Current pain assessment and treatment does not address every patient’s requirements. Although the Polish national guidelines for post-operative pain management have been published, many patients experience severe pain in the postoperative period. The main goal of our study was to assess pain severity among patients from different types of hospitals  after similar types of surgeries. We also aimed to determine if there were any differences in pain severity associated with anesthesia technique, type of surgery, and the patient’s age and sex.This was a prospective, observational study. A questionnaire form was used to collect demographic data, type of hospital, surgery, anesthesia, and patient satisfaction of pain control in the postoperative period. The visual analogue scale (VAS) was used to measure pain severity at four time points after surgery .The study was conducted from November 2015 to June 2016 in seven hospitals in Eastern Poland, and 269 women and 293 men participated. At the 4-h measurement, 39.32% of patients assessed the pain as moderate and 19.75% as severe. A difference was found in pain intensity between patients treated in primary and secondary hospitals. Vascular surgery patients had the lowest pain intensity (19 (13–26)), especially in comparison to those undergoing thoracic surgery (30 (27–33)). A sudden elevation in pain severity among patients anesthetized with single-shot spinal technique was observed. Only 4.9% of participants received strong opioids during the first 24 h after surgery.Postoperative pain control seems to be unexpectedly poor after single-shot subarachnoid anesthesia. Despite concerns, the use of analgesics may be insufficient in some groups of patients. Our study indicates new variables that influence the severity of pain, such as operated region, anesthetic technique, and type of surgical department. The results obtained in our study are in discrepancy with recommendations presented by the national guidelines for post-operative pain management.The online version of this article (10.1186/s12871-018-0551-3) contains supplementary material, which is available to authorized users. Over 200 million major surgeries are performed worldwide annually . Even thSurprisingly, the introduction of new analgesic techniques and drugs, as well as the implementation of national guidelines for acute pain management, did not significantly influence inadequately-treated postoperative pain. The guidelines endorsed by the Polish Society of Anesthesiology and Intensive Therapy in 2014 comprise many analgesic approaches that are relevant in most clinical scenarios . HoweverThe first step to assess the current pain control policies in the Polish healthcare system is to acquire data from a variety of hospitals across the country. Therefore, the main goal of our study was to assess the current postoperative pain management practices after publication of the guidelines endorsed by the Polish Society of Anesthesiology and Intensive Therapy in 2014.Ethical approval for this study (permit number KE-0254/282/2015) was provided by the Medical University of Lublin Ethics Committee. This was a prospective, observational, multi-center study, that involved postoperative patients who underwent scheduled surgeries in seven hospitals across eastern Poland. The data were collected by medical students, after obtaining written consent from eligible patients.The questionnaire form contained seven sections as follows: 1) patient demographics; (2) type of anesthesia; (3) type of operated region; (4) pain evaluation with visual-analogue scale (VAS); (5) drugs, routes of their administration, and techniques used to relieve pain; (6) patient satisfaction, apprehension, and complications associated with the perioperative period; and (7) type of department and hospital. The entire form is shown in Additional file  patient Patients over 18 years of age, who were able to sign the consent form and fill out the questionnaire and VAS scale form, were included in the study. Furthermore, only participants who underwent major surgical procedures that required hospitalization were asked to participate.The following patients were excluded from the study: (1) minors under 18 years of age, (2) patients admitted to the ICU (intensive care unit) after surgery, (3) patients who did not sign the written consent, (4) patients who were unable to fill out the form or mark pain severity on the VAS scale, (5) patients who received local anesthesia, and (6) patients who were not able to fill out the questionnaire form or the VAS form within 4 h after surgery.The main variable measured in the study was the VAS value (given in mm) obtained at 4, 8, 12, and 24 h following the end of the surgery. We also analyzed the relationship between the pain intensity scores and the following parameters obtained during data collection: patient demographics, type of surgery, type of anesthesia, hospital type, kind of surgical ward, and operated region.The analysis of variances (ANOVA), t-test, and multivariate regression were used for statistical analysis. Tukey’s HSD (honest significant difference) was used for post-hoc analysis. VAS results were presented as means and confidence intervals (CI). All measurements were performed using Statistica 12.5 software .The study was conducted from November 2015 to June 2016 in seven hospitals in eastern Poland, which were comprised of two university (284 patients), two secondary (154 patients), and three primary  (124 patients) hospitals. Each hospital was granted two weeks during the study period for data gathering. The VAS forms were collected from a total of 565 patients. Three patients were excluded from further analysis because of a local anesthesia procedure. The data regarding patient demographics and type of surgical ward are presented in Table Pain severity is summarized in Table The prevalence of analgesics used in the study is presented in Table p = 0.00001) . On the other hand, at 12 h after surgery, the mean VAS result was 20 (16–24) for primary and 31 (27–34) for secondary hospitals (p = 0.026).There was no difference in the overall pain intensity (measured with VAS) according to the reference type of hospital. However, significant difference was found between primary and secondary hospitals at the 4- and 12-h assessments .On data from the four VAS measurements, the highest level of pain was associated with surgery on the upper abdomen (36 (30–41)), while the lowest pain scores were found in patients undergoing surgical procedures in the head/neck region (26 (23–30) However, the difference was not significant .At the 4-h measurement, the highest VAS results were obtained in patients undergoing thoracic (41 (37–46)) and upper abdomen procedures (43 (34–51)). These results were significantly higher than the lower limb VAS measurements (24 (18–29)) in our study ) and, surprisingly, the lower limb (36 (31–41)).p = 0.039) between surgeries of the chest (21 (17–25)) and lower limb (31 (27–36)).At the 12-h measurement, there was a significant difference in VAS (p = 0.00064) and hypogastrium operations (22 (19–25) p = 0.011). The results are presented in Fig. Furthermore, this tendency was maintained at the 24-h measurement, and lower limb procedures were associated with the highest pain intensity scores (32 (28–36)). A significant difference was demonstrated between lower limb surgeries and head/neck (19 (16–23) p = 0.012).The total difference in VAS values (mean of the four measurements) between patients treated in vascular surgery (19 (13–26)) and thoracic surgery (30 (27–33)) were significant . VAS results at the 8-h measurement demonstrated no statistical significance between studied wards. At the 12-h assessment, there was a significant difference in VAS scores between the thoracic (20 (16–24)) and the orthopedic (34 (30–38); p = 0.0001) and urology procedures (37 (31–44); p = 0.0093). Furthermore, at the 24-h VAS assessment, orthopedic procedures (33 (30–37)) seemed to be the most painful, especially in comparison to gynecology (20 (16–24); p = 0.0005), laryngology (19 (14–24); p = 0.00037)), and general surgery procedures (21 (16–26); p = 0.0085). The results are presented in Fig. At the 4-h measurement, a difference was found between orthopedic (29 24–34)) and thoracic surgeries (42 (37–47); 4) and thThe types of anesthesia that were performed in our study are presented in Table For statistical analysis, in order to avoid bias associated with the small number of cases in some groups, patients were assigned to four groups as follows: general anesthesia (335), subarachnoid (111), epidural 43), and regional peripheral (73)  and peripheral regional groups (26 (20–32); p = 0.0077). No difference was found at the 8-h measurement; however, the most severe pain was noted in the subarachnoid group (36 (31–40)). Furthermore, statistical significance was detected at the 12-h VAS measurement between the subarachnoid (33 (29–37) and general anesthesia groups (24 (23–28); p = 0.017). No difference was found between groups at the 24-h VAS measurement.At the 4-h VAS measurement, a difference was found between the general anesthesia group (39 (37–42)) and the subarachnoid (26 (21–30); p = 0.044. However, that difference was only significant during the two first measurements (at 4 and 8 h). At the 4-h measurement, the mean VAS results for women and men subsequently reached 37 (34–40) and 31 (28–34), respectively; p = 0.012. At the 8-h measurement, the VAS values were 34 (32–37) for women and 30 (27–32) for men (p = 0.012).There was a significant difference in overall pain intensity according to the patient’s sex Fig. . Women ep-value was 0.0027, the calculated r2 value was 0.0159. However, after dividing the participants of our study into three groups, younger (up to 45 years), middle-aged (45–60 years), and older patients (over 60 years), a significant difference was found between the older patients (21 (18–24), n = 180) and the younger (29 (26–33), n = 176; p = 0.0031) and middle-aged patients (30 (26–33), n = 205; p = 0.0022).A statistical correlation was found at the 12-h measurement on the linear regression model between the patient’s age and VAS value. Although the Of the 562 patients, 526 (93.6%) were satisfied with the quality of postoperative pain control (good or very good marks in the questionnaire). In contrast, 33 patients were not satisfied with the quality of postoperative pain control (poor marks), and five ranked the postoperative analgesia as not satisfactory. Overall VAS values (given as a mean of the four measurements) reached 51 (45–57) among the patients with poor pain control and was significantly higher than in the patients with satisfactory pain control (28 (27–30)).Patients who were afraid of poor postoperative pain control had slightly higher overall VAS values (32 (29–35)) in comparison to participants with no preoperative concerns (26 (22–30)), but these results were not significant.p = 0.038) or postoperative pain (39 (34–45); p = 0.032). The same difference was observed at the 8-h measurement, but it was not significant. At the 12-h measurement, patients whose main concern was awareness indicated pain severity on the VAS score as the most intense (contrary to the previous observations), but this result was not significant. Furthermore, at the 24-h measurement, no difference in VAS scores was found, but slightly reduced pain was noted among the patients who were afraid of perioperative death (22.1 (17.8–26.3)).However, when comparing VAS values at the specific time measurements, statistically significant differences were found. At the 4-h VAS measurement, there was a significant difference in pain intensity between patients who were afraid of either awareness or intraoperative pain (22 (13–32)) and those whose main concern was death (40 (34–45); Our results highlighted new aspects of postoperative pain control, such as unsatisfactory analgesia of patients with single-shot subarachnoid anesthesia at 8 and 12 h after the surgery and a low number of strong opioids administered in the hospitals studied.The prevalence of moderate and severe pain was high among the study population, especially during the first hours after the surgery (39 for the 4-h VAS). However, at the same time, 93.6% of patients recognized pain control as good or very good.Of the patients, 50.5% were anesthetized in two university hospitals. Lower numbers of surgeries in low-volume units might have been more vulnerable to random deviations during statistical analysis. However, the impact of the patient distribution in our study is difficult to predict. The difference in pain intensity between primary and secondary hospitals at 4- and 12- h after surgery became evident after further analysis and is likely due to the presence of orthopedic wards and the quantity of these surgeries performed in secondary hospitals. Furthermore, the probable cause of the 12-h peak in VAS values in orthopedic patients, with the high prevalence of lower limb operations, was the use of subarachnoid anesthesia. Although spinal, single-shot anesthesia is a standard approach for hip and knee surgeries, and more intense pain at the 12-h measurement was a result of insufficient supplementary analgesic techniques. Currently, the early mobilization of patients after hip or knee replacements is one of the main goals and possesses beneficial effects , 12.The combined spinal-epidural technique or systemic opioid administration may postpone the rehabilitation process and delay the patient’s discharge. The femoral nerve, lumbar plexus, or adductor canal blocks are well-established alternatives , 14. HowYounger age of patients seems to be an independent risk factor for higher postoperative pain in our investigation. Nevertheless, such a difference was not presented in the study of Gagliese and Katz if non-verbal scales, such as VAS or NRS were utilized . ConversMoreover, the authors of these articles identified women as more vulnerable to postoperative pain. These results are consistent with those found by our study.Although opioid-related side effects are common, omitting these drugs in the postoperative period can lead to augmentation of pain. In the very recent study of Thiels et al., 93.9% of surgical patients received opioid prescriptions at discharge . In contThe Polish national guidelines for post-operative pain management present multiple analgesic methods and regimens . The gui, anesthetic technique, and the type of surgical department. The results obtained in our study are in discrepancy with recommendations presented by the national guidelines for post-operative pain management.Results presented in our study show that many patients still experience moderate or severe pain in the postoperative period, even though there are guidelines and methods to treat pain after surgical procedures. Moreover, postoperative pain control seems to be unexpectedly poor after single-shot subarachnoid anesthesia. Despite concerns, the use of analgesics may be insufficient in some groups of patients. Our study also indicates new variables that influence the severity of pain, such as operated regionAdditional file 1:Questionnaire form. (DOCX 15 kb)


Spirometra mansoni in East and Southeast Asia. The plerocercoid larvae sometimes invade the encephalon, resulting in severe cerebral sparganosis. Surgical removal of the larvae is considered a standard therapy for cerebral sparganosis. In contrast, the efficacy and safety of long-term, high-dose praziquantel treatment for cerebral sparganosis have not been explored.Sparganosis is a parasitic infection caused by the plerocercoid larvae of Spirometra. mansoni antibody titer. The efficacy of praziquantel treatment was similar to that of surgical lesion removal for cerebral sparganosis with respect to both the primary outcome and secondary outcomes. Although binary logistic regression models also supported the primary outcome after adjustment for age, sex, lesion location, and loss to follow-up, some unavoidable confounders might have biased the statistical power. No significant clinical complications or laboratory side effects occurred in the praziquantel group with the exception of a relatively benign allergic reaction.In this multicenter retrospective study, we assessed the records of 96 patients with cerebral sparganosis who consulted at three medical centers from 2013 to 2017. Forty-two patients underwent surgical lesion removal, and the other 54 patients received long-term, high-dose praziquantel . The primary outcome was the complete disappearance of active lesions on cerebral magnetic resonance imaging. The secondary outcomes included the modified Rankin scale score at 90 days, incidence of seizure, eosinophil count, and serological In this small-sample, nonrandomized, retrospective exploratory study, some patients with cerebral sparganosis were responsive to long-term, high-dose praziquantel with an efficacy similar to that of surgical lesion removal. These findings increase the treatment flexibility for this serious infection. Spirometra mansoni sometimes invade the brain parenchyma, resulting in cerebral sparganosis. In general, surgical removal of the larvae is considered a standard therapy for cerebral sparganosis. One alternative treatment for sparganosis is short-term, low-dose praziquantel, which has had limited success. However, the efficacy and safety of long-term, high-dose praziquantel treatment for cerebral sparganosis have not been explored. In this study, we evaluated the effectiveness of long-term, high-dose praziquantel for treatment of cerebral sparganosis in China. We conducted a retrospective exploratory study using routinely recorded data from 96 patients at three medical centers. Forty-two patients underwent surgical lesion removal, and the other 54 patients received long-term, high-dose praziquantel. Treatment of cerebral sparganosis by long-term, high-dose praziquantel showed an efficacy similar to that of surgical lesion removal with respect to the primary outcome . However, this was a small-sample, nonrandomized retrospective study, and the results should be further confirmed by a large-sample prospective study or other studies.Sparganosis is most prevalent in developing countries in East and Southeast Asia, probably because public health strategies have not prioritized its prevention. The plerocercoid larvae of  Spirometra mansoni [Spirometra mansoni by drinking water contaminated with procercoid-infected copepods, eating undercooked meat of snakes or frogs infected with Spirometra mansoni, or applying the flesh or skin of an infected frog or snake to poultice open wounds [Sparganosis is a type of parasitic zoonosis associated with infection by the larval cestode of  mansoni . Most ca mansoni , South K mansoni , Japan [ mansoni , and Tha mansoni . Humans n wounds , 6. The n wounds . Howevern wounds , 9, whicn wounds , 11. Chan wounds .Although surgical removal of the parasite has been considered standard therapy , failureet al. also found that high-dose praziquantel treatment (75 mg/kg/day for 7 days) was efficacious in a patient with inoperable cerebral sparganosis [In 2012, our group reported that three patients with cerebral sparganosis showed good therapeutic responsiveness to high-dose praziquantel (50 mg/kg/day for 10 days) . In 2013All patient data were anonymized in the manuscript and database. Because of the uncertainty of the efficacy and safety of long-term, high-dose praziquantel treatment for cerebral sparganosis, the routine clinical procedure was evaluated and approved by the institutional ethics review board of the First Affiliated Hospital of Nanchang University .This was a multicenter retrospective study using data collected by physicians monitoring patients with cerebral sparganosis in three academic medical centers: the First Affiliated Hospital of Nanchang University, Peking University People’s Hospital, and Jiangxi Provincial Institution of Parasitic Diseases. The primary objective of this research was to evaluate the efficacy and safety of long-term, high-dose praziquantel treatment  for cerebral sparganosis compared with surgical therapy. Because of the successful experience in our clinical centers before 2012 , we estaSpirometra mansoni antibody in both serum and cerebrospinal fluid (CSF) tests and/or pathological evidences; (3) patients underwent follow-up cerebral MRI and serological immunological tests in our centers. The exclusion criteria included: (1) patients lost to follow-up; (2) patients with severe cardio-pulmonary dysfunction, resulting in contra-indication for surgery; (3) patients with severe liver and/or renal dysfunction, resulting in contra-indication for surgery or praziquantel treatment; (4) patients with surgical lesion removal, who had initially received praziquantel; (5) patients with praziquantel formula treatment after surgical lesion removal.All consecutive patients with cerebral sparganosis from January 2013 to December 2017 were retrospectively retrieved from the database. The patient list was compiled by searching the electronic medical records using the International Classification of Diseases Tenth Revision (ICD10) discharge code B70.151. The inclusion criteria included: (1) patients showed cerebral symptoms associated with at least one structural lesion; (2) patients had definite evidence of sparganum infection that was proven by immunopositivity to The patients were classified into a surgical therapy group and long-term, high-dose praziquantel therapy group according to the following principles. All patients initially received a detailed clinical assessment, followed by medical education about cerebral sparganosis in order to enable an informed decision regarding the choice of either praziquantel treatment or surgical treatment themselves. The physicians did not make a decision regarding treatment options for them, except patients with multiple lesions who would directly receive praziquantel treatment. The final treatment plan was chosen according to the willingness of the patients or their legal guardians. The disease severity and high-risk lesions located at some important brain regions might have been overemphasized in some communications, but the proportion could not be determined in the retrospective study. However, high-risk lesions were not considered an operative contra-indication because our neurosurgeons had excellent technical skills and experience for the operation. The main reasons for opting for long-term, high-dose praziquantel treatment were refusal to undergo surgery, lesions located at important functional areas of the brain, and initial tentative therapy .Spirometra mansoni by drinking water contaminated with procercoid-infected copepods, eating undercooked meat of snakes or frogs infected with Spirometra mansoni, or applying the flesh or skin of an infected frog or snake to poultice open wounds. The laboratory variables were the cerebral MRI characteristics , blood eosinophil percentage, and serological and CSF levels of antibodies for a panel of parasitic infections including spirometra mansoni, schistosoma japonicum, cysticercosis, paragonimiasis, clonorchiasis, toxoplasmosis, and echinococcosis. Aggregated ring-like enhancement refers to conglomerate ring-shaped enhancing lesions on MRI, usually three to six bead-shaped rings  to prevent possible residual infection. In the praziquantel treatment group, the patients were initially treated with 50 mg/kg/day in three divided doses for 10 days, and the treatment cycle was then repeated at monthly intervals, until the active lesions had completely disappeared on MRI. The MRI scan was performed at the beginning of the next treatment cycle. The maximum number of repetitive cycles of praziquantel administration could not exceed eight cycles. If more than eight were needed, the patient would be treated by surgery. If a patient developed an allergic or hypersensitive reaction during therapy course, 5 mg/day of dexamethasone was intravenously administered for no more than five days.The clinical manifestations of cerebral sparganosis were closely related to the site of the lesions, and the clinical prognosis was significantly associated with the recovery of granulomatous lesions. Active ring-like or tunnel-like enhancements represented the direction of active inflammatory tunnels in different dimensions. Therefore, the primary efficacy endpoint was defined as the disappearance of active lesions on contrast MRI. All patients underwent an MRI scan before the treatment. The surgical patients underwent a follow-up MRI at one month postoperatively. The patients treated by praziquantel underwent an MRI scan at the beginning of each treatment cycle. If the active lesions disappeared, the praziquantel treatment was discontinued. If a patient developed neurological symptoms at any time after completion of the treatment regimen, cerebral MRI was performed immediately. Development of a new lesion after the active lesions had disappeared was defined as treatment failure.Spirometra mansoni antibody titer. The mRS is a 7-point scale ranging from 0 (no symptoms) to 6 (death). A score of ≤2 indicates functional independence. A seizure was defined as a clinical event occurring after the end of treatment regardless of whether seizures existed before treatment. The eosinophil count was determined at the end of treatment, and the number of patients with an eosinophil percentage of >5% was counted. Serological titers were only compared between the beginning and the end of treatment.The secondary efficacy endpoints were the clinical outcome assessed by the modified Rankin scale (mRS) score 90 days after the end of the treatment, the incidence of seizure, the eosinophil count, and the serological The clinical symptoms assessed in this study were vital signs, headache, dizziness, sleepiness, abdominal pain, diarrhea, and any reported adverse events. The laboratory indices were hematology parameters, alanine aminotransferase, aspartate aminotransferase, blood creatinine, blood urea nitrogen, urine parameters, and electrocardiography. An allergy to praziquantel treatment for cerebral sparganosis usually manifested as fever, chills, pruritus, and urticaria occurred in the first or second treatment cycle. Adverse events were defined as clinical symptoms with onset or worsening severity at or after the first dose of praziquantel until the end of the safety follow-up (day 30).All statistical analyses were performed using the Statistical Package for the Social Sciences 17.0 software , and a p-value of <0.05 was considered statistically significant. Categorical variables were presented as count (percentage). Continuous variables were reported as mean ± standard deviation. The statistical significance of intergroup differences was assessed by pooled-variance and separate-variance Student’s t-test, chi-squared test, or Fisher’s exact test as appropriate. To adjust for the confounders in this retrospective study, several binary logistic regression models were established in a sub-analysis to identify the outcomes.The patient disposition and analysis were depicted in All 42 patients in the surgery group initially underwent surgical lesion removal (24 by craniotomy and 18 by CT-guided stereotactic aspiration) and achieved complete lesion recovery one month after surgery. However, three patients developed new lesions during the postoperative follow-up: one had a new lesion in the second month after stereotactic aspiration, one reoccurred in the third month after craniotomy, and one reoccurred in the fifth month after stereotactic aspiration. The treatment effects between craniotomy and CT-guided stereotactic aspiration were not significantly different .Spirometra mansoni antibody titer were similar between the two groups at the end of treatment  and secondary efficacy endpoints  between the praziquantel and surgical groups. Quantitative assessments of disease severity before therapy were unavailable in this retrospective study. Naturally, it was possible that patients with milder severity whose clinical course showed little progression and who may not need invasive surgery might select praziquantel treatment. In addition, patients with complicated clinical course or multiple or high-risk lesions might not select surgical removal. As a result, although there were no significant differences in the available baseline data between the praziquantel and surgical groups, some confounders could have biased the primary outcome. To compensate for this bias, several logistic regression models were established to adjust for age, sex, lesion location, and loss to follow-up. These regression models showed that praziquantel still had an efficacy similar to that of surgery, but some of these results actually showed borderline significance and indicated a tendency toward a surgical benefit.Praziquantel can significantly damage and destroy the whole body of the plerocercoid except the scolex and neck. The spargana may regenerate from the remnants of the scolex and neck, which might be responsible for resistance to praziquantel . TherefoIt is generally acknowledged that praziquantel is highly safe without serious adverse reactions. Common adverse reactions to praziquantel are usually mild and include abdominal pain, diarrhea, dizziness, sleepiness, and headache . These cThis study had some limitations that need to be explicitly acknowledged. First, it was a small-sample, nonrandomized retrospective study; thus, the statistical power was low. Cases of cerebral sparganosis are rare, so it is necessary to include data from more medical centers. Second, the fact that the patients made the treatment decision themselves undermined the reliability of the results. Confounders such as the disease severity, multiple lesions, high-risk lesions, and doctor-patient communication skills might have produced some bias with respect to the treatment decision. Third, the clinical data were quite heterogeneous because the treatment with praziquantel was different in each patient based on the lesion site and response. It was impracticable to assess the outcome only once and at a fixed time to avoid biasing the results because of ethical considerations and the pharmacological properties of praziquantel. Overall, the outcomes of this study should be cautiously interpreted that long-term, high-dose praziquantel had an efficacy similar to that of surgical removal, though the logistic regression models supported these results. Indeed, several baseline outcomes and safety indices showed borderline significance with respect to the benefit of surgical removal of larva lesion. However, the findings in this exploratory study involving real-world practitioners with a high level of experience add treatment flexibility for this serious infection, and provide a basis to promote a large-sample, randomized, prospective study of long-term, high-dose praziquantel treatment for cerebral sparganosis in the future.S1 FigAggregated ring-like enhancement indicates a conglomerated ring-like enhancement, which is seen as bead shaped, usually four to six rings, on MRI (A). The tunnel sign is about 4 cm in length  and 0.8 cm in width , which shows marked enhancement on coronal and sagittal contrast MRI (B). Lesion migration indicates the presence of new (C) and old  lesions in different cerebral locations.(TIF)Click here for additional data file.S2 FigAmong patients with successful praziquantel treatment, two patients underwent one praziquantel cycle; five patients underwent two praziquantel cycles; 19 patients underwent three praziquantel cycles; 13 patients underwent four praziquantel cycles; five patients underwent five praziquantel cycles; two patients underwent six praziquantel cycles; one patient underwent seven praziquantel cycles; one patient underwent eight praziquantel cycles.(TIF)Click here for additional data file.S3 FigNo differences were found across the 2 groups.(TIF)Click here for additional data file.S1 Table(XLS)Click here for additional data file.S2 Table(XLS)Click here for additional data file.S3 Table(XLS)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S5 Table(DOC)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


Although inguinal hernia is one of the most common conditions requiring surgical treatment, no reliable information is available on the quality of life of patients with inguinal hernias before surgery. Additionally, patients with intense inguinal pain prior to surgery are more susceptible to postoperative chronic pain. In such cases, less invasive laparoscopic techniques can be used, allowing atraumatic mesh fixation to reduce postoperative pain. The aim of the study was to determine, whether these treatments for patients with preoperative pain would minimize upsetting experiences after surgery.Data were gathered prospectively from the National Hernia Repair Register for 146 patients who underwent TAPP repairs in the general surgery department (2013–2016). The demographic data were recorded, the pain intensity was determined and patients described the occurrence of pain during ten everyday activities.p < 0.001). Pain intensity before surgery was scored as 4.1, 4.3, and 4.9 among patients who had a hernia < 12 months, > 1 year, and > 5 years, respectively (p = 0.028). Twelve months after surgery, the pain was 0.26, 0.34, and 0.40 (p = 0.037), respectively. Patients < 40 years experienced pain before the surgery more often. The intensity of pre-/postoperative pain was significantly higher < 40 years (4.9/0.63) than > 60 years (3.8/0.29).The average surgery time was 56.4 min. The follow-up was 23.4 months. The pain before surgery was 4.28 and 12 months after surgery 0.38 (TAPP inguinal hernia repair with glue fixation significantly decreased the frequency and intensity of the pain compared to that experienced preoperatively. After TAPP repair, the influence of pain on basic everyday activities is substantially lower. Patients under 40 years of age experience frequent and intense pre- and postoperative pain. A longer hernia duration prior to surgery causes increased pre- and postoperative pain. Although inguinal hernia is one of the most common conditions requiring surgical treatment, little is known regarding changes in the quality of life after hernia repair because no reliable information is available on the quality of life of patients with inguinal hernias before surgery. Most researchers have primarily focused on evaluating postoperative pain, mainly in terms of recurrence and chronic pain . TherefoThe aim of this work is to compare the pain experienced by patients before and after transabdominal preperitoneal (TAPP) inguinal hernia repair with 3D mesh using glue fixation and its influence on quality of life.http://kropp.org.pl), which is an IT tool available to surgeons in Poland that aims at collecting detailed data from patients undergoing surgical treatments. Participation in the register is voluntary. In the database, answers to more than 92 meticulous questions are recorded; participation is mainly dedicated to centers interested in herniology.Data were gathered prospectively from the National Hernia Repair Register in Poland . The exclusion criteria were of age below 18 years, incarcerated hernia surgery, and conversion to open surgery. The collected data included information regarding patients’ age, sex, occupation, sport activities, hernia duration, incarceration incidents, and hernia size. The patients who reported preoperative pain determined its intensity using the visual analog scale (VAS) and answered additional questions regarding the nature and circumstances of the pain in detail. The patients described the occurrence of pain during ten everyday activities. Fourteen terms describing the nature of the pain were presented to the patients, and each patient chose the term that best described the nature of his pain (sensory description). In addition, the patients selected from six terms describing the emotional character of the pain. The patients marked the frequency of pain and its descriptive intensity at rest and while performing physical activities.2 with average thickness 0.39 mm , which was fixed using Glubran® 2 . The peritoneal defect was sutured using V-Loc™ 2-0  absorbable sutures. All patients received antibiotic prophylaxis (Cefazolin) and anticoagulants (Enoxaparin sodium). The patients were discharged to home on the first or second day after surgery. One week after the day of the operation, the patients reported to the clinic, where they answered questions regarding pain (VAS). After at least 12 months from the day of the operation, all patients again answered the questions over telephonic interview regarding pain in the groin area and recurrences. The demographic details of the patients are presented in Table All surgeries were performed under general anesthesia using standard three trocars technique . After rt test. A p value < 0.05 was considered statistically significant.All data are presented as the means, standard deviations, and percentages. Descriptive statistics were produced for the dataset. The parameter variables were analyzed using ANOVA, and a subgroup analysis was conducted using Student’s Unilateral inguinal hernia repair was performed in 146 patients. The average surgery time was 56.4 min (43–110). Significant intraoperative complications and complications during the period directly after the operation were not observed. In the analyzed material, one case of recurrence was identified, which appeared 11 months after surgery for a large medial hernia (M3). The average follow-up duration was 23.4 months after surgery.p < 0.001); and 12 months after surgery, it was 0.38 . Pain intensity at rest according to the VAS and the frequency of pain before and after surgery are presented in Figs. The average intensity of pain at rest according to the VAS prior to surgery was 4.28 SD 2.16); 7 days after surgery, it was 2.28  and the patients without pain (BMI 25.5) were not observed.p = 0.028). Twelve months after surgery, the pain intensity scores were 0.26, 0.34, and 0.40 (p = 0.037), respectively.Hernia persistence did not affect the frequency of pain before surgery. In the group of patients who had a hernia for less than 12 months, 61.5% felt pain at rest at some point of the time. A total of 58.5% of the patients who had a hernia for more than a year experienced pain, and 57.3% of the patients who had a hernia for more than 5 years reported pain. Furthermore, gradual increases in pain intensity were noted in these patient groups. In the patients who suffered from pain at rest, its maximum intensity reported at any time before surgery was scored in VAS as 4.1, 4.3, and 4.9 among patients who had a hernia for less than 12 months, for more than a year, and for more than 5 years, respectively, and the differences were statistically significant (p = 0.008) and the oldest group . Twelve months after the operation, pain intensity scores in these groups were 0.63, 0.41, and 0.29 (p = 0.038) for patients younger than 40, aged 40–60, and older than 60 years, respectively.Patients below 40 years of age experienced pain before the surgery more often (63.3%) than the patients aged 40–60 years (59.2%) and the patients older than 60 years (53.5%). Moreover, the intensity of preoperative pain was significantly higher in the youngest group (VAS 4.9) than that in the middle-aged group  questionnaire is a helpful tool for assessing the quality of life; however, its efficiency is limited to the evaluation of chronic disease . TherefoSeveral studies report that patients with inguinal pain undergo surgery; however, the type of pain is often not specified , 6, 7. ATAPP laparoscopic repair requires general anesthesia. Usually, an older age at surgery corresponds to a higher risk of requiring perioperative anesthesia according to American Society of Anesthesiologists (ASA). Consequently, some older patients may not qualify for general anesthesia . TherefoOne method of reducing postoperative pain in patients who undergo laparoscopy is to fix a mesh with glue , 19. GluTAPP inguinal hernia repair with glue fixation significantly decreased the frequency and intensity of the pain compared with that experienced preoperatively. After TAPP repair, the influence of pain on basic everyday activities is substantially lower. Patients under 40 years of age experience frequent and intense pre- and postoperative pain. A longer hernia duration prior to surgery causes increased pre- and postoperative pain.


To prevent open surgical procedures, minimally invasive techniques, like Dekompressor (PLDD), have been developed. The absence of reherniation is an important factor correlating with clinical success after lumbar surgery. In this retrospective, observational study, the frequency of additional open surgery after PLDD in a long time retrospective was examined. The correlation between clinical symptoms and outcome was assessed, and the time between PLDD and open surgery was analyzed. Consecutive patients after PLDD between 2005 and 2007 were included. MacNab's outcome criteria were used to evaluate patient satisfaction. The need for additional open surgery of the lumbar spine, the period between Dekompressor and resurgery, and the treated levels were analyzed. In total, 73 patients were included in this study. The patients were seen one month after PLDD. The majority of patients (76.7%) had additional radicular pain. The most common level treated was L4-5 (58.9%). The follow-up time was longer than 5 years in 30.1% of the patients and longer than 10 years in 6.82%. The short-term success rate was 67.1%. Additional surgery was performed in 26.0% of patients, with 78.9% of the reoperations undertaken during the first year after PLDD. These patients had a statistically significant worse outcome (P = 0.025). Radicular pain was present in all patients with an early subsequent surgery, but only in 50% of patients with late surgery (P = 0.035). Significantly more patients with poor pain relief had radicular pain (P = 0.04). The short-term success rate was worsened by a resurgery rate of 26.0%. Subsequent surgery, a short time after PLDD, suggests that PLDD is not a replacement for open discectomy. Because patients with radicular pain had a worse outcome and more frequent resurgeries, whether radicular pain is an ideal indication for PLDD should be discussed. Lumbar radicular pain caused by disc herniation is often treated with open discectomy . Its effPercutaneous lumbar disc decompression with Dekompressor (PLDD) uses the Archimedes' pump principle to mechanically remove a predetermined amount of disc material, reducing the pressure in the disc. The placement of the 1.5 mm cannula is similar to that used in a standard discography.PLDD has been shown to be superior to conservative treatment , 8, 9 anIt is important to find an ideal indication for PLDD. Unsuccessful conservative treatment is a prerequisite of any spine surgery. Patients with a clear indication for open discectomy are also not ideal candidates for a percutaneous technique. It seems that outcomes after microdiscectomy for contained herniations are worse than for sequestered herniations . As suchAdvantages of the Dekompressor system are the minimal damage to adjacent tissues . ProponeThe aim of this retrospective, observational study was to investigate the frequency of an additional open surgery after PLDD in a more than ten-year retrospective. The time between PLDD and open surgery was analyzed, and a correlation between the clinical symptoms and outcome was assessed.In this retrospective observational study, the patient data were drawn from an electronic medical record system. PLDD was performed in a practice setting. Open disc surgery was performed in a general hospital.Inclusion criteria were as follows: consecutive patients who underwent PLDD between January 2005 and December 2007. A history of pain for a minimum of 3 months was mandatory. Patients had either low back pain or radicular pain with or without a sensory loss. Patients with a lumbar spine surgery in their history were excluded.For PLDD, the 17-gauge Dekompressor probe  was used. Prophylactic antibiotics were administered prior to the procedure. A standard approach was used to place the introducer cannula with the stylet under fluoroscopic view intradiscally. The correct cannula placement was confirmed with anterior-posterior and lateral fluoroscopic images . The DekEvery patient was seen in the practice personally one month after the operation for follow-up and later according to the complaints of the patient. A physician interview and a clinical examination were performed. A long-term follow-up of more than ten years was possible.The age and gender of the patients, the treated levels, the follow-up time, and the pain characteristics (only lumbago or radicular pain with or without sensory loss) were evaluated. MacNab's outcome criteria  . Twenty-eight patients (38.4%) reported pain for more than one year before the treatment. Seventeen patients only had back pain. The majority of the patients (76.7%) had additional radicular pain. A sensory loss in the symptomatic leg was present in 43 patients (58.9%). No motor deficit was present.The most common level treated was L4-5 (58.9%). Two levels (either L3-4-5 or L4-5-S1) were treated in 11 patients (15.1%). In 50.7% of patients the left side was symptomatic, while in 42.5 % of the patients, the right side was treated. Five patients (6.8%) were treated on both sides. No PLDD-related severe complications occurred.The first follow-up examination one month after PLDD was mandatory for all patients. Further examinations were arranged according to the needs of the patients. This first follow-up was the only one in nine patients (12.3%). In 22 patients (30.1%), the follow-up was longer than 5 years, and in five patients (6.8%) it was longer than 10 years. The mean follow-up time was 35.6 months.One month after the intervention, excellent results were achieved in 17 patients and good results, in 32 patients. Therefore, the short-term success rate was 67.1%. Subsequent surgery at the index level was necessary in 19 patients (26.0%). In these cases, the herniated disc fragment was removed, and a discectomy or a bony decompression of the spinal canal was performed.α1 = 0.025)t(7)=2.365). Radicular pain was present in all patients with an early subsequent surgery, but only in 50% of patients with late surgery (P = 0.035). The mean time between PLDD and the additional surgery was at 10.8 ± 17.9 months (1–70 months).Most reoperations (15 patients) had to be performed during the first year after PLDD . These patients  had a stComparing the patients with excellent or good outcome  with the patients with poor pain relief , signifiThis retrospective observational study investigated the number of patients with a subsequent open surgery after PLDD. Patients with back pain only and patients with radicular pain were included. The short-term success rate was 67.1%; however, 26.0% of all patients had to undergo an additional surgery, most of them during the first year after PLDD. If resurgery was necessary, the primary outcome was worse compared to patients without surgery during follow-up. All patients with an early additional surgery had radicular pain. Patients with radicular pain had a worse outcome.The short-term success rate is comparable with the few available studies from the literature. The recent study of McCormick et al.  found a Also, the resurgery rate seems to be comparable with the only one study reporting these data. McCormick at al.  reportedAvoidance of surgery is an important goal in reducing morbidity and mortality . From thWith an early resurgery, it was suspected that the indication for PLDD was too generous. Another explanation for early resurgery was the risk of acute herniation after the puncture of the disc with the 17-gauge needle. The risk of acute herniation is dependent on the needle diameter. The most vulnerable site is the inner annulus . All patThere are limitations to this study. This audit is retrospective and observational and therefore does not represent a high level of evidence. However, the resurgery rate is an important factor for the outcome.At first sight, a satisfied patient level of 67% seems to be a good result. However, this short-term result is significantly worsened due to a resurgery rate of 26.0%. Subsequent surgery a short time after PLDD suggests that PLDD is not a replacement for open discectomy. A contained disc herniation causing low back pain without radicular pain appears to be a good indication for Dekompressor. Because patients with radicular pain had a worse outcome and more frequent resurgeries, whether radicular pain is an ideal indication for PDLL should be discussed. Further studies are needed to compare the outcome and rate of subsequent surgery in patient populations with and without radicular symptoms to find the ideal indications for PLDD.


Intravenous morphine titration (IVMT) is the French gold standard for opioid treatment in the emergency department (ED). Nebulized morphine titration (NMT) may represent an alternative without venous access, but it has not been adequately studied in adults. We test the hypothesis that NMT is at least as effective as IVMT to initially manage severe acute pain in the ED.We designed a multicenter (10 French EDs), single-blind, randomized and controlled trial. Adults between 18 and 75 years with visual analog scale (VAS) ≥ 70/100 or numeric rating scale (NRS) ≥ 7/10 will be enrolled. We will randomize 850 patients into two groups to compare two routes of MT as long as VAS >  30 or NRS >  3. In group A (425), patients will receive an initial NMT for 5–25 min associated with titration of an intravenously (IV) administered placebo of physiologic serum (PS). In group B (425), patients will receive IVMT plus nebulized PS placebo.NMT is defined as a minimum of 1 and a maximum of 3 5-min nebulized boluses of 10 mg or 15 mg (weight ≥ 60 kg), at 10-min fixed intervals. IVMT is defined as a minimum of 1 and a maximum of 6 boluses of 2 mg or 3 mg (weight ≥ 60 kg), at 5-min fixed intervals. Nebulized placebo titration will be performed every 10 min. IV titration of PS will be performed every 5 min. In both groups, after 25 min, if VAS > 30/100 or NRS > 3/10, routine IVMT will be continued until pain relief.Pain severity, vital signs, bronchospasm, and Ramsay score will be recorded every 5 min. The primary outcome is the rate of relief obtained 1 h from the start of drug administration. Complete pain relief in both groups will be compared with a non-inferiority design. Secondary outcomes are pain relief at 30 min (the end of NMT) and at 2 h and median pain relief. We will compare final doses, and study the feasibility and tolerance of NMT . Co-analgesia will be recorded. Discharge criteria from the ED and hospital are defined.This trial is the first multicenter randomized and controlled NMT protocol for severe pain in the ED using the titration concept. We propose an original approach of combined titration with an endpoint at 1 h and a non-inferiority design.NCT03257319. Registered on 22 August 2017.ClinicalTrials.gov, The online version of this article (10.1186/s13063-019-3326-3) contains supplementary material, which is available to authorized users. The treatment of severe acute pain in the emergency department (ED) has been a public health priority in France for several years –4. SpontDespite legal provisions and learned society recommendations, IVMT remains insufficiently applied or applied with delays . The avaHowever, data on the pain management of adults using a nebulized route in the ED are scarce. The majority of clinical studies involve patients in long-stay medical departments who have dyspnea and not pain (cancer or chronic respiratory insufficiency –26). SomPharmacokinetic data are also insufficient, even in healthy volunteers. Some data in healthy volunteers without any pain stimulus are available, but the results are not consistent and dyspnea seems to have been the priority area of research –40. The Considering the results reported in the literature and clinical practice, many questions remain before switching from IVMT to NMT. No simple conversion can be made between the 3-mg or 2-mg intravenous bolus, which is the reference for titration, and bolus doses to be nebulized. No preliminary study has determined which optimized and standardized dose of nebulized bolus could be repeated to achieve complete pain relief in patients and ensure safety and tolerance. The ideal times of the aerosol bolus and between each aerosol bolus have not been tested yet and cannot be deduced from what is proposed intravenously. Some clinical studies have tended to show relief, especially at the beginning of nebulization, in the first 5 min (when measured), and others have shown a greater rapidity of appearance of metabolites of morphine in the blood than in other routes of administration but without studying pain relief parallelism , 35, 36.In the absence of sufficiently robust data, further research on pain in healthy volunteers appears to be an essential prerequisite for a clinical trial on major emergencies. We performed AEROMORPH1  in order to determine, within a nebulized morphine protocol in healthy volunteers with pain , the pharmacokinetic characteristics and the feasibility of a single 5-min nebulized safety bolus of morphine which could be tested and repeated in the ED.Given the AEROMORPH1 preliminary data and taking into account the poor results in the literature, we decided to propose the initiation of morphine titration by a new route of administration rather than exclusive NMT. We aim to test the hypothesis that a combined method of morphine titration, initiated by a maximum of 3 nebulized boluses, is at least as effective as IVMT performed exclusively according to the reference protocol for the treatment of patients with severe spontaneous pain (VAS between 70 and 100 mm or NRS ≥ 7/10) in the ED. We decided to perform a multicenter, randomized, placebo-controlled study, a methodological design associated with the highest level of evidence.The aim of our study is to evaluate two different methods of analgesia by morphine titration for the management of severe acute pain in the ED. First we will compare a combined morphine titration started by NMT and then IVMT, and second the reference route of administration of morphine titration, i.e., exclusive IVMT.The primary outcome is to assess whether the two methods are as effective to provide pain relief at 1 h from the beginning of morphine titration.Secondary outcomes are first, to compare for each titration method all the parameters of analgesic efficacy, second to assess the feasibility of this new method of combined morphine titration, and third to evaluate the tolerance of the nebulized route of morphine administration.The CLIN-AEROMORPH trial is a multicenter, prospective, randomized, double-dummy, placebo-controlled trial conducted in 10 French adult EDs in tertiary care academic hospitals, with more than 30,000 patient visits per year. All these centers manage more than 2500 patients with severe pain per year routinely using IVMT according to French recommendations and have already participated in randomized controlled trials. Rouen University Hospital’s adult ED will coordinate the study and handle the data analysis. The coordinating investigator of this center and of the whole study has conducted large trials on IVMT before . The triCriteria for eligibility are adult patients, 18–75 years of age, presenting to the ED with a primary complaint of spontaneous severe acute pain who are being considered for admission to the ED observation unit whatever their pain etiology. An episode of severe pain is defined as the occurrence of pain that is rated 70/100 or more on the VAS (0–100), and when the VAS evaluation is impossible, pain that is rated 7/10 or more on the NRS (0–10). The VAS handheld slide rule will be shown and explained to the patients. When patients have difficulties in manipulating the VAS slide rule, nurses will be allowed to use the NRS (from 0 to 10), as these two scales are equivalent in the ED [Patients will be screened consecutively 5 days per week (Monday to Friday) during the day, when the organizational conditions for enrollment are met, until the sample size of 850 patients is reached. Patients cannot be consecutively enrolled in the study because high inflow or high workload in participating EDs is an obstacle, and is difficult to predict. Patients will be included when the study coordinator or a dedicated team member is available for enrollment and when a single examination room is available for treatment.Inclusion and exclusion criteria are presented in Table Informed consent may be waived at randomization, because patients may need urgent pain management and because acute pain impairs the ability to provide informed consent. Whenever a patient is included without written informed consent, such consent will be promptly sought from the patient when the pain has decreased, according to the French Law of Ethics. However, each patient will be introduced to the trial by a member of the research group and will receive an explanation of the study protocol (not including random assignment of the morphine treatment) before the senior ED physician in charge of the patient can obtain appropriate written informed consent.n = 425), patients will receive first, a combined morphine titration started by NMT plus IV placebo of physiologic serum (PS) for the first 25 min and then second, routine IVMT in case of persistent pain after 25 min of treatment as standard of care in the ED. Patients in arm B (n = 425) will receive IVMT and a nebulized placebo of PS during the same time (25 min). If the VAS score is > 30 or the NRS score is > 3 after the maximum number of IVMT boluses, routine IVMT without nebulized placebo will be performed until pain relief as standard of care in the ED.The randomization list will be generated before commencement of the study. We will use computer generated random numbers to generate the allocation sequence, without blocking. Patients will be randomized into one of two parallel groups stratified by sex and center using centralized software . In arm A  used will be comparable to the material routinely used in ED for other drug administrations like terbutaline in asthma (CE0120 marking - Class IIa). It allows the nebulization of drugs with an average mass diameter of 3.6 μm, at a rate of 0.25–0.3 ml/min. The nebulization technique proposed was tested in our previous study on healthy volunteers, AEROMORPH1. In arm A, morphine titration will be done by repeated nebulized bolus administration of morphine hydrochloride, using 10 mg (patient’s weight < 60 kg) and 15 mg (patient’s weight ≥ 60 kg). A morphine solution will be reconstituted by dilution with PS so that the final volume will be reduced to 3 ml in the aerosol mask tank. The morphine will be nebulized for 5 min at a constant airflow of 10 L/min, and 3 ml of PS placebo will be administered by intravenous push at the beginning and at the end of each aerosol. In arm B, IV morphine will be administered by intravenous push, using 2 mg (patient’s weight < 60 kg) or 3 mg (patient’s weight ≥ 60 kg) as recommended by French guidelines on acute pain management . At the Specific treatments required in case of adverse events (AEs) are described in the protocol. In case of severe ventilatory depression (respiratory rate (RR) < 10 breaths per minute), naloxone titration (intravenous bolus of 0.04 mg) will be administered until RR is more than 12 breaths per minute see see . An information sheet will be delivered on the risks of morphine titration  after the visit. Clinical monitoring will include RR measurements, pulse oximetry (SpO2), sedation according to Ramsay score , arteriaThe primary outcome of this study is complete pain relief, related to the final VAS (0–100 mm) or NRS (0–10). The primary endpoint is the relief rate defined as VAS ≤ 30/100 or NRS ≤ 3/10 at 1 h from the beginning of titration.Secondary outcomes are to compare all the parameters of analgesic efficacy for each method of titration and to evaluate the feasibility and tolerance of the nebulized route of morphine administration.Analgesic efficacy will be measured by assessing the total dose of morphine administered (based on weight and body mass index (BMI)), the median delay of relief, the proportion of patients relieved according to the duration of titration (pain relief at 30 min and 120 min from the start of titration), and the proportion of patients totally relieved by exclusive NMT. Feasibility will be evaluated by measuring the rate of deviation from the protocol . The data will be hosted on a secure server located in the Information System Department of CHU-Hôpitaux de Rouen . Backup copies of the contents of this server are made daily. The data will be entered by the investigator or the clinical study technician of each center, who will have personal and secured accounts  to access the database of the study. The person carrying out the data processing (biostatistician) will have access to the data once the base has been frozen on a secure server accessible only to the data manager and to the biostatistician of the study.The purpose of this study is to establish the non-inferiority of nebulized morphine titration as compared to IV morphine for relief of severe pain events in adults in the ED. The study is a repeated measures study, measuring pain scores before, during, and after treatment. The desired primary clinical outcome is that nebulized morphine titration is at least as effective in relieving pain as IV morphine 1 h after administration of medication.z. This analysis will be complemented by an adjusted analysis based on the linear model in order to adjust treatment comparisons for center and potential factors associated with complete pain relief. In order to obtain 80% power to reject non-inferiority for a 7% margin, and provided there is no difference between true proportions of complete pain relief , the required sample size is 404 patients per arm, i.e., 808 patients overall . Owing to the per protocol nature of the main analysis, and in order to account for the possibility of failure to completely or properly administer morphine , the target sample size is 850 patients overall in order to obtain 808 patients in the main per protocol analysis.In keeping with the non-inferiority nature of the test, a one-sided test at the nominal 0.05 significance level will be performed based on test statistic t test for quantitative variables, Pearson’s chi-square test for categorical variables, or the logrank test for time-to-event variables.Regarding secondary outcome criteria, comparative analyses between the two treatment arms will be performed in an intention-to-treat analysis. Comparisons will be based on Student’s We will provide a descriptive account of the two treatment groups at baseline in terms of demographics, recruiting center, and baseline values of all study outcomes. All patients and carers will be analyzed according to the group to which they were randomized. No interim analysis is planned.In terms of selection bias, we consider that this study targets a patient population to whom this research ultimately will be clinically applicable and valuable. The trial will be conducted in the flow of routine patient care. This approach will enable us to test morphine titrations in the real-world setting, giving high external validity to the results. Every effort will be made to ensure that recruitment of participants occurs 5 days per week, as patients will be recruited by the ED physician treating the patient, but inclusion will be done by another physician. Co-analgesia will be more evaluable due to this procedure. We anticipate that the randomized, controlled design of this study will minimize the effect of confounding variables on our analysis. The bias linked to the single-blind design is obvious, but the feasibility of this study at the bedside justifies this methodological choice. The bias linked to missing data is reduced because there is a dedicated research team in charge of the study in most of the EDs.All AEs that occur during the study period observed by one of the clinical staff, or reported by the patient or parent/guardian spontaneously or in response to a direct question, will be noted on appropriate forms, i.e., for AEs, serious adverse events (SAEs), or suspected unexpected serious adverse (drug) reactions (SUSARs). AEs will be classified on the form in terms of their severity, association with the study drug, expectedness, and seriousness. They will be recorded on an AE log. AEs will be reported to the sponsor as soon as possible and on a yearly basis as part of an annual safety report and at the end of the trial. The sponsor  has the responsibility to ensure all relevant and available information is forwarded to the competent authority (Irish Medicines Board) and the appropriate health ethics committee. It is important to note that a nurse and a physician will be immediately available (in less than 1 min) to manage any possible side effects during the study time.An independent monitoring committee (ICS) of three experts has been constituted to analyze and classify the critical events and their possible link with opiates, especially death, respiratory depression, and uncontrollable vomiting that do not respond to treatment plans. A committee of three independent external expert investigators will be established. This committee will monitor the study and may be requested at any time by the sponsor to issue a written report on accountability in any SAE processing opinions or data appearing in the study that are likely to change the risk/benefit ratio of the research. The committee will meet at least once per year and whenever necessary upon request of the sponsor. Written reports of meetings of the expert committee will be forwarded to the sponsor and investigators. The annual safety reports will be given to each member.This protocol will investigate an alternative route of administration of morphine to reduce the time delay to relief, without losing the benefits of titration. Previously, we had to manage with the poor results reported in the literature. This lack of available data led us to propose first a study protocol based on two different bolus doses of morphine, 10 mg or 15 mg, linked to body weight. According to a recent study , the safRegarding the primary endpoint of our study, we will measure the main outcome at 1 h for both pharmacokinetic and ethical reasons. First, this outcome is the same as that of our large study on IVMT in the ED  with theIncidentally, our study protocol shows many differences with the Grissa et al. study , such asPatient enrollment started on 19 September 2017 after Ethics Committee approval. The end of enrollment is scheduled for 19 September 2019.Additional file 1:Naloxone protocol. (DOC 25 kb)Additional file 2:Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist. (DOC 132 kb)


During 2017, opioids were associated with 47,600 deaths in the United States, approximately one third of which involved a prescription opioid  filled an opioid analgesic prescription within 7 days of the initial visit; the percentage varied by condition, from 1,229 (3.5%) for headache to 302 (27.6%) for dental pain . Among pThe adjusted probability of a refill appeared to decrease with increasing initial prescription duration for some conditions , whereas for other conditions, the adjusted probability of a refill remained relatively constant regardless of the amount initially prescribed  . For an These findings, drawn from the claims of nationwide commercial insurance beneficiaries, indicate that in 2014 the median duration of initial opioid analgesic prescriptions for acute pain indications in a primary care setting was 4–7 days. Fewer than one in five patients who filled an opioid analgesic prescription received a refill, suggesting that in most cases an initial prescription of this duration was considered sufficient (and possibly even more than necessary) for patients seen in primary care settings with acute pain, consistent with recommendations in the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain  to 41% , with refill probability <25% for most conditions.Initial opioid analgesic prescriptions of ≤7 days’ duration appear sufficient for many patients seen in primary care settings with acute pain. Treatment strategies should account for patient- and condition-specific characteristics, which might reduce or extend duration of benefit from opioid analgesic therapy.