In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria  the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized .The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.ISRCTN45877994ISRCTN:  In patients with chronic pancreatitis (CP), the most important clinical problem is the management of pain, which often occurs daily and is disabling ,2. CP isIn current practice, patients with CP are managed by a conservative step-up practice. The first step is medical management, ranging from pancreatic enzymes and mild analgesics to opioids. When medical management fails, the next step is usually endoscopic intervention. Surgical intervention is kept as an option of last resort when other treatments have failed and the severity of disease has increased substantially and pain becomes unmanageable ,7. This As an alternative to the current conservative step-up practice, there is emerging evidence to suggest that surgery early in the clinical course of CP is beneficial in terms of pain control and pancreatic function. First, pathophysiological studies of pain in CP have shown that prolonged periods of pain are associated with peripheral and central nerve sensitization. Consequently, a self-perpetuating pain state develops, which is very difficult to reverse and manage . SecondlFinally, in a small pilot randomized trial, 32 patients with early stage CP and dilated pancreatic duct were randomized between early surgical drainage and a conservative approach ,15. SubsDespite the evidence suggesting a benefit of early surgery, most patients with chronic pancreatitis are not managed by this approach in current practice. Therefore, the Dutch Pancreatitis Study Group designed a randomized controlled multicenter trial to evaluate the benefits, risks and costs of early surgical intervention: the Early Surgery versus Optimal Current Step-up Practice for Chronic Pancreatitis (ESCAPE) – trial.The ESCAPE trial is an open label randomized controlled, parallel, superiority multicenter trial.We hypothesize that early surgery can relieve pain early in the disease course of chronic pancreatitis. This will, consequently, improve patients’ health status, reduce health demand and costs and increase quality of life and social functioning.Primary study question: does early surgery, as compared to the current optimal step-up practice, provide better pain control in patients with CP and a dilated pancreatic duct?• Secondary study question: What is the impact of early surgery in these patients in terms of severe complications, mortality, quality of life, costs, endocrine and exocrine pancreatic insufficiency and other clinical relevant outcomes?• Patients with CP meeting the inclusion criteria for registration will be asked to participate in the study (registration informed consent). Consenting patients will be followed monthly as potential candidates for randomization. When a registered patient meets the randomization criterion he/she will be enrolled in the study after explicit informed consent. An expert panel of CP specialists  will oversee the assessment of eligibility and will ensure that allocation to either treatment arm is possible prior to randomization. Patients will be recruited from 24 hospitals of the Dutch Pancreatitis Study Group.• Age > 18 years• Confirmed CP: according to the following criteria (adapted from the M-ANNHEIM diagnostic criteria ):▪ typical clinical history of chronic pancreatitis , and:▪ one or more of the following additional criteria for the diagnosis of CP:1. Pancreatic calcifications on CT or MRI imaging.2. Moderate or marked ductal lesions (according to the Cambridge classification) on endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) imaging.3. Marked and persistent exocrine insufficiency .• Dilated pancreatic duct: dilated pancreatic duct of ≥ 5 mm, with or without enlargement of the pancreatic head .• Presence of moderate, non-debilitating pain. This will be defined as chronic or recurrent abdominal pain sufficiently relieved with non-opioid analgesics.Patients will be eligible for randomization if one of the following criteria is met:• In patients with chronic abdominal pain related to chronic pancreatitis: a need to upgrade pain medication from non-opioids to opioid analgesics (opioids needed at least 3 days per week) and persistently needed for at least 2 weeks.• In patients with recurrent flare-ups interspaced with pain-free intervals: flare-ups that have occurred at least 3 times during one year (i.e. 12 months), with each flare-up fulfilling the following criteria:▪ duration of at least 7 consecutive days;▪ necessitate opioid use during flare-up;▪ impairment of daily activities.Informed consent must also be acquired for randomization.• History of prolonged need of opioids: history for need for strong opioids for CP for a total period over 2 months or a history for need for weak opioids for CP for a total period of 6 months in the last 2 years. The following medications are considered weak opioids: codeine, dextropropoxyphene, dihydrocodeine, tramadol and partial agonists of morphine .• Previous pancreatic surgery• Previous endoscopic dilatation or stenting of the pancreatic duct• Episode of biliary obstruction in the previous 2 months (defined as jaundice or bilirubin levels ≥ 25 micromol / L) or the presence of a stent in the common bile duct• Autoimmune pancreatitis (including elevated levels of gamma-globulins (IgG))• Stones and strictures exclusively located in the tail of the pancreas (i.e. to the left of the vertebra) with relatively normal pancreatic head and corpus Figure .• Fully impacted stones casting the entire main pancreatic duct (from head to tail) and possibly side branches Figure .• Suspected or confirmed pancreatic malignancy• Life expectancy of < 1 year for any reason• Presence of duodenal obstruction necessitating surgery, as judged by the expert panel• Presence of a pseudocyst larger than 6 cm necessitating intervention, as judged by the expert panel• Contra-indications for surgery, as judged by the expert panel • PregnancyPatients will be randomly allocated to either early surgical intervention (group A) or step-up practice (group B). Figure The main aim of the surgical intervention will be surgical drainage of the dilated pancreatic duct. According to the size of the pancreatic head on the preoperative imaging (CT and MRI or ERCP), the following operation will be performed:• In case of a non-enlarged pancreatic head (< 4 cm): surgical drainage of the pancreatic duct by a pancreaticojejunostomy.• In case of an enlarged pancreatic head (≥ 4 cm): surgical drainage of the pancreatic duct and a duodenal-preserving pancreatic head resection (a Frey procedure).Surgery will be performed within 6 weeks after randomization by an experienced pancreatic surgeon. Experience is defined as having previously performed at least 25 pancreatic operations for chronic pancreatitis, not including pancreatic cyst drainage.A pancreaticojejunostomy is performed as described by Partington and Rochelle . The panA duodenal-preserving resection of the pancreatic head, combined with a longitudinal pancreaticojejunostomy, is performed according to the technique described by Frey and Smith . For thePatients randomized to the optimal current step-up practice will undergo the following stepwise treatment strategy as formulated by consensus of the Dutch Chronic Pancreatitis Expert Panel:Optimal pain control is attempted through the pain management guidelines as described below. A pain specialist and dietician will be consulted to optimize medical management. As long as pain control is achieved, the patient will remain in step 1.Guidelines for this medical management are ,21:Optimal pain medication according to the World Health Organization pain ladder, as follows:○ Non-opioid medication: paracetamol (up to 4 daily doses of 1000 mg), or non-steroidal anti-inflammatory drugs (NSAIDs) . When NSAIDs are used for a prolonged period of time, appropriate gastric protection should be given.○ Weak opioids: tramadol .○ Strong opioids: morphine, fentanyl, oxycodone, etc. Choice of medication and dose determined by treating physician .The type and dose of medication will be decided at the discretion of the treating physician and based on the clinical situation of the patient. As a guideline the physician should aim to maintain the pain VAS of the patient below a score of 4.– Co-medication for neuropathic pain: in consultation with the pain specialist starting of one of the following co-medications for neuropathic pain is allowed.○ Pregabaline .○ Gabapentine .○ Amitryptyline .– Dietary advice: patients will be referred for consultation with a dietician for analysis of nutritional status and starting of any necessary dietary program.– Screening and management of pancreatic insufficiency at baseline:○ Endocrine insufficiency will be screened by glucose level measurement. If endocrine insufficiency is established, the patient will be referred to a specialized internal medicine physician for management.○ Exocrine insufficiency will be defined as presence of steatorrhoea, or fecal elastase levels at baseline of < 200 microgram/gram . Patients with exocrine insufficiency will be treated with pancreatic enzyme substitution .If symptoms become intractable to medical management for a prolonged period of time despite adequate adjustment of medication, medical management is considered to have failed. This is defined as one of the following:– Unsatisfactory pain control: defined as a VAS pain score > 4 in three follow-up moments  despite adequate adjustment of medication.– If achieving satisfactory pain control is associated with clinically unacceptable side-effects, the medication should be discontinued. Such side effects might include sedation, nausea, vomiting, constipation or itching.Patients with failed medical management will be referred for endoscopic intervention by an experienced endoscopist. Experience will be defined as having performed at least 50 therapeutic endoscopic interventions for chronic pancreatitis. The goal of the initial endoscopic intervention will be to drain the pancreatic duct by means of a pancreatic stent. At the end of endoscopic treatment of strictures and stones, as described below, adequate alleviation of pain should have been achieved.Stone removal: in the absence of large (diameter ≥7 mm) intraductal stones in the pancreatic duct, patients will undergo an ERCP for stone removal. After sphincterotomy, a complete stone removal will be attempted. If stone removal is incomplete one or more pancreatic stents will be inserted and further stone removal will be attempted at the following ERCP. If large intraductal stones (diameter of ≥ 7 mm) are identified in the pancreatic duct on pre-intervention imaging studies, the patient will first undergo extracorporeal shock-wave lithotripsy (ESWL). After lithotripsy, stone fragments will be removed during the subsequent endoscopic intervention.1. Strictures and stent placement: the decision for need of stricture dilation, with either a balloon catheter or a Soehendra catheter, will be made by the treating endoscopist. If strictures are present, a stent will be inserted in the pancreatic duct.2. Progressive stenting: if a stent has been inserted, endoscopic treatment will be considered technically successful. From this point, the patient must have adequate pain control (with or without pain medication) in order to continue with endoscopic treatment (see section “Failure of endoscopic intervention”). Continuation of endoscopic treatment means the patients will undergo an elective endoscopic pancreatogram every 4 months. When complete runoff of contrast material is observed after removal of the stent and an extraction balloon can be passed through the pancreatic duct, endoscopic treatment is considered completed and stenting will be stopped. Persistent strictures will be treated by repeated endoscopic dilations and sequential insertion of new stents for a maximal period of 1 year, after which stenting must be stopped.3. Failure of endoscopic intervention is defined as:Persistent pain after 12 weeks of endoscopic therapy (assessed from 8 weeks onwards after the start of endoscopic therapy): defined as a VAS pain score > 4 in at least three out of four follow-up moments (with or without pain medication). When no endoscopic treatment was found to be possible after attempting by a skilled endoscopist and pain persists, failure of endoscopic intervention will also be a fact.If endoscopic intervention fails, the third en last step will be surgical intervention. Surgical intervention will be done as described for group A.The primary clinical outcome is the degree of pain as assessed by the Izbicki pain score at 2 weeks intervals during the follow-up period of 18 months. The Izbicki pain score is a validated pain score specifically designed for chronic pancreatitis ,22. It cSecondary outcomes are:• Severe complications related to disease progression, or endoscopic and surgical interventions ○ Disease progression: development of pseudocysts, pancreatic insufficiency (endocrine or exocrine), duodenum obstruction, chronic use of opioids (defined as need for opioids for a period > 6 months), hospital admissions for CP up flares.○ Endoscopic intervention: (acute) pancreatitis flare-up, cholangitis, acute cholecystitis, retroperitioneal or bowel perforation, haemorrhage.th postoperative day), any relaparotomy for other reasons.○ Surgical intervention: anastomotic leakage, bleeding, sepsis, intra-abdominal abscesses, burst abdomen, pneumonia, severe wound infection , severe delayed gastric emptying  and the EQ-5D questionnaires ,24.• Total direct and indirect costs• Endocrine pancreatic insufficiency: determined by use of anti-diabetic medication or abnormal serum glucose levels  .• Exocrine pancreatic insufficiency: determined by fecal elastase levels (< 200 μg/g).• Additional pain measurements: due to the heterogeneity in reporting of pain in previous trials, and in order for the results of this trial to be comparable with other studies, the following additional measures of pain will be reported as well:○ Proportion of patients with complete and partial pain relief at end of follow-up, defined as follows :▪ Complete pain relief: an Izbicki pain score ≤ 10 points▪ Partial pain relief: a decrease of >50% from baseline in the Izbicki score with a final score >10 points.○ Visual analogue score (VAS) for pain: measured as part of the Izbicki score.○ Büchler pain score: alternative pain measure based on the Izbicki questionnaire, and calculated by the multiplication of two of the four items of the Izbicki questionnaire (i.e. pain frequency and pain intensity) .• Number and duration of hospital admissions during study period.• Number of performed interventions: total number of endoscopic and surgical interventions, including initial intervention.• Number of pancreatitis flare-ups during the study period.Randomization will be performed using a central automated online assignment system ensuring random generation of allocation and concealment of allocation. Only after the expert panel ensures a patient fulfills the eligibility criteria, the patient’s information is entered into the central online randomization module, which subsequently allocates the patient to one of the two groups. Block randomisation with varying block size  is used. The randomization will be stratified to take into account the presence of enlarged pancreatic head (not enlarged pancreatic head (< 4 cm) versus enlarged pancreatic head (≥ 4 cm)).Due to the nature of the intervention, blinding of either patients or treating physicians is not feasible. To ensure reliability, all outcomes will be cross checked with data from primary sources by an independent investigator not involved in patient care and not involved in data analysis. In case of uncertainty about the definition of an outcome (e.g. complications), an independent adjudication committee will perform a blinded outcome assessment of that outcome variable in all patients.The Izbicki pain score will be assessed every two weeks during a follow-up period of 18 months. For this end, the Izbicki pain score will be assessed via a web questionnaire. Patients who do not have an email will be given a folder with Izbiki pain score forms and return envelops. Patients will be contacted by telephone every two weeks and reminded to fill in the questionnaire and send it to the trial coordinators. The Izbicki pain score is a one page questionnaire, easily completed in less than 3 minutes. The folder with the Izbicki score forms will be re-filled at every outpatient clinic visit (scheduled every 6 months).A standardized case record form (CRF) will be used. A study nurse, not involved in patient care, will monitor the CRFs at all sites. Once a year a minimum of 10% of the CRF data, including the primary and secondary endpoints, will be verified with source data.Other outcomes will be collected during scheduled visits to the outpatient clinic at baseline and at intervals of 6 months for the duration of the study period. Standardized evaluation of symptoms and laboratory investigations, as outlined in the ‘Outcomes measures’ section, will be performed at each follow-up visit. Questionnaires will be mailed prior to follow-up visits and collected during the visits. The questionnaires will be processed by medical research staff that is unaware of the allocated treatment.Additionally, relevant data will be collected regarding any hospital admissions or interventions during the study period. Interventions encompass all surgical and endoscopic procedures , placement of jejunal feeding tubes and nerve blocks.The hypothesis of the study is that early surgery will result in an early and persistent reduction of pain complaints during the 18 months follow-up. Since pain is associated with many of the negative effects of CP on costs, social functioning and quality of life, the average reduction of pain during this period is of interest.Calculation of a sample size based on the hypothesized difference between treatment arms was not possible due to unavailability of such data. We, therefore, decided to base this calculation on detecting the minimal clinically relevant difference of the Izbicki pain score. In a consensus meeting the Chronic Pancreatitis Expert Panel agreed that the trial should aim to detect a difference of 15 points or more on the Izbicki pain score  during follow-up. Attempting to detect smaller differences would not bring any clear advantage to the clinical decision making process, but would substantially increase the required sample size.In previous studies, the average within group standard deviation of the Izbicki pain score was in the order of 20 points. Based on these assumptions, it was determined that 39 patients per group are needed to detect the minimal clinically relevant difference of 15 points on average using an ‘area under the curve’-analysis, based on alpha of 0.05 with a power of 90%. Taking into account a drop-out of 10%, a total sample size of 88 patients will randomized.An independent data and safety monitoring committee unaware of treatment assignment will evaluate the progress of the trial and will examine safety parameters at regular intervals (60 days after randomization of every 25 patients). All involved physicians will repetitively be asked to report any potential adverse events during the study period. These adverse events will be listed and discussed with the monitoring committee. The monitoring committee can ask for a full report in order to discuss a specific adverse event. The outcome of the meeting of the monitoring committee will be sent to the ethics board and the physicians involved. Any mortality will be directly reported to the safety committee and evaluated for cause of death and possible trial related serious adverse events. All serious adverse events will be reported online to the Central Committee on Research involving Human Subjects. Any death will also be reported to the central ethics board and to the local ethics board.Figure Analysis of primary and secondary outcomes will be conducted by a statistician blinded for the treatment allocation and not involved in data collection. Comparison of dichotomous outcomes will be performed using the Chi-squared test or Fisher’s exact test where appropriate. Results will be presented as number and percentages of events, as well as relative risk ratios with 95% confidence interval. For comparing continuous outcomes between two groups the Students t-test or the Mann-Whitney U test will be used, depending on the normality of the sample distribution as tested by the Kolmogorov-Smirnov test. A two-tailed P < 0.05 will be considered statistically significant. All analyses will be presented with 95% confidence intervals. If despite randomization baseline differences between the two groups were present, a sensitivity analysis using a multivariate regression approach will be performed correcting for any skewed baseline findings. Data will be analyzed on an intention-to-treat basis.The study will be conducted in accordance with the principles of the Declaration of Helsinki, and according to the laws governing human research in the Netherlands and Good Clinical Practice. The internal review board (IRB) of the Academic Medical Center Amsterdam approved the protocol. Secondary approval was obtained from the ethics committees of each participating hospital prior to commencement of randomization at the respective hospital. Informed consent will be obtained from each participating patient in oral and written form prior to randomization.The ESCAPE-trial is a multicenter trial designed to answer the question of whether early surgical intervention for CP will lead to better pain control and pancreatic function compared to the current step-up practice. Reviews and experts have repeatedly indicated a lack of randomized studies comparing surgical to medical treatment in CP ,27. ThisAs described in the introduction, medical management is currently the first treatment for many CP patients. Although medical management may suffice to suppress symptoms early in the disease, it does little to influence the progression of disease and does not guarantee long-term relief of symptoms. Longitudinal studies show that of all CP patients, 40 to 75% will still require surgery for pain in the course of the disease ,8,30,31.The current expectative management of CP means that, even in patients with clear morphological changes, progression of disease to the extent of severe and debilitating pain is a necessity before surgical interventions are considered. This approach should be questioned in the light of the prior discussed evidence (see introduction) suggesting that early intervention could mitigate disease progression and benefit the patient in terms of pain control as well as preservation of pancreatic function. The ESCAPE trial allows to examine these potential benefits in a setting of a well designed, sufficiently powered randomized trial.Calculation of a sample size based on the hypothesized difference between treatment arms was not possible, because the anticipated difference in the Izbicki pain scores between the early surgery group and the optimal current step-up practice could not be estimated with precision. Earlier surgical studies only provided Izbicki pain scores for patients who are operated late in the disease process. These scores do not reflect the expected results after early surgery, since we hypothesized that early surgery will achieve better pain control. In addition, the optimal current step-up practice is a consensus treatment designed for the purpose of this study. No exact levels of Izbicki scores are known for this research arm. The one small RCT by Nealon et al. that has studied the topic of early surgery in chronic pancreatitis only presented pain as proportion of patients with pain relief  . We choo– Measuring the outcome continuously best serves our hypothesis. It enables us to describe and better quantify the degree of pain during the 1.5 year follow-up period, and thus relate the degree of pain with costs and quality of life more precisely.– The non-surgical arm in the above mentioned trial was not clearly described. In the ESCAPE-trial we optimized the management of those patients with our current practice step-approach.– The observed differences in the trial are very large whereas its sample size is very small and no formal sample size calculation had been made; this needs confirmation in a large trial.To be able to make a reliable sample size calculation we, therefore, decided to base this calculation on detecting the minimal clinically relevant difference in the average Izbicki pain scores between the two study groups. This is a recognized and well accepted method for sample size calculations ,33. FirsIn this trial, we aimed to select patients for which the two intervention arms are applicable in clinical practice. If patients can be managed satisfactory with non-opioid medication, there is no reason to seek more advanced treatment options. The low risks associated with non-opioid medication and adequate pain control do not justify a change of practice to more advanced modalities like early surgery. Progression of pain toward the need for opioid analgesics is a clear sign that pain management of a patient has become complex. We have, therefore, chosen this event as the most appropriate moment for randomization. Additionally, newly developed need for opioids is a transparent clinical event, thereby increasing the generalizability of the results to clinical practice.An Expert Panel of CP specialists  will oversee the assessment of eligibility and will ensure that allocation to either treatment arm is possible prior to randomization. The expert panel consists of 18 experts . The Expert Panel is already in use within the CARE project, a nationwide prospective registration and follow-up system for CP patients. Furthermore, the Expert Panel has already proven to be valuable and highly supportive during previous trial of the Dutch Pancreatitis Study Group -36.The current step-up practice arm represents optimal current practice in the management of chronic pancreatitis in the Netherlands. It is in concordance with international guidelines and current knowledge, and represents consensus of CP specialists within the Dutch Pancreatitis Study Group ,7. This Few published data exist about the proportion of patients that in current practice undergo surgery early in the disease. In a Dutch surgical cohort we observed that the median time between reported onset of first pain and endoscopic intervention was 16 months (10th - 90th percentile 2 to 56), while it took a median time of 15 months (10th-90th percentile 4 to 81) between first endoscopic treatment and surgical intervention . In the The ESCAPE is a randomized controlled multicenter trial aiming to evaluate the benefits, risks and costs of early surgical intervention in patients with chronic pancreatitis as an alternative to current step-up practice of pain medication, if needed followed by endoscopic treatment, and eventually if needed followed by surgery.CP: Chronic pancreatitis; CRF: Case record form; CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreaticography; ESCAPE trial: Early surgery versus optimal current step-up practice for chronic pancreatitis trial; ESWL: Extracorporeal shock-wave lithotripsy; MRCP: Magnetic resonance cholangiopancreatography; NSAID: Non-steroidal anti-inflammatory drugs; SF-36: Short form 36; VAS: Visual analogue scale.The authors declare that they have no competing interests. MAB received unrestricted grants from Baxter, Abbott Laboratories, LifeCell, Ipsen for an unrelated projects. MJB received an unrestricted grant for unrelated projects from Axcan Pharma.UAA drafted the manuscript. YI, HvS and MAB co-authored the writing of the manuscript. UAA, HGG, MGWD and MAB designed the study. All authors participated in the final design of the study during several meetings of the Dutch Pancreatitis Study Group. UAA and MGWD performed the sample size calculation. All authors edited the manuscript and read and approved the final manuscript.The Dutch Pancreatitis Study Group (DPSG) was founded in 2002. The DPSG is a multi-disciplinary cooperation between 24 hospitals in the Netherlands . Within this cooperation, all hospitals and specialties with expertise in clinical and experimental pancreatitis research are represented. Internist, gastroenterologist, surgeon and radiologists in these hospitals work together in this study group to advance the knowledge about and care for pancreatitis. The DPSG has an excellent track record in conducting multi-centre research and has in its 10 years of existence already conducted and/or initiated several large and demanding trials. The DPSG has already published results of three randomized controlled multicenter trials for the treatment of acute pancreatitis. Two other trials are currently ongoing.These trials have concentrated on acute pancreatitis since this was the initial focus of the DPSG. Since 2008, the DPSG has extended its study scope to include CP. The ESCAPE trial will be, therefore, the first trial to be conducted for CP within this cooperation. Since the DPSG included all experts in the field of pancreatitis in the Netherlands, both acute and chronic, the ESCAPE trial will benefit from the effective and productive organizational infrastructure available.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/13/49/prepub


Health-related quality of life (HRQoL) instruments have been of increasing interest for evaluation of medical treatments over the past 10–15 years. In this prospective, long-term follow-up study we investigated the influence of preoperative factors and the change in HRQoL over time after lumbar disc herniation surgery. 117 patients surgically treated for lumbar disc herniation (L4-L5 or L5-S1) were evaluated with a self-completion HRQoL instrument (EQ-5D) preoperatively, after 2 years (96 patients) and after 7 years (89 patients). Baseline data  and degree of leg and back pain (VAS) were obtained preoperatively. The mean age was 39 (18–66) years, 54% were men, and the surgical level was L5-S1 in 58% of the patients. The change in EQ-5D score at the 2-year follow-up was analyzed by testing for correlation and by using a multiple regression model including all baseline factors  as potential predictors. 85% of the patients reported improvement in EQ-5D two years after surgery and this result remained at the long-term follow-up. The mean difference (change) between the preoperative EQ-5D score and the 2-year and 7-year scores was 0.59 (p < 0.001) and 0.62 (p < 0.001), respectively. However, the HRQoL for this patient group did not reach the mean level of previously reported values for a normal population of the same age range at any of the follow-ups. The changes in EQ-5D score between the 2- and 7-year follow-ups were not statistically significant . There was a correlation between baseline leg pain and the change in EQ-5D at the 2-year  and 7-year follow-up . However, when using regression analysis the only statistically significant predictor for change in EQ-5D was baseline EQ-5D score. Our findings suggest that HRQoL (as measured by EQ-5D) improved 2 years after lumbar disc herniation surgery, but there was no further improvement after 5 more years. Low quality of life and severe leg pain at baseline are important predictors of improvement in quality of life after lumbar disc herniation surgery. The natural course of events after sciatic pain originating from lumbar disc herniation is most often favorable, but surgery is frequently performed in patients with persistent sciatic pain . There aIn recent years, outcome based on patients' own assessments, such as satisfaction with treatment , patientThe aim of using HRQoL instruments is to measure the influence of a disorder/disease on a patient's daily life and activities; they have come to be used frequently to evaluate outcome after different types of surgery . The mosThe main aim of the present prospective follow-up study was to follow the postoperative development of HRQoL after lumbar disc herniation surgery. Secondary aims were to evaluate potential relationships between preoperative factors and the development of HRQoL and to investigate differences between 2-year HRQoL and 7-year HRQoL (range: 5–8 years). The primary outcome variable was change in EQ-5D.Between September 1998 and March 2002, 117 consecutive patients surgically treated for lumbar disc herniation at a single center, a university clinic in Gothenburg, Sweden, were included in the study. The inclusion criteria were CT- or MRI-verified one-level disc herniation at L4-L5 or L5-S1 level without any other spinal diseases or previous surgery at the same level. The patients had a mean age of 39 (18–66) years. 54/117 patients (46%) were women. 49/117 patients (42%) underwent surgery at the L4-L5 level and 68/117 (58%) at the L5-S1 level. The regional ethics review board approved the study (numbers 393-96 and 577-97) and all patients gave their informed consent before inclusion.A midline approach was used to dissect the paravertebral muscles down to the laminae, and the interlaminar ligaments were resected. A partial laminotomy was performed when necessary. Herniated disc material and loose fragments from the disc was removed to decompress the affected neural structures. The surgery was performed with or without a microscope according to the surgeon's preference ) and intensity of leg and back pain (VAS) at the preoperative visit. Health-related quality of life (HRQoL) was measured at baseline, at 2 years, and at 7 (5–8) years using the EQ-5D. The EQ-5D is a HRQoL instrument designed for self-completion by the respondents, and it is in 2 parts. The first is the EQ visual analog scale (EQ-VAS), in the range 0–100 representing “worst to best imaginable health state”. The second part is a descriptive system consisting of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is divided into 3 levels of severity , resulting in 243 possible health states. The results can be presented as a health profile or as a global health index . The minThe EQ-5D was compared with the VAS scores for leg pain and back pain that were obtained at baseline and at the two follow-up visits. The EQ-5D questionnaire was mailed to the patients and brought by the patients to the outpatient clinic at the 2-year follow-up. Questionnaires for the 7-year follow-up were returned by mail. If no response was received after 2 mailed reminders the patients were reminded by telephone to complete the questionnaire.The primary outcome variables were change in EQ-5D between baseline and follow-up at 2 years and 7 years. The secondary outcome variable was change in EQ-5D between the 2-year and the 7-year follow up. The baseline factors analyzed were age, sex, duration of pain, surgical level, degree of leg and back pain (VAS), and baseline EQ-5D score.We used SPSS software version 17.0 for statistical analysis. For analysis of changes in EQ-5D score, we used the paired t-test. When comparing groups, we used the independent samples t-test (using the Welch–Satterthwaite equation). Correlations between different variables were evaluated by the nonparametric Spearmen rank correlation test. The change in EQ-5D score was also analyzed in a multiple linear regression model, including all baseline factors as potential predictors. In an explorative manner, we used the same model but excluded baseline EQ-5D as a predictor. Any p-values below 0.05 were considered to be significant. The term significant should only be interpreted in its statistical sense. Since many statistical tests were performed, all p-values should be interpreted with care.Mean VAS for back pain preoperatively was 51 (SD 22) and VAS for leg pain was 60 (SD 18). Less than 6 months' duration of leg pain preoperatively was reported by 41 of the patients, 6–12 months by 37, and more than 12 months by 39.96/117 of the patients (82%) completed the EQ-5D questionnaire at the 2-year follow-up and 89/117 (76%) completed the EQ-5D questionnaire at the 7-year follow-up. The mean difference (change) between the preoperative EQ-5D score and the 2-year score was 0.59 (p < 0.001) and it was 0.62 (p < 0.001) between the preoperative score and the score for the long-term follow-up. 82/96 patients (85%) showed improvement in the EQ-5D score between the baseline and the 2-year follow-up, and 81/89 (91%) between baseline and long-term follow up.22/89 of the patients had a decrease in EQ-5D score, 30/89 had an unchanged score, and 37/89 had a further improvement in EQ-5D score between the 2-year follow-up and the 7-year follow-up. However, the change in EQ-5D score between these follow-ups was not significant .Preoperatively, severe problems were reported by most patients for the dimensions pain and mobility, whereas the majority reported moderate problems for the other dimensions. At both follow-ups, the patients reported fewer problems for all dimensions. At the follow-up visits, the remaining problems that were reported were mainly for the dimension pain.The mean preoperative EQ-VAS improved from 38 at baseline to 71 at the 2-year follow-up (n = 88) (p < 0.001) and from 37 to 72 at the long-term follow-up (n = 89) (p < 0.001). 76/88 patients (86%) reported a higher EQ-VAS relative to baseline after 2 years and 77/90 (86%) after 7 years. There was no significant difference in EQ-VAS between the 2-year follow-up and the 7-year follow-up.There was no significant correlation between baseline EQ-5D score and age or duration of pain; there was, however, a significant correlation between baseline EQ-5D and baseline leg pain  and also back pain . The baseline EQ-5D was not significantly different between males and females or between different operation levels.There was no significant correlation between age and change in EQ-5D at any of the follow-ups, and there was no significant relationship between sex and change in EQ-5D.There was no significant correlation between the duration of pain and the EQ-5D score at any time point, or in change in EQ-5D with time. We did not find any significant differences in EQ-5D score at or between time points regarding either sex or surgical level (Table).The leg pain at baseline was correlated with the change in EQ-5D at 2-year follow-up  and at 7-year follow up . Back pain at baseline was not found to be significantly correlated with change in EQ-5D at any follow-up.There was a correlation between baseline EQ-5D score and change in EQ-5D at both follow-ups .The change in EQ-5D score at the 2-year follow-up was also analyzed in a multiple regression model including all baseline factors  as potential predictors. The only significant predictor was found to be baseline EQ-5D score. The influence of baseline EQ-5D score was estimated (b = –1.0 (95% CI: –1.2 to -0.8)), indicating that for every unit of increase in baseline EQ-5D score, we can expect one unit less of change (improvement) in EQ-5D.When baseline EQ-5D score was excluded from the model, the only significant predictor at the 2-year follow-up was leg pain (p = 0.04) (higher VAS leg pain score at inclusion resulted in higher change in EQ-5D). At long-term follow-up, none of the remaining predictors were significant.To our knowledge, there have been no 7-year results published on EQ-5D in patients who have undergone lumbar discectomy. 82/96 (85%) of our patients who were surgically treated for lumbar disc herniation reported an improvement in HRQoL at the 2-year follow-up and 81/89 (91%) reported an improvement at the 7-year follow-up.The mean preoperative EQ-5D score in our patients was only 0.12, which is lower than has been reported in previous studies for patients suffering from lumbar disc herniation: At baseline, there was a correlation between EQ-5D and leg and back pain. The only predictors that were significantly correlated with change in EQ-5D (at both follow-ups) were leg pain at baseline and EQ-5D at baseline. In the multiple linear regression model, baseline EQ-5D score was the only significant predictor of change in EQ-5D score. Leg pain at baseline was not a significant predictor in that model, which may be explained by multicollinearity, i.e. the intercorrelation between baseline EQ-5D and leg pain. When EQ-5D was excluded from the model, leg pain was significant at the 2 year follow-up but not at the long–term follow-up.Pain, and leg pain in particular, is the main indication for surgery in patients with disc herniation, and we found a strong correlation between EQ-5D and back pain—as well as leg pain—at baseline and at the 2-year and 7-year long-term follow-up visits. The correlation between leg and back pain was also found to be significant. Of the EQ-5D dimensions, the dimension “pain/discomfort” showed the highest frequency of “severe problems” preoperatively (68%). Compared to the study by Even though there was a large improvement in the pain dimension at the 2-year and 7-year follow-up, 8 of 89 patients still reported having severe pain at the 7-year follow-up and as many as 64 of these 89 patients reported having moderate or severe pain.Between half and two-thirds of the patients reported “moderate” or “severe” problems regarding mobility, self-care, anxiety, and usual activities preoperatively. However, for these 4 dimensions, more than two-thirds of the patients reported having no problems and very few reported severe problems at the follow-up visits. The postoperative values reported for these 4 dimensions at the two follow-up occasions are comparable to those of a normal population of the same age range  When comOur findings suggest that the EQ-5D instrument for disc herniation patients is highly influenced by the level of pain according to the patients' experience. Based on the fact that long-standing pain has a negative influence on most aspects of life, this result is not surprising.Our study has several limitations, including the limited number of patients. Some acutely admitted patients may have missed being included, there was a long waiting time for surgery (about one third had leg pain more than 12 months before surgery), and there was no short-term follow-up. Comorbidity of different types, not involving the spine, may also have influenced the EQ-5D score at the follow-up visits.In summary, in this patient population that was operated for lumbar disc herniation, health-related quality of life measured with EQ-5D was low at baseline and was strongly associated with leg pain (VAS). Quality of life improved after 2 years, with no further improvement after 5 more years. Low quality of life and severe leg pain at baseline were important predictors of improvement in quality of life after disc herniation surgery.


Cluster headaches (CH), characterized by strictly unilateral pain localized in or around the eye and accompanied by ipsilateral autonomic features, are the most painful form of primary headache. Probable cluster headache (PCH) is a subtype of CH fulfilling all but one diagnostic criteria for it: for example, with no ipsilateral autonomic features. CH is associated with severe pain and has a considerable impact on social functioning and quality of life. Like CH, PCH without ipsilateral autonomic features (PCHWOIAF) may be associated with severe pain and considerable impact, but PCHWIAF has not been studied. The present study aimed to clarify the clinical profile of PCHWIAF.Seven patients who had been diagnosed with PCHWOIAF according to the 2nd edition of the International Classification of Headache Disorders were compared with 86 patients with CH. We collected data on laterality and location of headache, pain intensity, impact, additional features , duration of attacks, and time of onset of attacks.Pain occurred in the forehead, occipital regions, and vertex significantly more often in patients with PCHWOIAF than in patients with CH. There were no significant differences between patients with PCHWOIAF and CH in the mean age at first consultation, mean age of onset, the ratio of males to females, laterality of headache, pain intensity, impact, additional features, duration of attacks, and time of onset of attacks.The impact of PCHWOIAF is similar to that of CH. Patients with PCHWOIAF should receive the same level of treatment as patients with cluster headaches.


Zoledronic acid (ZOL) is widely used for preventing bone loss in early breast cancer patients. However, the adverse effects caused by ZOL itself should not be neglected. Musculoskeletal disorders were common after ZOL administration and distressing to the patients. Up to now, no precise estimation of musculoskeletal disorders has been made.Relevant randomized clinical trials were selected by searching the electronic database PubMed, and a meta-analysis was conducted.P = 0.466 for heterogeneity) and bone pain . Three clinical trials reported the complications of upfront versus delayed ZOL treatment, including 1091 patients with upfront ZOL and 1110 patients with delayed ZOL. The rate of bone pain in upfront group (119/824) was significantly higher than that in delayed group (74/836) .Four trials reported musculoskeletal disorders of ZOL treatment versus no ZOL, including 2684 patients treated with ZOL and 2712 patients without ZOL treatment. Compared to patients without ZOL treatment, patients treated with ZOL had a significantly higher risk of arthralgia (risk ratio (RR): 1.162, 95% confidence interval (CI): 1.096-1.232, Our meta-analysis suggested that treatment with ZOL was significantly associated to the occurrence of arthralgia and bone pain. Moreover, higher rate of bone pain was observed in patients treated with upfront ZOL compared with delayed ZOL treatment. More attentions should be paid to patients treated with ZOL, especially for immediate ZOL. For patients with low risk of osteoporosis, immediate ZOL may be not needed due to additional musculoskeletal disorders and little benefit. Or it can be stopped after the occurrence of these adverse events. More patients with early breast cancer have been diagnosed with the development of screening techniques . FollowiZoledronic acid (ZOL) can prevent bone loss in early breast cancer patients . FurtherThe UK Expert Group  suggesteT-score fell below -2.0, after a nontraumatic clinical fracture, or if an asymptomatic fracture); (3) enough published data for estimated a risk ratio (RR) with 95% confidence interval (CI). In addition, to avoid duplication of information, only the report with longest follow-up was included for calculations when multiple reports pertained to overlapping groups of patients.The present study was conducted as described previously -23. ReleThe data of musculoskeletal disorders, including arthralgia, bone pain and muscle pain, were carefully extracted from all the eligible randomized trials independently by two investigators (Zhou WB and Liu XA). The following variables were extracted from each study: first author's name, the name of each trial, publication year, the median follow-up time, the number of total patients in every group, and the number of patients with musculoskeletal disorders in every group. All the data were reached consensus after discussion.P < 0.10) [P value less than 0.05 was considered significant. All analyses were performed using the software Stata version 11.0 .Crude RRs with 95% CI were used to assess the musculoskeletal disorders risk of ZOL. The between-study heterogeneity was tested with Q statistics (significant differences indicated by  < 0.10) . The fix < 0.10) . Otherwi < 0.10) . Funnel Ten randomized clinical trials, in which ZOL was used in adjuvant setting, were identified. Of these ten studies, the detail data of musculoskeletal disorders were not reported in three studies -29. In aP = 0.466 for heterogeneity)  .Table ) Figure . Bone pa) Figure . HoweverP > 0.05) existed (data not shown).Funnel plot and Egger's test were performed to access the publication bias of the four studies. No significant publication bias (P = 0.850 for heterogeneity). The similar results were observed about muscle pain between the two groups . The rates of muscle pain were 6.4%-16.3% and 5.1%-12.1% in upfront group and delayed group, respectively. Bone pain caused by ZOL was reported in Z-FAST and ZO-FAST trials. The rate of bone pain in upfront group (119/824) was significantly higher than that in delayed group (74/836)  (Figure The main results were also showed in Table Since only three trials were included in this analysis of musculoskeletal disorders between upfront and delayed ZOL groups, publication bias was not accessed.Previous randomized clinical trials showed that musculoskeletal disorders occurred in a high rate of patients treated with ZOL. This meta-analysis suggested that patients treated with ZOL had a statistically significant higher risk of arthralgia and bone pain compared to patients without ZOL treatment. Furthermore, patients treated with upfront ZOL had a significant higher risk of bone pain than patients with delayed ZOL.Although ZOL can bypass the potential disadvantages of the oral route used by other bisphosphonates, it may cause more musculoskeletal disorders than other bisphosphonates -32. A hiThree randomized clinical trials ,18,19 weSeveral limitations of this meta-analysis should be considered when interpreting these results. First, of these seven studies, most subjects were Caucasians, while seldom Asians were included. Second, the present results were based on unadjusted RRs. More precise estimation may be adjusted by other potential covariates. Third, due to lack of data on musculoskeletal disorders, three trials were excluded. Since these studies were with small sample size, they were unlikely to change significantly our results.This meta-analysis strongly suggested that patients treated with ZOL had a statistically significant higher risk of arthralgia and bone pain than those without ZOL treatment. Furthermore, patients treated with upfront ZOL had a significantly higher risk of bone pain than patients with delayed ZOL. More attentions should be paid to patients with musculoskeletal disorders. For patients with low risk of osteoporosis, immediate ZOL may be not needed due to additional adverse effects in some conditions. Or it can be stopped after the occurrence of these adverse events. Further randomized clinical trials with large sample size should be taken to evaluate the side effects of ZOL, especially for musculoskeletal disorders.AI: aromatase inhibitor; CI: confidence interval; DFS: disease-free survival; OS: overall survival; RR: risk ratio; ZOL: zoledronic acid.The authors declare that they have no competing interests.WH has contributed to the conception and design of the study, the analysis and interpretation of data, the revision of the article as well as final approval of the version to be submitted. WBZ and XAL participated in the design of the study, performed the statistical analysis, searched and selected the trials, drafted and revised the article. PLZ drafted and revised the article. TY participated in the design of the study and helped to revise the article. All authors read and approved the final version of the manuscript.


To evaluate the clinical and functional activity of patients with rheumatoid arthritis at one and two years after starting anti-TNF therapy.t test. The statistical study was analyzed by the SPSS 18,0.This is a retrospective study of 50 RA patients, who started ANTI-TNF theraphy between June 2006 and july 2009. The main variables in the study were: DAS28, HAQ and pain VAS. We analyzed evolution after 1 year and 2 years from the beginning of the treatment. The comparison with the basal state was made with Student’s The study includes 50 patients, 66% female, with RF in 76% and erosions in 64%, treated with etanercept (28), adalimumab (13) and infliximab (9). Most of them (70%) had recieved at least 2 FAMES before biological. In the below table we compare changes in clinical parameters for different biologics after one and two years.All anti-TNF significantly improve disease activity, functional status and pain VAS after the first year. This improvement continues but not significantly increases the second year.Etanercept is the only drug with a significant reduction for HAQ, DAS28 and pain VAS.


Remifentanil, an ultra-short-acting opioid, is widely used for pain control during surgery. However, regular dose (RD) remifentanil exacerbates postoperative pain in a dose-dependent manner. Recent studies suggest that high-dose (HD) remifentanil offers sustained analgesia in experimental studies. We thus hypothesized that intraoperative administration of high-dose remifentanil may attenuate postoperative pain.−1min−1 (HD group) remifentanil during thyroidectomy. A visual analogue scale (VAS) was used to measure pain intensity. Mechanical pain threshold on the forearm was assessed using von Frey filaments before surgery (baseline), 2 h postoperatively and 18–24 h postoperatively. The primary outcome was to compare the difference of VAS score at different time points after operation and morphine consumption 24 h postoperatively between RD and HD groups. The second outcome was to compare the difference of mechanical pain thresholds in the forearm postoperatively between RD and the HD groups.In this prospective, randomized, double blind, controlled clinical study, sixty patients undergoing thyroidectomy (18–60 years-of-age) received an intraoperative infusion of 0.2 (RD group) or 1.2 μg kgVAS scores were lower 30 min postoperatively in the HD group  compared with the RD group  . Postoperative morphine consumption was much lower in the HD group compared with the RD group . In both groups, mechanical pain threshold was decreased 18–24 h postoperatively (2.93±0.209 Ln(g) vs. 3.454±2.072 Ln(g), p = 0.032 in RD group; 2.910±0.196 Ln(g) vs. 3.621±0.198 Ln(g), p = 0.006 in HD group, 18–24 h postoperatively vs baseline).Intraoperative administration of high-dose remifentanil decreased VAS scores and morphine consumption postoperatively. Thus, modulation of intraoperative opiates may be a simple and effective method of postoperative pain management.ClinicalTrials.gov, with the Name: Effect of Higher Doses of Remifentanil on Postoperative Pain in Patients Undergoing Thyroidectomy, and ID number: NCT01761149.This trial is registered in  However, remifentanil, like other μ-opioid receptor agonists, exacerbates postoperative pain as indicated by enhanced pain sensitivity, increased postoperative pain scores, and opioid consumption during remifentanil withdrawal −1h−1) prevented the LFS-evoked spinal LTP of C-fiber evoked field potential. However, relatively low-dose remifentanil (225 μg kg−1h−1) infusion could not reverse the activated spinal LTP of C-fiber evoked field potentials. Furthermore, a 1-h infusion of HD remifentanil inhibited capsaicin-induced mechanical allodynia for more than 6 h −1min−1 remifentanil for 20 min inhibited thermal hyperalgesia in a neuropathic pain model Interestingly, an experimental study by Drdla-Schutting and colleagues revealed that brief application of HD remifentanil reversed various forms of activity-dependent long-term potentiation (LTP) at C-fiber synapses, a synaptic model of hyperalgesia The present study hypothesized that intraoperative infusion of HD remifentanil attenuated postoperative pain and aimed to test this hypothesis in the patients undergoing thyroidectomy. Here we showed that HD remifentanil decreased VAS scores and reduced morphine consumption postoperatively. However, HD remifentanil still reduced mechanical pain thresholds in the forearm, a site remote from the surgical site. Thus, the present study suggested that different mechanisms may regulate the effect of remifentanil on pain sensation in intact sites relative to injured sites; and intraoperative modulation of high dose opioids may offer a convenient and effective technique for postoperative pain control.The protocol for this trial and supporting CONSORT checklist are available as supporting information; see 2 in the left central volar forearm and the visual analogue scale  was shown to the patients. A set of 10 hand-held Von Frey monofilaments calibrated to deliver an increasing force on the skin from 4 to 300 g was used for this purpose  as described previously On the day before surgery, baseline mechanical pain thresholds were measured in a delimited area of 3×3 cm−1) based on the BIS value. Once the BIS value was below 60, 0.15 mg kg−1 cisatracurium was administered to facilitate tracheal intubation. After tracheal intubation, patients were ventilated with 40% oxygen without any inhaled anesthetics. Maintenance of anesthesia was achieved with propofol only by target controlled infusion to maintain BIS values between 40 and 60.Anesthesia was induced with continuous propofol infusion and remifentanil by target-controlled infusion . Before the study began, a random-number table was constructed. For each patient, an envelope containing the group assignment was prepared, sealed, and sequentially numbered. On the day of surgery and before induction of anesthesia, an anesthesiologist not involved in the evaluation of the patient opened the patient’s envelope and prepared remifentanil syringes. The patients and the anesthesiologists involved in assessing postoperative pain, morphine consumption, VAS data collection and data analyses were unaware of any group assignment. In case of emergency, the attending anesthesiologist was allowed to break the code.The two treatment groups were as follows:−1min−1 starting from 1 minute prior to skin incision to the completion of surgery.Clinical-regular-dose remifentanil (RD): patients were administered with remifentanil at a rate of 0.2 μg kg−1min−1.High-dose remifentanil (HD): The procedure was similar to the HD group except that the dose was 1.2 μg kgIn the case of hypotension, defined by a systolic arterial pressure less than 80 mm Hg or a mean arterial pressure less than 60 mm Hg, ephedrine  was given and additional intravenous fluids were administered as needed by the anesthesiologist. If the patient’s heart rate was less than 50 beats per min, then atropine (0.3 mg) was administered to maintain a heart rate greater than 50 beats per min.All patients were transferred to the post-anesthesia care unit and extubated there. An anesthesiologist, blinded to the patients’ group assignment, evaluated the VAS score in the post-anesthesia care unit at 30, 45, 60, 75, 90, 120 min and 18–24 h postoperatively. When the patients described VAS ≥4, morphine was infused  until the VAS<4. Patient-controlled analgesia was not used because of its rarity in this clinical situation. Postoperative nausea and vomiting were prevented with ondansetron  after surgery was concluded.Postoperative mechanical pain thresholds were measured at 2 h and 18–24 h after surgery in a manner identical to that described previously. To avoid inter-rater variations, all pain measurements were performed by one trained investigator.The primary outcome was to compare the difference of VAS score at 30 min, 45 min, 60 min, 90 min, 2 h and 18–24 h after operation and cumulative morphine consumption 24 h postoperatively between the RD group and the HD group. The second outcome was to compare the difference of mechanical pain thresholds in the forearm at 2 h and 18–24 h postoperatively between the RD group and the HD group.In the preliminary study (unpublished data), VAS scores were 2.32±0.33 for the RD group and 1.44±0.45 for the HD group 30 min postoperatively. The estimated sample size was 4 patients per group with a β-risk of 80% at an α-level of 0.05 for detecting a difference in postoperative VAS at least of 0.8 at 30 min postoperatively. In contrast, baseline mechanical pain thresholds for the forearm were 3.6±0.8 Ln(g), and 3.0±0.8 Ln (g) at 24 h after surgery in the HD group  t test. Hemodynamic parameters including systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP), heart rate (HR), the BIS scale, mechanical pain thresholds and VAS scores were analyzed by two-way ANOVA for inter-group comparisons. In cases of statistical significance, post hoc tests were conducted with a Bonferroni’s adjustment. The χ2 test was used to compare gender, ASA levels, number of patients requiring ephedrine or morphine, and postoperative complications . All analyses were performed using SPSS 13.0 and GraphPad Prism 5.Age, weight, height, BMI, duration of surgery, intraoperative propofol consumption and postoperative morphine consumption were analyzed with an unpaired  = 2.356, p = 0.0236). At 30 min postoperatively, VAS scores were significantly higher in the RD group  compared to the HD group  . At later time points, no significant differences were observed between VAS scores in these two groups.As shown in In the RD group, ten of 29 patients required morphine treatment, but only two of 28 patients in the HD group required morphine treatment  = 15.40, p<0.0001). Compared with baseline, mechanical pain thresholds were significantly lower at 18–24 h postoperatively in both groups (2.93±0.209 Ln (g) vs. 3.454±0.207 Ln (g), p = 0.032 in the RD group; 2.910±0.196 Ln (g) vs. 3.621±0.198 Ln (g), p = 0.006 in the HD group, 18–24 h postoperatively vs baseline, two-way ANOVA followed by Bonferroni’s test). In the HD group, mechanical pain thresholds at baseline and 2 h postoperatively did not differ significantly . However, in the RD group, mechanical pain thresholds were significantly lower 2 h postoperatively (2.910±0.203 Ln (g)) compared with baseline (3.454±0.2072 Ln (g)) . Post hoc Bonferroni’s test also showed that no significant difference in the mechanical pain threshold in the post-operative 2 h  and 18–24 h  between the RD and the HD groups.No significant difference was observed in propofol consumption, waking time or extubation time in these two groups. Patients requiring ephedrine treatment did not differ significantly between the RD and the HD group. Two patients in the HD group and one patient in the RD group reported postoperative nausea or vomiting .The present study has made two important findings. First, HD remifentanil attenuated early postoperative VAS scores and reduced morphine consumption after mildly painful surgery (thyroidectomy), indicating that intraoperative HD remifentanil exerts a persistent analgesic effect, which may be a novel strategy for postoperative pain control. Second, HD remifentanil also reduced mechanical pain thresholds of the forearm, a site remote from the surgical site, implying that different mechanisms regulate the effect of remifentanil on pain sensation in intact sites relative to injured sites.−1h−1 remifentanil was continuously infused in rats to block capsaicin-evoked hyperalgesia −1h−1 as used in this study) −1min−1) remifentanil on postoperative pain, previous studies indicated that patients receiving an intraoperative infusion of 0.05 μg kg−1min−1 remifentanil during thyroidectomy had high VAS scores 6 h postoperatively and that 70% of those patients required analgesics This HD dosage was based on a recent experimental study in which 450 μg kg−1min−1 remifentanil decreased the mechanical sensory threshold in the forearm after septorhinoplasty, suggesting increased pain sensitivity −1min−1) increased sensitivity of painful pressure stimulation In present study, both RD and HD remifentanil reduced the mechanical pain threshold in the forearm, a site distant to the surgical site. Echevarria and colleagues recently reported that 0.2 μg kg2+ concentrations −1min−1) induced mechanical hypersensitivity in the forearm are consistent with animal studies. NMDA receptor antagonists, ketamine, magnesium sulfate and propofol reduced remifentanil-induced hypersensitivity, further suggesting the involvement of the NMDA receptor in opioid-induced mechanical pain hypersensitivity Nevertheless, recent studies of spinal LTP induction by C-fiber-evoked field potential as a synaptic model of hyperalgesia to investigate the effect of HD remifentanil on hyperalgesia indicated that HD remifentanil may have opposing effects on spinal LTP induction in naïve or noxious-stimulated rats The persistent analgesic effect of HD remifentanil suggests that intraoperative infusion of HD opioids may be a novel strategy for postoperative pain control. This method may be simpler to undertake during surgery and postoperative treatment may not be required. In addition, reducing the use of other analgesics may also reduce side effects such as respiratory depression and itching. However, the development of hyperalgesia and the cost of remifentanil may limit potential clinical applications of remifentanil. Further studies are required to examine the effect of HD remifentanil on postoperative pain in other more painful surgeries such as coronary artery bypass graft. In the latter case, the potential attenuation of postoperative pain by HD remifentanil would greatly improve the quality of postoperative recovery and this has obvious clinical significance.Of note, in the present study, we used propofol for maintenance of anesthesia. Numerous studies suggest that propofol, as a NMDA receptor antagonist, may attenuate the development of acute postoperative hyperalgesia by remifentanil withdrawal, and thereby reduce postoperative morphine consumption In conclusion, the present study showed that compared to RD remifentanil, HD remifentanil attenuated postoperative pain by reducing postoperative VAS score and morphine consumption. Thus, intraoperative modulation of high dose opioids may offer a convenient and effective technique for postoperative pain control.Checklist S1Supporting CONSORT checklist.(DOC)Click here for additional data file.Protocol S1Trial Protocol in Chinese submitted to the hospital ethical committee.(DOCX)Click here for additional data file.Protocol S2English copy of trial protocol.(DOCX)Click here for additional data file.


The dominant cognitive model that accounts for the persistence of delusional beliefs in schizophrenia postulates that patients suffer from a general deficit in belief revision. It is generally assumed that this deficit is a consequence of impaired reasoning skills. However, the possibility that such inflexibility affects the entire system of a patient's beliefs has rarely been empirically tested. Using delusion-neutral material in a well-documented advice-taking task, the present study reports that patients with schizophrenia: 1) revise their beliefs, 2) take into account socially provided information to do so, 3) are not overconfident about their judgments, and 4) show less egocentric advice-discounting than controls. This study thus shows that delusional patients' difficulty in revising beliefs is more selective than had been previously assumed. The specificities of the task and the implications for a theory of delusion formation are discussed. Belief change is a complex process by which rational agents shift from one belief state to another as a way to improve their knowledge delusional beliefs. The latter are defined as rationally untenable beliefs based on incorrect inference about reality. These beliefs persist despite the evidence to the contrary and are not ordinarily accepted by other members of the person's culture or subculture One can reasonably assume that a dysfunction in such a mechanism would prevent an individual from correctly assessing her/his beliefs and eliminating those that are patently false in light of compelling counter-evidence. This could lead her/him to hold ill-founded, irrational or even To account for delusions, the authors thus postulate the existence of another factor, namely a deficit in belief evaluation and revision.In line with this view, clinical observations show that deluded patients, such as those suffering from schizophrenia, tend to hold their delusional beliefs with a high degree of conviction and ignore any evidence, arguments, or outside opinion that could lead them to revise their views It has been proposed that the failure to revise one's own delusional beliefs and generate alternative beliefs may result from a deficit in inductive reasoning and hypothesis testing, which manifests itself in reasoning biases disconfirmatory evidence  significantly increased over time and this increase was not less pronounced than for control participants. In other words, they did not show any bias against confirmatory evidence (BACE) and the authors did not report any evidence that their patients discovered the correct interpretation with less ease than their control participants. This result is a marker of a revision process since patients show a preference for one answer over others, and this preference is supported by a new piece of evidence disclosed as the picture becomes identifiable.Although Moritz and Woodward's study Second, other cognitive deficits than a belief revision impairment might account for the BADE score. It is well-established that schizophrenic patients have difficulties in focussing their attention and in overcoming potentially disruptive stimuli Third, in order to establish a general deficit one needs to explore various situations where such a deficit is likely to arise. Since each task has its own peculiarities, any deficit reported in a given situation may be specific to that situation. The greater the variety of situations showing the same kind of deficit, the greater the chance that such a deficit is general. As indicated below, it might be the case that the belief revision impairment only afflicts a selected category of beliefs. For reasons we suggest in the discussion, this particular set of beliefs will be more difficult to revise and will thus constitute what is called delusions. The work of Woodward and Moritz is thus of high relevance since it explores belief revision when more neutral beliefs are formed. However, their task obviously involves its own specific characteristics and thus one needs to go one step further and explore situations including different features.advice taking situation. Since delusional beliefs are usually not accepted by other members of the patients' culture or subculture In the present study, beliefs were related to encyclopaedic knowledge and the context of revision was that of an general and extends to non-delusional beliefs. We thus explore a very basic and well-investigated situation of social influence that may lead people to revise their views: the individual produces an initial estimate  in a certain task, then receives the estimate of another person, and ultimately makes a final estimate. This typically illustrates what is referred to as an advice taking situation in the decision making literature. The difference between the initial and the final estimates offers a measure of the extent to which people combine advice with their own opinion. Results obtained with healthy participants indicate that the weight assigned to advice varies according to a number of factors such as the trustworthiness of the adviser egocentric advice discounting  as they tend to outweight their own opinion as compared to that of the advisor(s). For example, if participant's initial opinions are assigned the value of 0, and the advice the value of 100, the final opinions tend to be situated around 30 on average In the wake of Moritz and Woodward's work The present experiment involves a task devised by Yaniv All participants gave written informed consent for the study which was approved by the local Ethical Committee . All patients consented to participate in the research on their own behalf. Prior to the task, the experimenters made sure that patients had the capacity to consent by asking a series of questions about their understanding of the study.Thirty patients with schizophrenia  and 30 control participants  participated in the study. All patients fulfilled DSM-IV criteria of schizophrenia SAPS Following Yaniv We did not indicate to participants whether the advice was obtained from patients or from healthy individuals. They were only told that those estimates came from people who were of approximately the same age and education level as themselves and who also took part in this study. We considered that providing more details about the population of advisers might have biased the extent to which they would have taken the advice into account. On one hand, had we indicated that the opinions were obtained from healthy participants, patients may have considered these advisers to be more knowledgeable than them. On the other hand, had we presented the advisers as suffering from any sort of disease, patients might have considered these advisers as less competent. It turned out that during the experiment, neither patients nor controls inquired about who gave the advice. Following Yaniv (−5) but no main effect of group  = 0.23, p>0.6) nor significant interaction between these two factors  = 0.18, p>0.6). The improvement of performance can easily be explained by the fact that the advice estimates were much more accurate than the initial responses of the participants for both groups: 16.9 years better for the control group  and 17.1 years for the group of patients . Note that the difference of performance between controls and their advice was similar to the difference of performance between patients and their advice  = 0.04, p>0.9). The absence of difference in performance in initial answers was not only quantitative but it was also qualitative as the difficulty orders of the questions highly correlated between the two groups  This means that both groups had lower and higher accuracy for the same questions: difficult questions (i.e. those which had the lowest level of accuracy) for the patients were also difficult for the controls. Finally, the level of accuracy (as measured by the number of years away from the correct answer) and the number of education years did not significantly correlate and for patients, the level of accuracy did not significantly correlate with any of the clinical scores .Accuracy was assessed by the measure of the absolute number of years away from the correct response. For each participant the averaged accuracy across the 35 questions was calculated. In the control group the averaged accuracy was 28.2 years for the initial answer and 15.8 years for the final answer. In the group of patients, the averaged accuracy was 30.4 years for the initial answer and 16.4 years for the final answer. Hence, participants of the two groups showed a similar level of performance and tended to change their answer and improved their performance after receiving the advice see . This wa−4) but no main effect of group  = 0.23, p>0.6) and a marginally significant interaction between these two factors  = 2.86, p = 0.096) indicating that controls' confidence increased a bit more than that of patients.The level of confidence was also similar across the two groups and both controls and patients increased their confidence after receiving the advice see : The levThe weight of advice (WOA) is our main variable of interest as it is a measure of the extent to which participants took the advice into account in their final estimate. It is calculated with the following formula In order to obtain a well-defined estimate of WOA, the following two criteria have to be met. First, the advice should differ from the initial answer; otherwise one cannot distinguish between a final answer sticking to the initial response and a final answer adhering to the advice. Because the advice estimates were randomly taken from a pool of actual estimates that were selected before knowing participants' answers, we were exposed to the risk of such equalities. Indeed, 2.33% of the answers (2.29% of answers in the Control group and 2.38% in the group of patients) turned out to be identical to the advice and were thus excluded from the WOA analysis. Second, the final answer should fall between the initial answer and the advice. Exceptions to such criterion include 1) final answers which are even further away from the advice than the initial answer  and 2) final answers which are even further away from the initial answer than the advice . The rate of answers that did not meet this criterion represented 6.29% of the total answers,  = 0.64, p>0.5) which were excluded from the WOA analysis. Once these two exclusion criteria were applied, we calculated, for each participant, the mean WOA across the 35 questions. In line with the observations reported by the literature, participants in the control group showed egocentric advice discounting choosing strategy. In fact, fine-grained analyses of the WOA distributions indicated that the level of choosing was quite high and was largely underestimated in past studies  indicating that the less confident the participants in their initial estimates, the more likely they are to take advice into account. Second, we examined the relation between the increase of confidence over time and the mean WOA. In both groups the two measures were positively correlated  indicating that the more participants take advice into account the more their level of confidence increases.R2) and a p-value<0.05 are reported.Regression analyses were conducted to evaluate the influence of WOA on patients' clinical symptoms. In particular, we assessed whether the WOA was predictive of the symptom severity on the different dimensions of schizophrenia measured . For each clinical score, we conducted regression analyses using the mean WOA as a predictor variable. We used both this raw score (simple linear regressions), or its transformed values . Models with the highest adjusted R-squared  and several of its subscores, namely the delusion subscore , the bizarre behaviour subscore  and the formal thought disorder subscore  to increase one's own confidence when taking advice more into account. Since patients showed a greater WOA they also ended up with a greater increase of confidence. In short, measures of confidence indicate that patients did consider advice to be worthwhile. Ultimately, the absence of overconfidence in patients' initial judgements also challenges the general deficit view according to which greater belief entrenchment could have been expected in patients. Also, the greater WOA for patients is unlikely to be accounted for by the fact they are immersed in a medical environment where they are used to following advice from medical staff. Indeed the mean WOA and the duration of illness  did not significantly correlate. Moreover, the greater WOA for patients cannot be accounted for by “weakness of will” either as their mean WOA and Avolition clinical score did not significantly correlate.How can one account for the fact that patients did actually revise their beliefs? The specificities of the task obviously need to be considered here. First, it should be noted that most of our encyclopaedic beliefs are acquired through social transmission, as we obtain them from various social sources such as teachers, newspapers, TV, books or friends. They thus differ from beliefs acquired only by oneself, which arise from direct perception or inference. In this respect, encyclopaedic beliefs radically differ from delusional beliefs and the kind of hypothetical beliefs involved in Moritz and Woodward's task Second, it might be the case that when non-delusional neutral beliefs are at stake, being in a situation where advice is available may help patients revise these beliefs. This would again indicate that when hints to revise are embedded within a social context they are more likely to be effective. Such a claim would have to be experimentally tested by comparing the impact of contrary evidence when advocated by an individual to the impact of contrary evidence available in the physical environment as in Moritz & Woodward general deficit assumption). Although the present experiment did not aim to manipulate belief strength, the degree of confidence can however be exploited to explore the possibility that a deficit in belief revision concerns only strongly held beliefs. We thus analyzed the WOA when participants were highly confident in their initial answer . In order to obtain a relatively reliable score for each participant, we only considered patients and controls that reported at least three confident answers, resulting in 17 participants in the control group and 15 in the patient group. Unsurprisingly, both groups discounted advice, but as previously observed, patients did not do so more than control participants . The data thus do not support the hypothesis that patients would revise their strongly held beliefs less than controls. However, a better controlled experiment could be devised in order to investigate the impact of belief strength in a more systematic way. After all encyclopaedic beliefs are likely to be of a little importance to the participants as they are not personally relevant to them and do not carry rich emotional significance. Hence, even though patients are confident in these beliefs, the willingness to stick with them might be relatively weak. Future research should thus investigate how belief content may differentially affect belief revision in control participants and schizophrenic patients. Overall, a deficit in belief revision may well arise for non-delusional beliefs but the conditions and the type of beliefs that would render such a deficit observable still need to be thoroughly explored.Third, it is important to note that the degree of confidence in the initial answer was relatively low in both groups, and one could therefore conjecture that a deficit in belief revision arises only after a certain threshold of belief entrenchment has been exceeded. In line with this possibility, Woodward and colleagues Finally, an important result that needs to be discussed is the greater WOA for patients. How can one account for such a finding? First of all, it is important to note that not all patients took more advice into account. Regression analyses indicate that patients who were more likely to take advice into account showed greater positive symptoms  while those who were less likely to take advice scored high on the anhedonia-asociality subscale. One explanation that could account for the greater WOA among patients relates to the way they weight and attend to information accessible in their environment. Past studies indicate that deluded schizophrenic patients tend to weight immediately available information much more than background and contextual knowledge as compared to controls. They are thus less likely to link a stimulus they are currently processing to its proper context. This phenomenon has been referred to as the Immediacy mechanism In the present task, if patients pay more attention to immediate than to remote stimuli they may therefore ascribe a greater weight to advice than do controls, as advice is the last information available in the environment when patients make their final estimates. According to this account, belief revision is likely to arise when contradictory evidence is the most immediately available piece of information in the patient's environment. In this respect, an earlier study by Garety et al. In a more recent paper Speechley et al. In the present task, the very possibility of the Immediacy mechanism will need to be further investigated as the initial opinion might still have been part of the immediate environment. Indeed, the advice and the initial opinion were presented almost simultaneously as patients had to report their initial answer on a line above the advice . Moreover, given that there were only two pieces of information  it is quite likely that both could be easily compared within the same attentional window. Finally, even though the Immediacy mechanism could account for belief revision in the present experiment it would still need to be understood why the self  could be so easily isolated from the immediate environment (symbolized by the advice). Indeed, it is quite intuitive to consider that the self is almost always immediately accessible Clinical observations and phenomenological accounts report blurred delimitation between self and other in schizophrenia as well as disturbed perception of «myness» Click here for additional data file.


Administration of either substance causes the patient to be comfortable yet alert and facilitates a short turnover. Advantages of these drugs include rapid onset and offset of action, analgesic and anxiolytic effects, ease of titration to desired level, rapid recovery, and an excellent safety profile.Colonoscopy is a proven method for bowel cancer screening and is often experienced as a painful procedure. Today, there are two main strategies to facilitate colonoscopy. First, deep sedation results in satisfied patients but increases sedation-associated risks and raises costs for healthcare providers. Second, there is the advocacy for colonoscopies without any form of sedation. This might be an option for a special group of patients, but does not hold true for everybody. Following Moerman’s hypothesis: “If pain is the crucial point, why do we need sedation?” this review shows the analgesic options for a painless procedure, increasing success rates without increasing risk of sedation. There are two agents, with the potential to be a nearly ideal analgesic agent for colonoscopy: alfentanil and nitrous oxide (N Screening by colonoscopy is a proven instrument for early diagnosis of colorectal cancer. This is an important reason why colonoscopies belong to the most frequently performed endoscopic procedures. In the Netherlands, there was a 64 % increase in colonoscopies from 2004 to 2009 . HoweverThe lack of knowledge among patients about the nature of colonoscopy may be an important barrier hindering patients from accepting and undergoing such a screening procedure. Commonly colonoscopy is associated with anxiety and pain. Additionally, patients complain about disruption of normal daily activities by bowel preparation, hangover effects from sedation , and neePain during colonoscopy is considered to be visceral, resulting from the activation of sensory afferent nerves that innervate the intestines. The main factors involved include stretching of the sigmoid wall and mesenteric attachments from looping of the colonoscope shaft and overinsufflation . VisceraAlthough pain is a physiologic response to tissue damage, it also includes emotional and behavioral responses based on individuals’ past experiences and cultural background, which often seem to be resistant to analgesic treatments. Pain is less well tolerated by younger females with a low body mass index (BMI) and is better accepted by older patients. Unfortunately, it is impossible to predict how painful the examination for the individual patient will be.P < 0.001).Sedation during colonoscopy is currently a subject of debate; in the United States (US), sedation has become standard for colonoscopies, and different studies advocate either moderate or deep sedation. Other parts of the world argue for medication-free colonoscopy –10. In oSedation guidelines have universally defined levels of sedation, reaching from moderate to deep sedation.Deep sedation is generally achieved using propofol, which has a rapid onset and short duration of action, allowing for a reduced recovery time. Therefore, there is increasing interest in propofol sedation among gastroenterologists. However, propofol has a relatively narrow therapeutic range that enhances the risk of sedation-related cardiopulmonary events. Most states in the United States do not allow the use of propofol by non-anesthesiologists. The European guidelines concede the administration of propofol to trained nurses or endoscopists who are solely responsible for sedation [sedation . HoweverThis means deep sedation is likely to be more resource-intensive due to a higher need for specialized staff and monitoring . The perDeeply sedated patients may have inadequate spontaneous ventilation and therefore may require assistance to maintain a patent airway. Closed claim analyses of anesthesia suggest that serious injury can occur during deep sedation, even with properly trained providers . Coté etModerate sedation was defined as a drug-induced depression of consciousness in which patients could purposefully respond to verbal commands, and where spontaneous ventilation was adequate, without the risk of losing a patent airway [t airway . The drut airway . A combiThe duration of action of the respective drugs might last longer than the duration of the procedure, resulting in prolonged recovery with a delay in hospital discharge, increased costs, and disruption of daily activities of the patients.The properties of an ideal analgesic agent for colonoscopy aiming at a comfortable yet alert patient and facilitating a rapid turnover of patients would include rapid onset and offset, analgesic and anxiolytic effects, ease of titration to a desired level, rapid recovery, and an excellent safety profile with the existence of a specific, rapidly acting antagonist—all this without the need for additional personnel.Following the hypothesis “If pain relief is adequate during colonoscopy, sedation is no longer being required” , the queMeperidine is a synthetic analgesic, which has its peak onset of action within 10–15 min and then lasts for 2 h with a plasma half-life of 3–4 h. It is rapidly metabolized to normeperidine, which undergoes renal excretion with an elimination half-life of 17 h. The pharmacokinetic profile strongly argues against the use of meperidine for relatively short procedures like colonoscopies .Fentanyl is an opioid that has a faster recovery profile than meperidine. Onset of action is within about 1–2 min, peak effect occurs at 3–5 min, and duration of action ranges between 30 and 60 min.For colonoscopies, fentanyl is usually combined with a benzodiazepine or propofol. Only Lazaraki et al.  evaluateRemifentanil is an ultra short-acting synthetic opioid  with an analgesic potency similar to that of fentanyl, and is metabolized by nonspecific esterases. Owing to remifentanil’s rapid systemic elimination, with a half-life of 8–10 min, it should have pharmacokinetic advantages in clinical situations requiring predictable termination of effect. Akcaboy et al.  using reMoerman et al.  comparedIn a recent study by Manolaraki , the safAlfentanil is a short-acting μ-opioid analgesic chemically related to fentanyl, but less lipophilic. Comparable to remifentanil, alfentanil has a rapid onset of action. The maximal analgesic and respiratory depressant effect occurs within 1–2 min. Alfentanil is metabolized mainly within the liver, with only 1 % of the active substance found non-metabolized in the urine. Thus, in patients with liver dysfunction, a more prolonged and pronounced effect can be expected. The terminal elimination half-life is 90–111 min. Dose dependency allows for achieving different levels of awareness, cooperation, and psychomotor capacity more easily.n = 11) and meperidine/midazolam (n = 11). Patients receiving alfentanil (n = 13) were less likely to require oxygen supplementation because of desaturation  and suffered from less pain. There were no differences in tolerance and discomfort, ease in operation, recovery time, complications, electrocardiogram (ECG) changes, and effects on blood pressure, and therefore, the authors concluded that alfentanil alone had no further advantage. However, the safety aspect—significantly less desaturation episodes—makes the substance worth to be examined in more detail.The only study addressing the use of alfentanil (10 μg/kg) for colonoscopies as a mono-drug was performed by Di Palma et al. . The autUsta et al.  compared2), though without any clinically relevant respiratory depression. This effect was aggravated by additional sedation using benzodiazepines [No other studies addressed the use of alfentanil for colonoscopies. In neurosurgical patients undergoing stereotactic brain biopsy, Bilgin et al.  comparedazepines .®/Relivopan®/Livopan®), it has been widely used as an analgesic in obstetric and dental practice for more than 160 years [2O induced the release of opioid peptides in the brainstem followed by the activation of descending noradrenergic inhibitory pathways. Hence, N2O modifies pain processing in the spinal cord and induces analgesia—without loss of consciousness [Nitrous oxide is an inert gas of low solubility which is rapidly absorbed (within 60 s) and eliminated unchanged via the lungs. Available in a fixed 50:50 combination with oxygen  and extent of exposure. Animal studies suggest a problem associated with chronic exposure to N2O. The exact level of exposure that induces patient harm cannot be predicted. Only long-term exposure to N2O in sufficient concentrations seems to produce irreversible, toxic changes and has been associated with reproductive, hematologic, immunologic, neurologic, liver, and kidney disorders. Hence, administration of N2O to patients for a short-term colonoscopic procedure seems to be safe. Attention should be paid to the safety of personnel working in environments in which N2O is used the whole day, especially without an adequate extraction system.The only proven toxic effect of N2O exposure is yet not clearly defined. The National Institute for Occupational Safety and Health recommended an exposure limit for N2O of 25 parts per million (ppm) as a time-weighted average for a normal 8-h workday and a 40-h workweek [2O a threshold limit value of 50 ppm as a time-weighted average. In Germany, the Occupational exposure limit is 100 ppm [The safety level for Nworkweek . The Ame 100 ppm . Lacking2O apparatus must have a scavenging system [2O is used. Patients should wear an on-demand valve mask perfectly fitting their faces and be advised not to speak during colonoscopy. After finishing the procedure and stopping N2O, patients should receive 100 % oxygen for 3–5 min via the mask.Every Ng system  with ade2O instead of intravenous drugs is “no laughing matter” [2O with a loading dose and continuous administration provides adequate analgesia with a patient being awake and cooperative. After cessation, the patient is awake, ready to get the information necessary, and to leave the hospital soon after the procedure. In particular, patients who live alone or wish to drive home on their own may benefit from the rapid recovery of psychomotoric function provided by N2O. However, there are some limitations of N2O like uncertainty about chronic side effects and need for air-conditioning and efficient ventilation together with efficient active scavenging systems.Overall, the discussion on the ideal agents demonstrates that in fact none of the agents is ideal compared to standard conscious or deep sedation. Almost all have side effects, have lower patient satisfaction scores, have been used with sedatives, or have been studied in very small trials. But if pain is relieved adequately during colonoscopy, sedation is indeed not required in a very large number of patients. The use of N matter” , for sevAlfentanil is a strong analgesic, facilitating a fast turnover of satisfied, pain-free patients, who are able to cooperate with the endoscopist. Its respiratory depressant effects are without clinical impact. Moreover, all actions of alfentanil can be immediately reversed by naloxon, making the substance safe in general use.Further studies are needed to assess efficiency and last but not least patient and physician satisfaction levels with use of these two forms of analgesia.