authorized users. Chronic pain, continuous or recurrent, lasting for more than 3 months affects 11–35% of children with varying disabilities . AlthougN-methyl-d-aspartate receptors, evidence is emerging for antagonism of calcium channels in the CNS and peripheral nerves  visit V10), four venous blood samples will be taken for assessment of PK: One predosing and three at different times postdosing (four times 1.5 ml and for children less than 15 kg four times 1 ml).After dose optimization, patients will continue to take medication (gabapentin or placebo) next to morphine for an additional 12 weeks. Dose adjustments are not allowed during the maintenance period.For all patients who terminate or complete the dose maintenance period, medication will be tapered according to a schedule over 0–4 weeks. During this tapering period, site staff will contact the patients to ensure that they are complying with the taper schedule. At EOS visit V10, venous blood sampling will be done once again .All patients who are tapered off medication will return for a visit 1–4 weeks after their EOS visit for the collection of final safety evaluations.Seven days after the last dose of investigational medication, follow-up by phone will take place to collect information about pain intensity, global health, and ongoing or new (serious) adverse events and concomitant medication until all safety concerns are resolved.Gabapentin and placebo  will be indistinguishable in appearance to maintain the study blinding. Also, labeling will not allow recognition of actual treatment. During the trial, blinding will be broken by the investigator for emergency purposes only, where knowledge of the blinded treatment could influence further patient care. In addition, the safety contact will unblind safety reports, as per regulatory requirements. Study blinding will be broken after database lock.The following scales will be used to assess pain intensity at all visits throughout the study. The FLACC scale is used for children between 3 months and 7 years of age who are unable to self-report their pain. It is a five-item scale that raters  use to score in five categories , each assigned a score of 0, 1, or 2 and total score between 0 and 10.The FPS-R is a self-report measure of pain intensity. It consists of six line drawings of faces that are scored 0 to 10. In this study, the FPS-R will be used for assessment of pain in children 3 years and older because it has not been validated for younger children. In children of 3 and 4 years old who are unable to self-report using the FPS-R, the FLACC scale will be used.The Numeric Rating Scale (NRS-11) is designed for pain score to be used by children from 8 years of age. The user has the option to verbally rate their scale from 0 to 10 or to place a mark on a line indicating their level of pain, with 0 meaning absence of pain and 10 meaning the most intense pain possible.To be able to compare data from the different pain scores, all scores will be reported on a scale of 0–10, as indicated by the individual scores.Baseline assessment: average pain score of twice-daily assessment on 3 consecutive daysDuring trial: daily in the morning and when breakthrough pain is noticedEndpoint: average pain score of twice-daily assessments on 3 consecutive daysPain will be assessed at the following time points:Furthermore, parents and/or subjects are asked to keep a daily patient diary recording the following items: study drug intake changes, comedication intake including rescue medication, adverse events, and abnormalities in sleep.Global satisfaction with treatment (at EOS visit V10) using NRS-11Clinical Global Impressions Scale (CGI-EI [Investigator]) at V2, V6, and EOS V10Patient Global Impression of Change (PGIC) Scale at V6 and EOS V10Pediatric Quality of Life Inventory (PedsQL) Generic Core ScaleFive Point Facial Hedonic Scale at EOS V10 for acceptability of the oral suspensionAdverse events collectionColumbia Suicide Severity Rating Scale (C-SSRS) at V1 and EOS V10Modified Overt Aggression Scale at V2, V6, and EOS V10Additionally, the following items will be scored:The primary outcome of the study is the average pain score (defined as average pain score of twice-daily assessments of 3 consecutive days) at the end of the study period in both treatment groups. Secondary endpoints are percentage of responders with 30% reduction in pain score, average daily pain intensity by age-appropriate scale, observational pain assessment with use of NRS-11 by parents/caregivers and investigator at each visit, number of episodes of breakthrough pain > 4/10 pain score and use of rescue medication, number of rescue interventions, number of pain-free days with < 4/10 pain score without rescue medication, participant dropouts due to lack of efficacy, total cumulative weight dose of each rescue drug, quality of life scored with the PedsQL at baseline (V2) and EOS visit (V10), acceptability of treatment  at EOS visit, global satisfaction with treatment (NRS-11 completed by parent/patient) at EOS visit, CGI-S at V6 and EOS (CGI-S by investigator), patient/parent PGIC at V6 and EOS, PK parameters: apparent clearance (CL/F), apparent volume of distribution (Vd/F), absorption rate constant (Ka), area under the curve (AUC), maximum (peak) concentration (Cmax), time of maximum concentration (Tmax), concentration at steady-state (Css), minimum concentration (Cmin) incidence of adverse events, percentage of adverse events, percentage of subjects discontinuing the trial due to adverse events, aggressive behavior in children > 6 years old  at V2–V6 and EOS, and suicidal ideation (C-SSRS) at V1 and EOS.The protocol structure follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement. The SPIRIT schedule with a complete overview of the study procedures for this trial is summarized in Fig. A total sample size of 66 is needed. It will allow detection of a significant difference between morphine plus placebo and morphine plus gabapentin groups in mean pain scores at EOS. Mean baseline pain scores of 8.5 are assumed for both groups, with estimated EOS pain scores of 5.4 for morphine alone versus 4.5 for morphine plus gabapentin based on percentage change in pain scores in a previous trial in adults .A minimum number of patients is defined per age group: (1) at least 5 patients aged 3 months to less than 3 years, (2) at least 15 patients aged 3 years to less than 7 years, and (3) at least 20 patients aged 7 years to less than 18 years. No maximum number of patients per age group is specified. A two-tailed test will be applied with a significance level of 0.5 and a power of 80%, and 10% dropout is anticipated.The primary efficacy analysis of this study is aimed at assessing the superiority of treatment with morphine and gabapentin compared with morphine and placebo. The hypothesis to be tested is that the average pain scores (average of two measures each day for 3 days before EOS visit V10) assessed by age-appropriate pain scales  are lower in the treatment group (morphine + gabapentin) than in the control group (morphine + placebo).The primary analysis of efficacy will be conducted using one-way analysis of covariance (ANCOVA) with baseline average pain score as a covariate. Other covariates will include center, treatment, and age (three subgroups). A second ANCOVA model including a treatment × center interaction term will be used to assess consistency across sites.t test or Wilcoxon-Mann-Whitney tests.Intergroup differences as breakthrough pain and frequency and dosage of rescue medication will be assessed using sample Statistical analysis will be performed using IBM SPSS Statistics 21  or SAS 9.4  software for PC.PK data will be analyzed by nonlinear mixed effects modeling with NONMEM  to estimate PK parameters, including volume distribution, clearance of gabapentin and morphine, and variability and precision. Also, influence of potential covariates will be evaluated.Using predicted drug concentrations, a population PK-pharmacodynamic (PD) model will be developed to link drug exposure to pain response.Ethical approval was obtained from the Medical Ethical Committee of the Erasmus Medical Centre, Rotterdam, The Netherlands.Medical ethical review is under way in the other participating centers , and the study is registered at ClinicalTrials.gov (NCT03275012).The study safety and progress will be reviewed by an independent data and safety monitoring committee (DSMC) according to the DSMC charter. All adverse effects reported by the subjects or observed by investigators or staff will be recorded. A continuous evaluation will be performed by an independent DSMC. In case of disproportionate adverse effects or prolonged inclusion, the DSMC can decide to terminate the study. No interim analysis for efficacy is planned.The GABA-2 study is an exploratory, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy of gabapentin added to morphine in pediatric patients with severe neuropathic or mixed pain.Although strong opioid use for benign pain is met with cultural barriers in many countries, the use of morphine is recommended by the WHO guidelines for persistent pain in children as a first-line treatment . Also, tHence, the use of morphine for severe NP in children should be seriously considered and studied clinical trials. Because treatment with first-line agents such as antidepressants and anticonvulsants as monotherapy for severe NP is not always sufficient , and becAlthough opioids other than morphine, based on PD properties, might be more suitable , they weChronic pain, specifically NP in children, is often difficult to treat. Children are often undertreated owing to a lack of evidence or medication is used off-label because it often is not registered for use under a certain age. For example, in The Netherlands, gabapentin is not registered for treatment of NP in patients younger than 12 years. Moreover, high-quality studies investigating the efficacy and safety of gabapentin for this indication in children are lacking. Hence, we believe our trial is necessary and timely.Pediatric PK studies of gabapentin , 36 haveJustification of this dosing regime will be further investigated by assessing drug exposure using sparse sampling techniques. A correlation between exposure and analgesia will be explored.The dosing regimen for morphine and slow-release morphine is based on the WHO guideline for morphine in children , and it The primary endpoint of the study will be the differences in average pain scores for the two treatment groups (average of two measures each day for 3 days before the EOS visit) assessed by the age-appropriate pain scales . Because the age range of the study population is wide, different pain scores were needed to ensure the most optimal scale for the different age groups. FLACC is a validated, observer-based scores for younger children. For school-age children, the FPS-R was chosen as a validated self-reported pain score, whereas the NRS-11 was considered most appropriate for older children. We realize that these scores are only validated for acute pain, but in the absence of validated pain tools for chronic pain, these scores were considered the best validated alternatives. Another limitation is that the data need to be analyzed in an aggregate way . For this reason, we also used scores that are expressed on a 10-point scale and can be analyzed together, although we acknowledge that cross-validation of the absolute scores has not been done, to our knowledge. In general, a pain score of 4 is accepted as a cutoff for pain that needs treatment for all scores; hence, we considered the combined use of scores acceptable.To our knowledge, this is the first randomized controlled trial studying the effectiveness of the combination therapy morphine and gabapentin for pain in children. Although very challenging in design and in potential recruitment and retention of patients, we believe this trial will provide more solid evidence of the efficacy of gabapentin in combination with morphine to ultimately improve the treatment of severe NP in children.For the Gaba-2 study, ethical approval has been obtained in one of the participating centers, and the study is under review in the other centers. No patients have yet been included.Additional file 1:SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOC 122 kb)


Introduction: Acute myocardial infarction (AMI) patients present with variable clinical manifestations such as shortness of breath, nausea, etc. among which chest pain is the most common. Previous studies have reported that the clinical presentation of AMI patients with branch vessel disease is indistinguishable from epicardial coronary vessel disease. However, our experience suggests patients with branch vessel disease experience severe chest pain, especially those with a diagonal branch. Therefore, we aim to study the association of chest pain severity with isolated diagonal branch vessel disease as a culprit vessel in AMI patients.Methods: It is a retrospective case-control design, where 10 cases and 40 historic controls were recruited in the study. Cases were patients with isolated diagonal branch disease, whereas controls were patients with epicardial vessel disease in AMI. We reviewed Coronary Angiograms of adult patients who presented with acute myocardial infarction and had undergone coronary angiography at Aga Khan University Hospital, Karachi (AKUH). Information on pain scores was measured using the Numeric Pain Rating Scale (NRS) before administration of analgesics. Other relevant variables were also recorded on a pre-structured questionnaire.Results: The mean age of all the participants in the study was 60 ± 11.0 years, with 16% of the patients being women. Among all AMI patients, the intensity of chest pain in patients with isolated diagonal branch vessel disease was 2.6 units higher as compared to those with other epicardial coronary vessel diseases .Conclusion: This preliminary study indicates severe chest pain can be a differentiating symptom in AMI patients with diagonal branch disease. It emphasizes clinicians to look for a possibility of a diagonal branch as a culprit vessel in AMI for better judgment, as it is often overlooked. future studies may be conducted at multiple centers for larger sample size and better generalizability. Acute myocardial infarction (AMI) is one of the leading causes of death worldwide . It resuChest pain characteristics such as intensity, onset, relieving and aggravating factors may differ from patient to patient . Many reIn our practice, we often noticed patients with occlusion of a diagonal branch [branch arising from the left anterior descending artery (LAD)] to present with more severe chest pain as compared to patients with occlusion of other major epicardial vessels [left circumflex (LCX) and right coronary artery (RCA)] as infarct-related artery. In these patients, without suggestive findings of occlusion in epicardial vessels, there is a high likelihood of missing the involvement of a diagonal branch as a culprit vessel. In such circumstances, it may lead to a diagnostic dilemma if significant attention is not given while interpreting coronary angiograms. Therefore, in this pilot study, we aimed to study the association of intensity of pain with isolated diagonal branch vessel disease as compared to epicardial vessel disease in AMI patients.Study design and populationThe study incorporated a case-control design and was conducted at the Aga Khan University Hospital, Karachi (AKUH). Data was extracted for patients who presented with AMI to the emergency department at AKUH from the period of June 2014 to June 2016. Participants who were ≥ 18 years and had complete medical records were included in the study. We excluded patients who were on mechanical ventilation, had received analgesics prior coming to the emergency department from health care facilities outside AKUH, had collateral circulation to the obstructed diagonal branch or epicardial vessel, and those with known symptomatic neuropathy. Patients who were known opioid addicts were also excluded as they may have altered pain thresholds because of opioid use.We defined cases as patients who had isolated diagonal branch, without the involvement of LAD or any other major vessels (such as LCX and RCA). Controls were defined as patients whose coronary angiogram revealed other epicardial coronary vessels , LCX, and RCA).Data collectionWe began with the identification of cases during the period of June 2015 to June 2016 by reviewing coronary angiograms of AMI patients brought to the cardiac catheterization lab. Upon ascertainment of eligibility criteria, cases and controls were enrolled in the study. As we identified each case, we randomly selected four historic controls upon reviewing the coronary angiograms of previous AMI patients during the study period.Ascertaining outcome: pain assessmentOur hospital utilizes the Numeric Pain Rating Scale (NRS) as the most common tool for quantifying pain perception among adults with no cognitive or communication difficulties . The NRSAs a standard of care, upon initial assessment of vital signs, a trained doctor or nurse assesses the pain of all AMI patients using the NRS scale. Electrocardiogram (ECG) of these patients is then performed in order to reach an affirmative diagnosis of AMI. Pain medications are administered to the patients before shifting them to the cardiac catheterization lab for the intervention. These initial assessments are documented in the patient’s progress notes, which become part of the hospital record upon the patient’s discharge. For this study, the maximum pain score of each patient before the administration of analgesics prior to the procedure was recorded. Information on the history of co-morbid conditions and interpretation of ECG at the time of arrival was also noted.Ethical approval was sought from the Ethics Review Committee, AKU (4358-Car-ERC-16) which granted an exemption for ethical approval and permission to review the hospital records for this study.Sample size and statistical analysis planThe prevalence of diagonal branch vessel disease as culprit vessel in AMI is very low in the general population, i.e., 0.5%-1% -10. TherFor continuous variables, we report means and standard deviations for normally distributed variables, whereas, for non-normally distributed variables, we report median and interquartile range. For categorical variables, we determined frequencies and proportions. To examine the difference in baseline characteristics of quantitative variables, t-test for an independent sample was applied. Chi-square or Fisher Exact test were applied for categorical variables, as appropriate. A multiple linear regression was performed to determine the association of pain intensity between cases and controls keeping pain score as an outcome, while controlling for other factors and comorbidity profile of participants. Confounding and interaction were also assessed for biologically plausible variables. Data were analyzed using STATA version 12. A p-value of ≤ 0.05 was deemed significant.A total of 50 participants (10 cases and 40 controls) were included in the study upon review of the records. Among controls, 55% of the patients had LAD, 25% had left circumflex and 20% had RCA as culprit vessel in AMI. As the continuous variables in the data followed a symmetrical distribution, we report means ± standard deviation here. Cases and controls had a similar distribution of characteristics with respect to age, gender, co-morbid conditions ) and smoking status. However, more of the patients had been hypertensive in the control group  as compared to those with epicardial vessel disease (controls) [95% CI: 1.67 - 3.46], adjusted for all other covariates in the model  were done which revealed no difference in the value of RPain perception of patients with a family history of coronary artery disease was slightly higher (adjusted β-coefficient: 1.2), however, the difference was marginally statistically insignificant . There was no association of pain intensity with age, hypertension, and diabetes. Future studies may look into a larger sample population from multiple centers to explore the impact of family history and knowledge about the symptoms of AMI among these patients.This preliminary study highlights a distinct clinical feature of acute myocardial infarction patients with diagonal branch as an infarct-related artery. We observed AMI patients present with severe chest pain without evidence of disease in any major epicardial vessels on the coronary angiogram in our practice. On the contrary, we found disease in one of the branch of major epicardial vessels, which was mostly a diagonal branch causing severe pain. From the review of the existing literature, we know that the severity of chest pain per se does not correlate with the severity of CAD . In addiOur preliminary data confirms our observation that patients with diagonal branch vessel CAD have more severe chest pain in the condition of AMI. One of the possible pathophysiologies can be explained by the diameter of the vessel. The delivery of oxygen-rich blood to the myocardium is influenced by coronary artery diameter, the presence of collaterals and perfusion pressure determined by the pressure gradient from the aorta to the coronary arteries . Due to The strength of our study is that it highlights the evidence on the association of pain and diagonal branch vessel disease emphasizing on possible mechanisms between pain pathways and ischemic territories being sensitive to particular branches or vessels. However, the study has certain limitations inherent to the design of retrospective studies and cannot determine causality. As the condition under study is less common , the single-center study contributed to a limited number of cases, while a random selection of controls permitted us to limit selection bias. Future studies involving multiple centers may make this primitive population more accessible for exploration and may be proposed to observe a difference in pain perception between the two groups incorporating knowledge of AMI symptoms and total ischemic time.To conclude, our research suggests that if patients present with severe chest pain without significant disease in the major epicardial vessels, one should always look for disease in the diagonal branch vessel, especially in the absence of significant ECG changes. A more aggressive strategy towards the management of chest pain in patients with diagonal branch vessel disease may be required and may lead to higher patient satisfaction and comfort.


Burn pain is a unique and complex challenge for all health professionals and the patients. The only way to insure quality burn pain relief is the patient's self-report. Thus, assessment of severity of pain and its associated factors are important in treatment plan. To assess severity of burn pain and associated factors in Yekatit 12 Hospitals burn unit from January 1, 2017, to March 30, 2017. Hospital based cross sectional study design was conducted. Data was collected by using structural questionnaires from all eligible patients, those admitted to burn unit of Yekatit 12 Hospital during the study period. Severity of burn pain was assessed by using numerical, facial, and behavioral pain scale measurement tools. Pain assessment scale was deployed for patients by data collectors before medication and dressing change. Multivariate logistic regression analysis was conducted to identify significant predictors based on p value less than 0.05 with 95% confidence interval. A total of 62 burn patients were included in the study. 87.1% of the patients feel severe pain and 12.9% of the patients feel moderate pain. Pediatrics age groups were about 11 times more likely to feel severe pain than adults, and patients with TBSA ≥ 25% were about 8 times more likely to feel severe burn pain than those with TBSA < 25%  (P = 0.033). Majorities of burn patients had severe pain and burn pain was not appropriately treated. Therefore, appropriate pain management was strongly recommended. Burns are extremely painful and the most common causes of distress to the patients . Burn inThere are different factors that affect the severity of burn pain. Burn patient with large area full-thickness burn suffers more pain than patient with small area full-thickness burns. The experience of pain is largely related to patient development age, prior experience with pain cultural characteristics of the patient, degree of burn, source of burn, duration of burn, and management gaps .Unrelieved burn pain has been described as a significant public health problem. The long-term risk of undertreated pain is associated with the development of chronic pain, depression, and Posttraumatic Stress Disorder (PTSD) . A succePain scales are used to monitor pain by using point scale of 0–10. People have a means to communicate their pain intensity and clinicians have means to track it, just as they would keep track of other vital signs, like blood pressure, respiration, and pulse rate. Even though pain is a subjective experience that cannot be verified by traditional diagnostic methods, it cannot be effectively treated unless it is measured .According to National Institute for Health, the most commonly used pain assessment methods are numerical and behavioral assessment scale. Numerical scales can be used for both adults and children who can express themselves where 0 is having no pain, 1-3 mild pain, 4-6 moderate pain, and 7-10 severe pain. For children and adult patients who are unable to provide a self-report of pain, behavioral assessment scale can be used to assess pain [WHO “pain ladder” guidelines recommend that pain is treated according to its severity. Mild pain can be treated by nonopioid drugs like paracetamol and anti-inflammatory drugs. Then, if complete pain relief is not achieved, a weak opioid such as tramadol is added to the existing nonopioid regime. If this also becomes insufficient, a weak opioid is replaced by a stronger opioid, such as morphine, fentanyl, and pethidine while continuing the nonopioid therapy. If the initial presentation is severe pain, this stepping process should be skipped and a strong opioid should be started immediately in combination with a nonopioid analgesic .Nonpharmacological therapy is an important measure complementary to medication to manage pain and anxiety in burn patients. It should be initiated as early as possible in order to prevent the development of anxiety, which can prolong the cycle of pain .The study was conducted in burn unit of Yekatit 12 Hospital, Addis Ababa, Ethiopia, from January 1, 2017, to March 30, 2017. Yekatit 12 Hospital is one of the hospitals under Addis Ababa City Administration Health Bureau that has been giving routine health services for Addis Ababa and other referral cases from different regional states of Ethiopia. The hospital provides services for a population of approximately 4 million people. It has 9 departments and 6 units and has 265 beds. It has been the main referral hospital for treatment of burns patients for many years. The burn unit has 19 beds, 12 of them for adults and 7 for pediatrics. Study Design. Hospital based cross sectional study design was employed. Source Population. All burn patients in Yekatit 12 Hospital burn unit constituted the source population. Study Population. Selected burn patients who fulfill inclusion criteria and admitted to burn unit of Yekatit 12 Hospital during the study period were the study population. Sample Size Determination and Sampling Technique. Census was used to include all burn patients in Yekatit 12 Hospital burn unit. Inclusion Criteria. Inclusion criteria were all eligible burn patients who provide consent. Exclusion Criteria. Very critically ill burn patient, patients who refused to give consent, and patients who were referred for further management were excluded from the study. Data Collection Tools and Procedure. Data was collected using pretested structured questionnaires by two degree holder nurses and supervised by one M.S. anesthetist. A numerical, facial, and behavioral pain scale measurement tool was employed to assess the severity of burn pain. Numerical assessment scale is used for adults and older children (>12 years), facial pain assessment scale is used for children between 4 and 12 years and behavioral pain assessment scale is used for children 1–4 years old. Pain assessment scale was deployed for patients by data collectors before medication and dressing change. The data was collected by chart review and patient's interview. Each of the five categories , F = face, L= legs, A = activity, C = cry, and C = consolability, is scored from 0 to 2. This results in a total score of 0–10. Muscle tone was assessed in patients with spinal cord lesion and hemiplegia of unaffected side ).Faces Pain Scale-Revised for children 4–12 years .The Numeric Pain Rating Scale for adults and older children (>12 years)  . Among them, the highest number of 41 (66.1%) is found in the age group of 1–14 years and 21 (33.9%) are in the age groups of ≥15 years. The mean age of respondents was 12.84 with the SD of 11.05 and minimum 1 year and maximum 40 years .Out of 62 of the patients, 41.9% were Amhara, 35.5% were Oromo, 11.3% were Gurage, 6.5% were Tigre, and 4.8% were others (Afar and Wolaita) . MajoritThe major causes of burn were hot water 35.5%, electricity 30.6%, fire wood 16.1%, gas 11.3%, and others (stove) 6.5%. Majority of the burns (56.5%) were second-degree burns and the rest (43.5%) were third-degree burns. Majority total surface area of burn was >25% which accounts for 38.7%. Majority of burns duration (62.9%) were within one month and the rest (17.7%) were between one and two months, 12.9% were more than three months, and 6.5% were between one and two months .In multivariate analysis, where 95% CI for the adjusted odds ratios were calculated among these variables, severity of pain is statistically significant with ages (P = 0.039) and those patients whose TBSA ≥ 25% (P = 0.033) of the study groups. Those study participants whose age ≥ 15 years are 0.09 times less likely to feel severe burn pain than 1–14-year-old patients . Those study subjects whose TBSA ≥ 25% are 7.773 times more likely to feel severe burn pain than those TBSA < 25% of patients  .χ2 = 3.106, P = 0.082) [In this study also females feel more severe burn pain than male patients, but the difference was not statistically significant P = 0.102) which is comparable with the above study. The study done in South Korea shows that female patients reported more severe pain than male patients, but the difference was not statistically significant ; i.e., pediatrics age groups are 11.1 more likely to feel more severe pain than adults. According to Blankenburg M et al., there is a difference between adults and children in pain sensitivity. Children are more sensitive to pain stimuli compared to adults. Sex differences were minimal, during childhood [rd-degree burns are the least painful as compared to 2nd-degree burns, and this is because the nerve endings have been burned and patients with 2nd-degree burns experience greater pain as the ultrasensitive nerve endings are exposed and as TBSA increased the patients suffer more intense pain as compared with patients with small body surface area burned [According to Miller C NS, severity of burn pain depends on degree of burn and percentage of total burns surface area (TBSA). Usually 3a burned .This study also revealed that burn patients with high percentage of total surface area (TBSA ≥ 25%) are 7.773 times more likely to feel severe pain than those with TBSA < 25% . Second-degree burn patients also feel more severe pain than third-degree burn patients but the difference was not statistically significant (P = 0.072).The study done in India General Hospital, in 2015, showed that the percentage of patients who were suffering from pain increased with the level of education from 8% in the illiterates to 19% in the partially educated and then 46% in the university graduates. This is due to increased awareness levels, and they give more attention to pain which intensifies it .This study also shows that among adult patients severity of burn pain is increased with the level of education from 9.8% in the illiterates to 14.3% in the partially educated and then 19.1% in the university graduates which is comparable. According to WHO “pain ladder” guideline of pain management, mild pain should be treated with nonopioid drug like paracetamol and NSAIDS. Moderate pain is treated with weak opioid such as tramadol. Severe pain is treated with strong opioids such as morphine, fentanyl, and pethidine while continuing the nonopioid therapy [In this study even though majority of the patients (87.1%) were feeling severe pain, most of them (48.4%) took paracetamol and 30.6% took tramadol, which exacerbate the intensity of burn pain. This may be due to management gaps (skill or resource).The study, conducted in Toronto, showed that, in addition to gender, ethnicity was also an important factor for pain. The differences were found in white Americans and African Americans living in the same social and geographical environment. African Americans felt more pain than white Americans . HoweverMajorities of burn patients had severe pain and there was inadequate management of burn pain. Therefore, health care providers should treat burn patients according to pain management protocol as mentioned in WHO pain ladder of pain management, hospital administration should provide adequate resources needed for burn pain management as there is lack of adequate resources to manage burn pain, and patients were recommended to report severity of burn appropriately so that appropriate drug can be used for the treatment of burn pain.


Chest pain is common in acute ambulance transports. This study aims to characterize and compare ambulance-transported chest pain patients to non-chest pain patients and evaluate if patient characteristics and accompanying symptoms accessible at the time of emergency call can predict cause and outcome in chest pain patients.Retrospective, observational population-based study, including acute ambulance transports. Patient characteristics and symptoms are included in a multivariable risk model to identify characteristics, associated with being discharged without an acute cardiac diagnosis and surviving 30 days after chest pain event.In total, 10,033 of 61,088 (16.4%) acute ambulance transports were due to chest pain. In chest pain patients, 30-day mortality was 2.1% (95%CI 1.8–2.4) compared to 6.0% (95%CI 5.7–6.2) in non-chest pain patients. Of chest pain patients, 1054 (10.5%) were diagnosed with acute myocardial infarction, and 5068 (50.5%) were discharged without any diagnosis of disease. This no-diagnosis group had very low 30-day mortality, 0.4% (95%CI 0.2–0.9). Female gender, younger age, chronic pulmonary disease, absence of accompanying symptoms of dyspnoea, radiation, severe pain for > 5 min, clammy skin, uncomfortable, and nausea were associated with being discharged without an acute cardiac diagnosis and surviving 30 days after a chest pain event.Chest pain is a common reason for ambulance transport, but the majority of patients are discharged without a diagnosis and with a high survival rate. Early risk prediction seems to hold a potential for resource downgrading and thus cost-saving in selected chest pain patients.The online version of this article (10.1186/s13049-019-0659-6) contains supplementary material, which is available to authorized users. Chest pain is one of the most frequent symptoms among patients contacting the emergency medical services (EMS) and emergency departments (EDs) , 2. In tSince chest pain is associated with potential life threatening conditions like acute myocardial infarction (AMI), pulmonary embolism or acute aortic dissection, the EMS response is most often dispatched in an “all or nothing”-fashion with a high triage level and immediate response. This level of triage is relevant in patients with a subsequent confirmed serious/adverse diagnosis and may favour an improved outcome , 7. WhilConsequently, there is a need for evaluating prehospital over-triage and non-relevant EMS use in chest pain patients by examining diagnoses and mortality rates in patients presenting with chest pain and a need for addressing ways of early discrimination between high- and low-risk patients and thus support the decision of when an acute EMS response is relevant or may be down-graded. Structured use of patient characteristics and presence/absence of accompanying symptoms could be a key factor in improving the triage in chest pain patients . TherefoTo describe the prevalence of chest pain and compare patient characteristics, mortality rates, diagnostic patterns, LOS, and place of primary admittance between chest pain and non-chest pain patientsTo compare mortality rates and LOS among chest pain patients according to the final diagnosesTo identify predictors (available at the time of ambulance dispatch) of “potential for downgrading EMS response” in chest pain patients, indicated by discharge without an acute cardiac diagnosis and survival for more than 30 days after chest pain event.The specific aims of the present study were, in patients transported to hospital by ambulance:This retrospective, observational population-based study was approved by The Danish Data Protection Agency, Central Denmark Region (ref. number 1–16–02-788-17) and the Danish Patient Safety Authority (ref. number 3–3013-2321).The Danish health care system, including the EMS system, has previously been described , 14. In We collected dispatch information and information on the preceding 1-1-2 call and merged these with data from the Danish National Patient Registry to include data on hospital admissions and existing comorbidity . We acquThis study included patients transported to hospital by ambulance in the Central Denmark region in a 1-year period from May 1st 2015 to April 30th 2016. We included patients transported after 1-1-2 call and patients transported following request from GP. We excluded transports missing information on symptoms or index diagnosis and transports terminated before reaching hospital, see Additional files Way of entrance into the EMS system was categorized as “112-requested” or “GP-requested”. Chest pain was identified through dispatch codes for patients undergoing criteria-based dispatch (112-requested) and through specific text searches in electronic prehospital patient files (in GP-requested transports). The automatic text search to identify chest pain/discomfort in the patient files was verified by manual review of 3500 patient files (5%). Details on the automatic text search and validation are described in Additional file Acute cardiac conditions Other diagnoses according to ICD-10 chaptersNo final diagnosis We categorized final diagnosis according to the ICD-10 codes assigned to the patient as primary diagnoses during the admission following the EMS transport (=index admission):See Additional file Primary outcome: Death within 30 days of admission.Secondary outcome: Acute cardiac diagnosis during index admissionComposite secondary endpoint: To investigate if the ambulance transport and the succeeding hospital admissions in chest pain patients were appropriate or not, we constructed a combined secondary outcome of being discharged without an acute cardiac condition and surviving more than 30 days after chest pain event.See Additional file Categorical data are presented as numbers and proportions. Continuous data are presented as means with 95% confidence interval (CI) or medians and interquartile ranges (IQR). For comparison between groups, Fisher’s exact test and Pearson’s chi-squared test were used for categorical data, and unpaired samples T-test and Wilcoxon Rank Sum for continuous data as appropriate. Mortality is described as Kaplan-Meier curves truncated at 30 days. Follow-up was terminated November 14th 2016 and only first transport registered for each patient was included into mortality analysis, see flowchart in Additional file We performed two predefined multivariable prediction models, using binary regression analyses in patients with chest pain, to evaluate the association between the secondary composite endpoint of not being diagnosed with an acute cardiac condition and surviving more than 30 days and different patient characteristics and accompanying symptoms – information that is potentially available at the time of emergency call. The first model, applied to all patients suffering chest pain, included: 1) age, gender, prior AMI, diabetes mellitus, known congestive heart disease, chronic pulmonary disease, and moderate to severe renal disease. The second model included the same patient characteristics as in model 1, but also accompanying symptoms. This was systematically registered only for those patients undergoing criteria-based dispatch (not GP requested dispatch) and thus, this model was applied to that sub-group only.Age was included as age-groups . The mentioned predictor variables were included in multivariable analysis.P-values < 0.05 were considered statistically significant. Analyses were performed using STATA Intercooled software, version 15.1.Regression models were evaluated 1) by plotting predicted and observed frequencies against age group as relevant in subgroups according to the remaining variables, 2) by likelihood-ratio test, and 3) by calculation of goodness-of-fit. All calculations were two-sided and We identified 71,891 acute ambulance transports in the prehospital dispatch system during the study period, see flowchart in Additional file p < 0.001 for all mentioned variables), see Table Chest pain was the main symptom in 10,033 (16.4%) of ambulance transports. This equals eight transports due to chest pain per 1000 inhabitants per year in the Central Denmark Region. Thirty-day mortality rate was considerably lower in chest pain patients than in patients without chest pain, 2.1% (95%CI 1.8–2.4) compared to 6.0% (95%CI 5.7–6.2), Fig. p < 0.001), see Table p < 0.001). The 30-day mortality in chest pain patients was lowest in those not receiving a disease specific diagnosis during index admission (< 0.5%), Table A disease-specific diagnosis was established in 49.5% of chest pain patients  whereas 50.5% received no disease-specific diagnosis during index admission, Table When including all chest pain patients into our multivariable model (Model 1), female gender, younger age, congestive heart disease, and chronic pulmonary disease were all associated with being discharged without an acute cardiac diagnosis. Age below 70 and no chronic pulmonary disease were all associated with surviving 30 days after a chest pain event, see Table When combining Model 1 with accompanying symptoms as predictors in the multivariable analysis (Model 2) in the subgroup of chest pain patients undergoing criteria-based dispatch, both absence of dyspnoea, absence of radiation/severe pain for > 5 min and absence of clammy skin/uncomfortable/nausea were associated with being discharged without a severe cardiac diagnosis. Absence of an accompanying symptom of non-responsiveness and dyspnoea were associated with surviving 30 days after a chest pain event, see Table Female gender, younger age, chronic pulmonary disease, absence of dyspnoea, absence of radiation/severe pain for > 5 min and absence of clammy skin/uncomfortable/nausea were associated with the combined endpoint of being discharged without an acute cardiac diagnosis and surviving 30 days after chest pain event.When applied in a diagnostic model, Model 2 identified 14% of the patients eventually discharged without an acute cardiac diagnosis and surviving 30 days after a chest pain event, with a sensitivity of 99%, a negative predictive value (NPV) of 98%, and a negative likelihood-ratio of 0.08. Thirty-day mortality in these patients was 0.7%.This large study is based on all registrations of ambulance transports in the Central Denmark Region in a 1 year period, combined with diagnoses and vital status from validated national registers. However, we did exclude 6% of the cohort due to missing data on either symptom or diagnosis, and selection bias cannot be excluded. Available characteristics, diagnoses and outcome in these patients are presented in Additional file In mortality analysis 70 patients are lost-to-follow-up, meaning that they are registered as inactive in the Danish civil registration system. However, only 13 of these where registered as inactive within 30 days after their chest pain event, while the remaining 57 where inactive at the time of their chest pain event (e.g. migrated or without residence in Denmark).The study is limited by its retrospective design, which affects both the identification of symptoms (if specific information is missing) and potentially biases the effect of patient characteristics, symptoms and comorbidity, since we cannot definitely differentiate between correlation and causality. The identification of chest pain could be limited by the fact that only 37% of patients were triaged using symptom-based dispatch. Instead, symptom-identification relied on automatized text search in notes from electronical prehospital patient records. This method may be sensitive to spelling and abbreviation of words in the records. We sought to compensate for this by including several spellings and known abbreviations of each word, by excluding terms describing rejection of chest pain symptoms and by manual validation of the method in > 5% of the cohort. The automatized text search showed very good agreement with the manual reviews (kappa = 0.95), Additional file This retrospective study in a large cohort of patients being transported by ambulance has three major findings. Firstly, chest pain is a very common reason for acute ambulance transport and hospital admission, accounting for one in six emergent ambulance transports. Secondly, acute ambulance transport in chest pain patients is associated with a high degree of overtriage with more than 50% of transported chest pain patients discharged without any diagnosis of disease and with a very low (< 0.5%) 30 day-mortality risk. Thirdly, it may be possible to identify a very-low-risk group already at the time of emergency call based on patient characteristics and symptomatology, indicating a potential for downgrading the response in selected chest pain patients.The rate of chest pain patients transported by ambulance was comparable to the chest pain rate found in recent Swedish and Danish studies, but substantially higher than earlier reported in studies from Norway and the UK , 20–23. When compared to patients without chest pain, chest pain patients were more often diagnosed with an acute cardiac condition including AMI (13% vs 2%), but also more often discharged with no final diagnosis (51% vs. 19%). This is a paradox and reflects on one hand the relevance of chest pain as a symptom of acute cardiovascular disease, but on the other hand also an overtriage of chest pain patients compared to patients presenting with other symptoms. The burden added to the EMS by chest pain patients is exaggerated by the fact that 88% of these patients were allocated a “grade A” response, thus representing 31% of all “grade A” responses. The decision to dispatch a “grade A” response is currently not based on an individual risk-estimation, but rather a “no miss” strategy, where the majority of patients with symptoms with even the slightest risk of AMI, are offered the highest level of care. The result is a significant overtriage, where more than half of all chest pain patients are discharged with no disease specific diagnosis and extremely low 30-day mortality below 0.5%. This advocates the use of a systematic differentiation between high-risk chest pain patients with urgent need of treatment and very low-risk chest pain patients without need for hospital admission. In the EMCC, this may be achieved by including patient characteristics and symptoms  in a risk assessment tool.In explorative analyses on the present cohort Tables  and 4 feClinical implementation of a risk assessment strategy may further unfold as the patient pass through the EMS system. Early rule-out of AMI in the ED using patient characteristics and clinical presentation in combination with high-sensitive troponin has been validated in several recent studies –28. EvenChest pain is the reason for 16% of all ambulance transports. AMI is only diagnosed in 11% of chest pain patients. The mortality in chest pain patients is lower than in other patients transported to hospital by ambulance, and particularly low in chest pain patients not receiving a diagnosis of disease during index admission. Structured risk assessment using patient characteristics and symptoms seems to hold a potential for early resource downgrading in low risk chest pain patients, already in the prehospital setting.Additional file 1:Patient flowchart. Flowchart of study patients. (PDF 121 kb)Additional file 2:Prehospitally terminated transports and transports missing symptoms or final diagnosis. Characteristics, symptoms and diagnoses in transports terminated prehospitally, or in which either symptoms or final diagnosis is missing. (PDF 424 kb)Additional file 3:Identification of chest pain. Details on Danish Index codes indicating chest pain and the automatic text search and validation of this. (PDF 605 kb)Additional file 4:ICD-10 codes. ICD-10 diagnoses used to categorize final diagnosis, calculate Charlson Comorbidity Index (CCI), and to identify known comorbidity. (PDF 531 kb)Additional file 5:Data for Fig.


Low back pain (LBP) is ranked as one of the most prevalent health conditions. It is likely that some inflammatory mediators could be associated with pain and disability in these patients. Photobiomodulation therapy (PBMT) is a non-pharmacological therapy often used in patients with LBP and one of the possible mechanisms of action of therapy is modulate inflammatory mediators. However, to date there are no studies that evaluated the effects of PBMT on the levels of inflammatory mediators in patients with LBP. The aim of this study is to evaluate the acute effects of PBMT on systemic levels of inflammatory mediators and pain intensity in patients with chronic non-specific low back pain.2 (PGE2). The secondary outcomes will be levels of necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and pain intensity. Biochemical and clinical outcomes will be measured at baseline and 15 minutes after the single treatment session.This is a prospectively registered, two-arm randomized placebo-controlled trial with blinded patients, assessors and therapists. Eighteen patients with chronic non-specific LBP will be randomized into 2 groups: placebo or active PBMT. The treatment will be provided in a single session. The primary outcome will be levels of prostaglandin EDespite PBMT be used in musculoskeletal disorders such as LBP, to the best of our knowledge this is the first study that will investigate a possible biological mechanism behind the positive clinical effects of PBMT on non-specific chronic low back pain.The study was approved by the Regional Research Ethics Committee. The results will be disseminated through publication in peer-reviewed international journal and conferences.NCT03859505. Some aspects can be associated with low back pain, and the identification of these aspects is helpful in both prevention and management of this condition. One of these aspects is the possible association between inflammatory mediators and low back pain, since the increased of pro inflammatory cytokines levels is often observed in painful conditions.,5Non-specific low back pain is a complex and extremely frequent condition demonstrated increase of plasmatic levels of necrosis factor alpha (TNF-α) in patients with chronic low back pain when compared to healthy individuals, for example. However, no significant correlation of TNF-α levels to pain intensity or disability were identified. Moreover, it was observed that there is an increase of TNF-α ,8 and interleukin (IL) 6 levels in patients with acute low back pain. Thus, the presence of some inflammatory mediators might be associated with pain and disability in patients with low back pain, since pro inflammatory cytokines such as IL-6, TNF-α and IL-1 contribute to the activation of nociceptors that generate potential of action and pain hyper sensibility.,5Evidences have demonstrated increase of pro inflammatory cytokines levels in patients with low back pain. Wang et al However, the mechanisms of action of available therapies to reduce pain and disability in these patients still remain uncertain. According to the abovementioned studies,–8 the modulation of inflammatory mediators levels could be considered a possible strategy in the low back pain management and thus, the use of photobiomodulation therapy (PBMT) could be interesting in this case.Several nonpharmacologic and noninvasive management options are available for patients with low back pain . PBMT is often used in the treatment of musculoskeletal disorders such as low back pain;,12 however, the exact mechanism of action through PBMT decreases pain intensity and disability in these patients is still unknown. Evidences suggest that PBMT is effective in modulate inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-10 and prostaglandin E2 (PGE2), both in experimental and clinical studies,–18 contributing to pain relief,19 and tissue repair.,21 The biological responses of PBMT on these inflammatory mediators may be targeted as possible mechanism of action for its beneficial clinical effects.PBMT is a non-pharmacological and non-thermal intervention that consists in applying a non-ionized form of light, which includes LASER (light amplification by stimulated emission of radiation) and LED (light-emitting diodes) from visible to infrared spectrum.2) and pain intensity in patients with chronic non-specific low back pain.However, currently there are no studies about the effects of PBMT on inflammatory mediators in patients with non-specific low back pain, investigating whether this could be a possible mechanism of action. Therefore, the aim of this study is to evaluate the acute effects of PBMT on systemic levels of inflammatory mediators , placebo-controlled trial will be performed. The protocol of this study has been prospectively registered on Clinicaltrials.gov (NCT03859505). The study will be conducted at Department of Global Public Health and Primary Care, University of Bergen, Norway.2.2The present study will follow the ethical guidelines and was approved by the Regional Research Ethics Committee (Protocol No. 2018/1361/REK nord). Patients will be informed about all study procedures and asked to sign the Informed Consent Form prior to their enrollment in the study. Research personnel will take all appropriate and customary steps to ensure that data remain secure and that patient privacy and confidentiality will be maintained.2.32 (primary outcome of the present study) of 1.05 pg/μl (0.42 standard deviation), whereas applying the placebo in patients with non-specific low back pain resulted in levels of PGE2 of 1.52 pg/μl (0.39 standard deviation). We used the Researcher's Toolkit to calculate the sample size . Based on the aforementioned parameters used to calculate the sample, we found a sample of 9 patients per group, for a total of 18 patients. Since the phototherapy device used in the study causes no harmful thermal effects, patients of different skin colors will be recruited. The patients will be recruited through primary care doctors and physiotherapists.Since no studies assessing the effects of PBMT on inflammatory mediators in patients with non-specific low back pain are available, the number of patients per group in the present study was calculated based on a pilot study. This pilot study was recently conducted by our research group with 3 patients per group in order to estimate the sample size. A β value of 20% and an α of 5% were used to calculate the sample size. The pilot study showed that applying PBMT in patients with non-specific low back pain resulted in levels of PGE2.4Inclusion criteria:Patients with chronic non-specific low back pain ;Persistent low back pain for at least 3 months;Pain intensity of at least 3 points, measured by Pain Numerical Rating Scale;Aged between 18 and 65 years;Both genders.Exclusion criteria:Patients with severe skin diseases ;,26Patients with low back pain associated with nerve root compromise ;Serious spinal pathologies such as fractures, tumors, inflammatory and infectious diseases;Serious cardiovascular or metabolic disorders;Previous spinal surgery;Pregnancy.2.5The patients will be welcomed by the study's blinded assessor who will determine whether they will be eligible to participate in the study. Subsequently, a file will be completed with the patient's sociodemographic data and clinical history. Next, the primary and secondary outcomes of the study will be collected and all eligible patients will be randomized and allocated into 2 interventions groups: active PBMT or placebo PBMT. Fifteen minutes after the end of the single treatment session, the primary and secondary outcomes of the study will be collected again. The Consolidated Standards of Reporting Trials flowchart summarizing experimental procedures and patients is shown in Figure 2.6Prior to the single treatment session, patients will be randomized into their respective intervention groups: placebo or active PBMT. The randomization will be generated by a computer program (Excel Office 2010) and performed by a participating researcher not involved with the recruitment or evaluation of patients. This same researcher will be responsible for programming the PBMT device according to the result of the randomization (active or placebo mode) and will be instructed not to disclose the programmed intervention to the therapist, any of the patients or other researchers involved in the study until its completion. Concealed allocation will be achieved through the use of sequentially numbered, sealed and opaque envelopes. To ensure blinding for therapists and patients, the device will emit the same sounds and the same information on the display regardless of the programmed mode. Thus, patient and therapist will be blinded throughout the treatment.2.7Patients will undergo the treatment (active PBMT or placebo), according to prior randomization, in a single session:1.2) and LaserShower (emitter with an area of 20 cm2) cluster probes as emitters. Nine sites will be irradiated on the patient's lumbar region: 3 central sites on top of the spinous processes , using the SE25; in the same direction, but laterally, 3 sites on the left and 3 on the right , using the LaserShower (LS). PBMT irradiation sites and parameters were chosen based on a previous study. The treatment will be performed in a single session and the patients will receive a total dose of 220.05 J. Table Active PBMT: The PBMT will be performed using the Multi Radiance Medical Super Pulsed Laser MR4 console , with the SE25  and secondary outcomes (levels of TNF-α and IL-6 and pain intensity) of the study will be obtained at baseline and 15 minutes after the single treatment session by an assessor who will not be aware of patients’ allocation to their treatment groups:The primary outcome (levels of PGE2 (inflammatory mediators): measured by enzyme-linked immunosorbent assay (ELISA) method. Blood samples (10 ml) will be collected by a qualified nurse  and will be obtained from the antecubital vein. One hour after collection, each sample will be centrifuged at 3000 rpm for 20 minutes. Pipettes will be used to transfer the serum to Eppendorf tubes, which will be stored at −80°C until analysis. The levels of TNF-α, IL-6 and PGE2 in the blood samples will be determined by ELISA, using a commercial kit and following the manufacturer's instructions . Spectrophotometric readings will be performed in a SpectraMax Plus 384 Absorbance Plate Reader  with 450-nm wavelength and correction to 570 nm. The results of TNF-α and IL-6 will be expressed in pg/ml and the results of PGE2 will be expressed in pg/μl.Levels of TNF-α, IL-6 and PGE Pain Numerical Rating Scale evaluates pain intensity levels perceived by the patient on an 11-point scale ranging from 0 to 10, with 0 being ‘no pain’ and 10 ‘the worst possible pain. Patients will be instructed to score the level of pain intensity based at the time of evaluation.Pain intensity: measured by the Pain Numerical Rating Scale.2.9 The findings will be tested for their normality using the Shapiro-Wilk test. Parametric data will be expressed as mean and standard deviation and non-parametric data as median and respective upper and lower limits. Parametric data will be analyzed by two-way repeated measures analysis of variance  with post-hoc Bonferroni correction. Non-parametric data will be analyzed using the Friedman test and, secondarily, the Wilcoxon signed-rank test.The statistical analysis will be conducted following the principles of intention-to-treat analysis.2.10The datasets generated and analyzed during the current study will be available from the corresponding author on reasonable request.3Despite PBMT be used in musculoskeletal disorders such as low back pain, to the best of our knowledge this is the first study that will investigate a possible biological mechanism behind the positive clinical effects of PBMT on non-specific chronic low back pain. We strongly believe that this investigation can be helpful in the management of this condition. Over the years, it has been believed that some subgroups of this population can benefit from specific treatments, responding favorably to specific therapies.,31 In this way, knowing the mechanism of action of available therapies becomes an important aspect in this process.Non-specific low back pain is a complex health condition and several treatment options may be used for symptoms relief. cytochrome c oxidase modulation and ATP synthesis, besides modulating some inflammatory biomarkers.,18 Thus, if PBMT is able to modulate inflammatory mediators in non-specific low back pain, patients with increased levels of these mediators might be more responsive and consequently benefit more with the use of therapy.PBMT triggers positive effects acting in different ways, including increase of microcirculation,It is important to highlight that the present study is innovative and present high methodological quality . The sample size was calculated to provide the appropriate statistical power to detect precise differences for the primary outcomes of the study; however, the sample size has not powered enough to be correlated with the secondary outcome (pain intensity). One of the limitations of the study is that although the PBMT parameters were based on previous studies, there was no optimization and only one dose will be tested.3.1The study will be disseminated through publication in peer-reviewed international journal and conferences.SST, LOPC, ECPLJ and JMB contributed to the concept and design of the study, established the hypothesis and wrote the original proposal. SST, LOPC, JJ, MBS, IFN, ECPLJ and JMB contributed significantly in creating the manuscript. ECPLJ and JMB performed critical revisions of the manuscript. SST wrote the final version of the manuscript. All authors read and approved the final version of the manuscript.Conceptualization: Shaiane Silva Tomazoni, Leonardo Oliveira Pena Costa, Jon Joensen, Martin Bjørn Stausholm, Ingvill Fjell Naterstad, Ernesto Cesar Pinto Leal-Junior, Jan Magnus Bjordal.Funding acquisition: Shaiane Silva Tomazoni.Investigation: Ernesto Cesar Pinto Leal-Junior.Methodology: Shaiane Silva Tomazoni, Jon Joensen, Martin Bjørn Stausholm, Ingvill Fjell Naterstad, Ernesto Cesar Pinto Leal-Junior.Project administration: Shaiane Silva Tomazoni, Jon Joensen.Supervision: Leonardo Oliveira Pena Costa, Jan Magnus Bjordal.Writing – original draft: Shaiane Silva Tomazoni, Leonardo Oliveira Pena Costa, Ernesto Cesar Pinto Leal-Junior, Jan Magnus Bjordal.Writing – review & editing: Shaiane Silva Tomazoni, Leonardo Oliveira Pena Costa, Ernesto Cesar Pinto Leal-Junior, Jan Magnus Bjordal.


Implementation of the ATLS algorithm has remarkably improved the resuscitation of trauma patients and has significantly contributed to the systematic management of multi-trauma patients. However, pain remains the most prevalent complaint in trauma patients, and can induce severe complications, further deterioration of health, and death of the patient. Providing appropriate and timely pain management to these patients prompts early healing, reduces stress response, shortens hospital Length of Stay (LOS), diminishes chronic pain, and ultimately reduces morbidity and mortality. Pain has been proposed to be evaluated as the fifth vital sign and be recorded in the vital sign charts in order to emphasize the importance of pain on short- and long-term outcomes of the patients. However, although the quality of pain treatment seems to be improving we believe that pain has been underestimated in trauma. This article aims to provide evidence for the importance of pain in trauma, to support its management in the emergency setting and the acute phase of patients’ resuscitation, and to emphasize on the necessity to introduce the letter P (pain) in the ATLS alphabet. Originating in ancient Greek medical terminology, the word “trauma” illustrates a physical injury, a wound, or a defeat. Then, combat trauma was significant and well represented in the literature of the Ancient Greeks. Nowadays, trauma constitutes the leading cause of death in people younger than 44 years old and the leading source of disability in the laboring age population –3, beingPain has been proposed to be evaluated as the fifth vital sign and is recorded in the vital sign chart , in ordeThe management of trauma patients mandates a prompt survey and rapid implementation of targeted interventions . Trauma Pain is the most common complaint among trauma patients in the Emergency Room (ER) . It is aA recent study reported that pain management in trauma patients varies significantly among emergency healthcare providers, highlighting the importance of consistent pain registration in patients’ files . More toCohen et al.  targetedHowever, assessment of trauma patients is difficult, and attention should be paid to specific occasions that are complicated in origin. For instance, patients with alcohol or drug abuse, polytrauma, severe head injury or limited level of consciousness, and elderly trauma patients may not be able to provide helpful information , 17, 21.Stress response is a sequence of changes, which occurs in neuroendocrine, immune, and metabolic systems . With reStress response is amplified by the presence of pain, evoking a sequence of alterations in neuroendocrine system . Pain stHigh levels of catecholamines and SNS activation have been repeatedly highlighted by the literature for their deleterious effects in the cardiovascular system . ArrythmElevated catecholamines and SNS activation modulate multilaterally the neuroendocrine function and metabolic status. ACTH, which is produced by the anterior pituitary, stimulates glucocorticoid secretion by the adrenal cortex. Cortisol then promotes catabolism and gluconeogenesis, inhibits the uptake of glucose by the cells  , and disA prompt response to painful stimuli activates the production of proinflammatory cytokines through immunoactive cell activation at the site of the injury . The latThe SNS and the HPA axis prompt vasoconstriction, hemoconcentration, and endothelial dysfunction, while it enhances acute inflammatory tissue reactions . In addiThoracic trauma constitutes the most studied field in trauma with respect to trauma-related pain and consequences –39. In tHowever, the best analgesic technique in thoracic trauma is unclear. Manay et al.  reportedTo optimize pain management, the implementation of the so-called multimodal analgesia that is defined as the utilization of a variation of medications and analgesic techniques, acting with different mechanisms and at multiple sites in the central and/or peripheral nervous system is well established . This coPain has been proposed to be evaluated as the fifth vital sign , 13, 45.In the event of acute pain, it is considered a proper approach to carefully appraise patients based on OPQRST. OPQRST is the acronym of Onset of the event, Provocation or palliation, Quality of the pain, Region and radiation, Severity, and Time (history). The aforementioned factors are important while examining patients upon admission, and the Visual Analog Scale (VAS) and Verbal Rating Scale (VRS) are assessed in order the severity of pain is understood , 47. UniPatients’ discomfort due to severe pain can also influence the responsiveness of physicians to difficult situations. Inexperienced physicians who are flustered and flurried in emergency settings, lose rapidly and irretrievably the confidence of their patients. A vicious cycle, therefore, is initiated that may lead to uncontrolled reactions from both sides. For this reason, not only does effective and thorough pain treatment guard doctors against patients’ emotional instability but it also cements their practice, in that, they will be able to interact with the medical environment through resilience and calm in the face of any adversity. On the other hand, definitely, any measures to promptly identify and treat life-threatening conditions, to preserve life and avoid secondary injury take priority in the management of trauma patients. Pain is important and vital to be managed; however, under no circumstances should interventions toward pain alleviation hinder the resuscitation process. Therefore, the letter P should be taken into account at the end of a successful resuscitation and at the beginning of any post-resuscitation interventions; in that way, it could bridge the ATLS protocols and any intervention following resuscitation. Once the primary survey of the trauma patient is completed, the resuscitation of pain could be integrated in the secondary evaluation, where a thorough clinical examination is carried out; in that case, the management of pain in trauma could form an indispensable part of the ATLS algorithm.Pain evaluation and management from the prehospital/emergency settings up to patients’ discharge should be considered a basic principle and plank for patients’ psycho-physical integrity. Patients’ holistic care encompasses five vital signs, the fifth of which should be Pain. Very importantly, the letter P (pain) should be introduced to the ATLS algorithm, and pain management of the trauma patients should be converted from an absolute challenge into a daily practice in the context of emergency medicine.All authors declare no conflicts of interest.


Headaches and abdominal pain are among the most common pediatric pain conditions. Mast cells have been implicated in the pathophysiology of migraines, as well as functional dyspepsia (FD) and irritable bowel syndrome (IBS). The primary aims of the current study were to assess headache prevalence in patients with FD and to assess the association between headaches and mucosal mast cells and eosinophils. An additional aim was to explore associations of headache with other symptoms.We conducted a cross-sectional retrospective chart review of 235 consecutive patients with chronic abdominal pain. All patients had completed a standardized questionnaire as part of their routine clinical evaluation. Both gastrointestinal and non-gastrointestinal somatic symptoms were included in the analysis. All patients diagnosed with FD had undergone upper endoscopy with biopsies obtained from the gastric antrum and duodenum and these specimens were utilized to assess eosinophil and mast cell densities, respectively.P = .001). Duodenal mast cell densities were significantly increased in those reporting headaches. Headache was not associated with any specific gastrointestinal symptoms but was associated with a wide array of non-gastrointestinal symptoms including fatigue, dizziness, muscle pain, joint pain, and chest pain.Overall, 86% of patients fulfilled Rome IV criteria for FD. Headache was reported by 73.8% of FD patients versus 45.2% of non-FD patients (Headaches are common in children and adolescents with abdominal pain and, utilizing Rome IV criteria, are specifically associated with FD. In patients with FD, headaches are associated with increased duodenal mast cell density and a variety of somatic symptoms, all of which are possibly the result of mast cell activation. Chronic or recurrent abdominal pain is estimated to affect up to 19% of the pediatric population, with the majority reporting symptoms that fit into discrete diagnostic categories under the broader heading of functional gastrointestinal disorders (FGIDs).,6 Understanding associations between these 2 common pediatric pain conditions may help to better define the pathophysiology underlying both.Pediatric chronic pain is increasingly recognized as a significant public health issue, with headaches and abdominal pain among the most commonly reported pain conditions.,8 The most current version of the criteria, Rome IV, was released in 2016 and significantly altered the criteria for FD and IBS. Previously, under Rome III, FD was defined as upper abdominal pain or discomfort unrelated to stools. Under Rome IV, FD is defined by the presence of epigastric abdominal pain unrelated to stools, early satiety, or postprandial fullness. IBS is defined by the presence of pain related to a change in stool frequency, a change in stool consistency, or by a change in pain with stooling. Previously, Rome III criteria required two of these symptoms to be present while Rome IV criteria only requires one of these symptoms to be present.,9Similar to pediatric headache, criteria exist to subdivide the population of youth with abdominal pain into discrete categories. These criteria, commonly referred to as the Rome Criteria, were initially defined and subsequently revised by expert panels. Currently, there are 4 FGIDs related to abdominal pain with the 2 most common being functional dyspepsia (FD) and irritable bowel syndrome (IBS).,11 Le Gal et al reported an increase of FD, IBS, and abdominal migraines (another FGID), respectively, in children and adolescents presenting to an emergency department with migraine headaches, as compared to pediatric patients presenting with mild trauma and no history of headaches. Similarly, headache and other somatic complaints appear common in pediatric patients with FGIDs. Specifically, migraine-like headaches have previously been reported in 40% of children with FGIDs.Some literature exists to suggest that abdominal pain symptoms may be more common in the headache population, and vice versa. Previous studies of adults with headache have demonstrated an increased incidence of upper abdominal symptoms, while migraine headaches in youth have been associated with both FD and IBS, as defined by Rome III.–16 To a lesser degree, environmental allergens have been implicated in both headaches and FD.,18 Taken together, these contributors would seem to suggest a common process involving mast cells.The association between headaches and chronic abdominal pain opens up the possibility of common pathophysiologic triggers or mechanisms. There are several contributors that these 2 pain conditions share. Stress and anxiety have been highly implicated in both conditions and are generally viewed as frequent significant contributors.–21 In a sample of 56 youth with FD (as defined by Rome III), Yeom et al reported an increase in gastric body and duodenal mast cells for patients who also reported headaches, as compared to those without headaches. This association appeared specific, as they found no associations with lymphocytes, neutrophils, and enteroendocrine cells based on headache status. Eosinophils, which share many physiologic processes with mast cells, were not evaluated. In adults with IBS, mast cells have been extensively evaluated. Generally, results have demonstrated increased mast cell density and degranulation; further, the density of mast cells in close proximity to nerves correlates with pain frequency and intensity.,23,24 These associations make intuitive sense, as mast cells may be activated by a number of factors which have been implicated in both headaches and abdominal pain, including stress and allergen exposure.To date, mast cells have been implicated in the pathophysiology of migraines, as well as FD and IBS.The primary aims of the current study were to assess headache prevalence in patient with FD and IBS, respectively, and to assess the association between headaches and densities of gastric and duodenal mast cells and eosinophils, respectively, in children with FD defined by Rome IV. This second aim was limited to FD patients because, unlike IBS, mucosal biopsy is a standard part of the diagnostic evaluation of dyspepsia yielding an unselected clinical group for comparison. An additional aim was to explore associations of headache with specific gastrointestinal and somatic symptoms.2We conducted a cross-sectional retrospective chart review of a convenience sample of 235 consecutive patients diagnosed with an FGID by a single board-certified pediatric gastroenterologist in a subspecialty abdominal pain clinic at Children's Mercy Kansas City. This study was approved by the Institutional Review Board of Children's Mercy Kansas City. Patients ranged in age from 8 to 17 years and reported having abdominal pain at least once weekly for a minimum of 8 weeks. All patients had completed a standardized questionnaire as part of their routine clinical evaluation. The questionnaire asked about gastrointestinal symptoms used to classify symptoms according to Rome IV criteria, as well as an array of non-gastrointestinal symptoms. Both gastrointestinal and non-gastrointestinal somatic symptoms were included in the analysis.Helicobacter pylori. Their previously obtained biopsy specimens were utilized to assess eosinophil and mast cell densities, respectively, in both the gastric antrum and the duodenum. Hematoxylin and eosin (H & E) stained slides, obtained from these patients as part of routine care, were used to assess eosinophil density. An immunohistochemical stain for tryptase was performed on the antral and duodenal biopsies of all study patients to determine mast cell densities. A mouse monoclonal antibody, anti-human mast cell tryptase, from Dako (clone AA1) was used at a dilution of 1:2000 on the Bond automated immunostainer following routine immunohistochemistry protocol for the stainer.All patients diagnosed with FD had undergone upper endoscopy with biopsies obtained from the esophagus, gastric antrum, and duodenum after failing to respond to acid reduction therapy. All patients were negative for nodularity, erosions, ulcers, and To determine eosinophil and mast cell densities, sections were initially scanned at a low magnification (× 10 objective magnification) to determine areas of maximal density. Using an Olympus CH30 microscope with a combination of 40 × objective and 10 × eyepiece, cells were counted in 5 consecutive high-power fields. Both cell types were counted only in the lamina propria of the mucosa. For the eosinophils, only cells demonstrating its nucleus were enumerated. For the mast cells, both spindled and epithelioid forms showing a nucleus were enumerated. Peak and mean cell densities were determined for the eosinophils and mast cells, respectively, in both the antrum and the duodenum. All cell counts were performed by a single observer (MS).3t test. Frequencies of specific gastrointestinal and non-gastrointestinal somatic symptoms were compared between patients reporting headaches and those who did not by chi square analysis. A P < .05 was considered statistically significant for all analyses.SPSS version 23  was used to perform statistical analysis. The frequency of a positive report of headache was compared between patients who met criteria for FD and IBS, respectively, as compared to those who did not meet criteria for each variable independently. All subsequent analyses were performed only on patients meeting FD criteria. Mean and peak eosinophil and mast cell densities, respectively, were compared between patients reporting headaches and those who did not by the student 4P = .001). Headache was reported by 57.9% of IBS (regardless of FD status) patients versus 56.3% of non-IBS patients (P = .82). As headache was only associated with FD, all other analyses were performed only with FD patients.Overall, 86% of patients fulfilled Rome IV criteria for FD and 58% fulfilled criteria for IBS. Fifty percent of patients fulfilled criteria for both FD and IBS. Overall, headache was reported by 69.8% of the patients. Headache was reported by 73.8% of FD patients (regardless of IBS status) versus 45.2% of non-FD patients (P = .022) and peak  mast cell densities were significantly increased in those reporting headaches.For the FD patients, 77.9% were female and the mean age was 13.2 ± 2.6 years. The duration of abdominal pain ranged from 2 to 190 months with a mean of 30.0 ± 38.0 months. Abdominal pain occurred daily in 75.5%, several times per week in 17.2%, and weekly in 7.3%. Early satiety was reported by 80.4%, postprandial bloating by 58.8%, and epigastric pain by 48.0% of patients. Eosinophil and mast cell densities by location for FD patients with and without headache are shown in Table The frequencies of gastrointestinal and non-gastrointestinal symptoms for patients with and without headache are shown in Table 5Headaches are common in patients with pain-associated FGIDs being reported by nearly 70% of patients in the current study. In the current study evaluating consecutive patients referred to an abdominal pain clinic, we found headaches to be specifically and uniquely associated with a diagnosis of FD, by Rome IV criteria, when compared to abdominal pain patients not meeting criteria for FD. Differences from previous studies may be accounted for, in part, by the differences in FD criteria between Rome III, which was used in previous studies, as compared to Rome IV, which was utilized in the current study. Specifically, the criteria for FD became narrower, while the criteria for IBS were liberalized, creating a more heterogeneous group of patients who would be classified as IBS, or non-FD more generally. who demonstrated increased mast cell density in the body (but not the antrum) of the stomach and the duodenum of patients fulfilling Rome III criteria for FD who were also experiencing headaches. They found no association with other inflammatory or enteroendocrine cells, just as we found no association with eosinophils; this suggests that the immune response as related to headaches may be limited to, or primarily driven by, mast cells. Mast cell biologic effects are the result of mediator release, with subsequent mediator-driven actions. Thus, biologic effects are not only a function of mast cell density, but also the degree of mast cell mediator production and release. We have previously demonstrated active degranulation of mucosal mast cells in children with FD, providing initial support for this pathway.In the current study, the presence of headaches was associated with increased duodenal mast cell density in patients with FD as defined by Rome IV criteria. This is consistent with the findings of Yeom et al,,27 Adults have demonstrated luminal release of tryptase and histamine from jejunal mast cells under stress conditions at a magnitude similar to that seen in allergic food reactions.The potential mechanism of mast cell involvement in the generation of headache and FD may be demonstrated more clearly by examining the stress response, as anxiety and stress have been highly implicated in both pain conditions. A main feature of the stress response is the release of corticotropin releasing hormone (CRH). Mast cells express CRH receptors which, when activated, result in the release of inflammatory cytokines. Once released, mast cell mediators, including histamine and leukotrienes, can stimulate afferent nerves signaling pain or can sensitize afferent nerves resulting in hypersensitivity and changes in electromechanical function. In children and adolescents, mucosal mast cell density correlates with higher anxiety scores, slower gastric emptying, and gastric electrical dysrhythmias.,30 Combining an H1 antagonist with an H2 antagonist has been reported to relieve pain in 50% of children with FD associated with mucosal eosinophilia and in 79% of adults with FD associated with increased mucosal mast cell density who had previously failed to respond to acid reducing medications.,32 Increased urinary leukotrienes (LT-E4) has been shown to increase significantly during migraine headaches in children. Although there are not controlled trials, an open-label trial of a leukotriene inhibitor, montelukast, demonstrated a > 50% reduction in migraine headache occurrence in over half of a group of adults with migraine headaches. Montelukast also has demonstrated efficacy for relief of pain in a controlled trial in children and adolescents with FD. The use of montelukast to treat migraine headaches or FD should be considered investigational.Histamines, as well as leukotrienes, have been implicated in both headaches and FD. Histamine infusion induces headaches in patients with muscle contraction and migraine headaches, but not in controls without headache; further, this effect is blocked by H1 antagonism and, to a lesser degree, by H2 antagonism.,37 Our previous studies have demonstrated an association between mucosal mast cell density and somatic complaints and, further, that headaches cluster with the same somatic symptoms as found in the current study.,38 Consistent with the current study, non-gastrointestinal somatic symptoms were uniquely associated with the presence of an FD diagnosis in the previous study. Of note, all of these non-gastrointestinal somatic symptoms have previously been reported to occur with mast cell activation.In the current study, headaches were associated with a Rome IV diagnosis of FD, but not any specific gastrointestinal symptoms in isolation. In contrast, patients with headaches reported fatigue, dizziness, muscle pain, joint pain, and chest pain more frequently than did patients without headaches. Previous community studies have demonstrated that abdominal pain in children and adolescents is associated with high rates of somatic symptoms, especially in those who fulfill Rome criteria for an FGID.Strength of the current study is the systematic collection of symptoms in a large population of children and adolescents. A weakness is that because the data was collected in an abdominal pain clinic, the specific headache type is not routinely determined and therefore could not be analyzed. Future studies should evaluate mucosal mast cells in relation to the specific type of headache.In conclusion, headaches are common in children and adolescents with abdominal pain and, utilizing Rome IV criteria, are specifically associated with FD. In patients with FD, headaches are associated with increased duodenal mast cell density and a variety of somatic symptoms, all of which are possibly the result of mast cell activation. Future studies should evaluate headache treatment responses to mast cell stabilizers or antagonists of specific mast cell mediators in children and adolescents with FD.Conceptualization: Craig Friesen, Meenal Singh, Vivekanand Singh, Jennifer Schurman.Data curation: Craig Friesen, Jennifer Schurman.Formal analysis: Craig Friesen, Meenal Singh, Vivekanand Singh, Jennifer Schurman.Investigation: Craig Friesen, Meenal Singh, Vivekanand Singh.Methodology: Craig Friesen, Meenal Singh, Vivekanand Singh, Jennifer Schurman.Project administration: Craig Friesen.Writing – original draft: Craig Friesen.Writing – review & editing: Craig Friesen, Meenal Singh, Vivekanand Singh, Jennifer Schurman.


Vascular pain is a common adverse drug reaction in colorectal cancer patients receiving peripheral venous administration of oxaliplatin. The aim of this work was to identify risk factors for vascular pain, and to examine whether currently used treatments reduce its incidence.We conducted a multicenter retrospective study in Japanese colorectal cancer patients receiving peripheral venous administration of oxaliplatin. The effects of various treatments  on the incidence of vascular pain were assessed. Risk factors for vascular pain were identified by multiple logistic regression analysis.2 versus dose reduction) were identified as independent risk factors for development of vascular pain. The incidence of oxaliplatin-induced vascular pain was significantly higher in patients who had two or more risk factors.One hundred and ninety patients who had received an oxaliplatin-containing regimen via a peripheral venous route were analyzed. None of the preventive methods examined significantly reduced the incidence of vascular pain. BMI (BMI < 22), clinical stage (I-III) and oxaliplatin dosage (130 mg/mBMI, clinical stage and oxaliplatin dosage were identified as independent predictive markers for oxaliplatin-induced vascular pain. Existing treatments for vascular pain are not effective in reducing its incidence. Oxaliplatin (L-OHP) is a third-generation platinum analog that is mainly used for treatment of advanced colorectal cancer  and adjuPropofol has also been reported to cause vascular pain, like L-OHP –8. It waIt is important to elucidate the risk factors for adverse drug reactions in order to develop effective preventive methods. For example, the use of epirubicin liquid preparation was identified as a risk factor for phlebitis , and we The present multicenter retrospective study was conducted in order to determine whether currently used treatments are effective to reduce the incidence of vascular pain in colorectal cancer patients receiving peripheral venous administration of L-OHP. We also investigated the risk factors for L-OHP-induced vascular pain.The present study was conducted in accordance with the Declaration of Helsinki and its amendments, and the protocol was approved by the Ethics Committee of Kanazawa University , as well as by the ethics committees of all participating hospitals, which were Ishikawa Prefectural Central Hospital, Houju Memorial Hospital, Komatsu Municipal Hospital, and Japan Community Healthcare Organization Kanazawa Hospital . Patients who had received peripheral venous administration of L-OHP during April 2011 to March 2014 were collected from 5 hospitals in Ishikawa prefecture. We excluded patients who were fitted with a peripheral venous catheter port, or for whom any of the clinical data required in the study protocol were missing.Data were collected from the nursing records and computerized medical records. Clinical data included age, gender, previous history of chemotherapy, dosage and infusion time of L-OHP, development of venous pain, concomitant drug used for analgesia, addition of dexamethasone, volume of infusion solution, and use of hot gel. For patients with a history of L-OHP-induced vascular pain, data were selected for the first cycle in which vascular pain occurred, while for patients who did not encounter vascular pain in any cycle, we selected data from the first cycle of L-OHP.We assessed the incidence of L-OHP-induced vascular pain in patients classified according to use of analgesics, addition of dexamethasone, volume of infusion solution, or use of hot gel to warm the injection site, compared to patients who did not receive that treatment. Univariate analysis and multiple logistic regression analysis were conducted to identify independent risk factors associated with L-OHP-induced vascular pain. Based on the multiple logistic regression analysis, we also examined the relationship between the number of risk factors and the incidence of L-OHP-induced vascular pain.P < 0.20 in univariate analysis were selected for multiple logistic regression analysis.The incidence of L-OHP-induced vascular pain in patients who received each preventive therapy was compared with the incidence in those who did not receive it by applying Fisher’s exact test. The relationship between the number of risk factors and the incidence of L-OHP-induced vascular pain was also analyzed by means of Fisher’s exact test. To identify risk factors associated with L-OHP-induced vascular pain, multiple logistic regression analysis was performed. Factors for which P values of < 0.05 were considered statistically significant.Data were analyzed using IBM SPSS Version 19 and One hundred and ninety colorectal cancer patients who had received peripheral venous administration of L-OHP were studied. The total number of infusions of L-OHP was 1, 264. There were 117 males and 73 female with a mean age of 64.2 ± 11.3 years  as independent risk factors of L-OHP-induced vascular pain. Generally, treatment to prevent vascular pain is given to patients who have already experienced vascular pain during a previous administration. Our results suggest that patients with two or more two risk factors might be at particular risk of vascular pain even in the first course.In this study, we identified BMI (BMI < 22), clinical stage (I-III) and L-OHP dosage , clinical stage I-III and BMI < 22 are risk factors for L-OHP-induced vascular pain in patients with colorectal cancer. These findings could be useful to assess the risk of vascular pain in clinical settings. Based on the results of this study together with previous findings, we suggest that the best option for management of L-OHP-induced vascular pain may be carefully timed pretreatment with fast-acting oxycodone.The results of this retrospective study indicate that L-OHP dose (130 mg/m