Optimal postoperative pain management is important to ensure patient comfort and early mobilization.In this double-blind, placebo- and active-controlled, randomized clinical trial, we evaluated postoperative pain following knee replacement in patients receiving placebo, etoricoxib (90 or 120 mg), or ibuprofen 1800 mg daily for 7 days. Patients ≥18 years of age who had pain at rest ≥5  after unilateral total knee replacement were randomly assigned to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen 1800 mg (N = 224) postoperatively. Co-primary endpoints included Average Pain Intensity Difference at Rest over Days 1–3 (0- to 10-point NRS) and Average Total Daily Dose of Morphine over Days 1–3. Pain upon movement was evaluated using Average Pain Intensity Difference upon Knee Flexion (0- to 10-point NRS). The primary objective was to demonstrate analgesic superiority for the etoricoxib doses vs. placebo; the secondary objective was to demonstrate that the analgesic effect of the etoricoxib doses was non-inferior to ibuprofen. Adverse experiences (AEs) including opioid-related AEs were evaluated.The least squares (LS) mean (95% CI) differences from placebo for Pain Intensity Difference at Rest over Days 1–3 were -0.54 ; -0.49 ; and -0.45  for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.05 for etoricoxib vs. placebo). Differences in LS Geometric Mean Ratio morphine use over Days 1–3 from placebo were 0.66 ; 0.69 ; and 0.66  for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.001 for etoricoxib vs. placebo). Differences in LS Mean Pain Intensity upon Knee Flexion were -0.37 ; -0.46 ; and -0.42  for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. Opioid-related AEs occurred in 41.8%, 34.7%, 36.5%, and 36.3% of patients on placebo, etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively.Postoperative use of etoricoxib 90 and 120 mg in patients undergoing total knee replacement is both superior to placebo and non-inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption.NCT00820027 Total knee replacement surgery is an option taken by patients who suffer from debilitating pain and loss of function, in association with demonstrated loss of cartilage due to a variety of conditions, but most commonly associated with osteoarthritis. The procedure has established efficacy and provides pain relief as well as functional improvement -3. AdditPostoperative pain management serves several goals including reduction of suffering and improvement of recovery. After the initial immediate postoperative period, good pain management also improves quality of life and satisfaction with the procedure . MultimoThe present study evaluates the use of etoricoxib, a selective COX-2 inhibitor, as part of a multimodal analgesic treatment in total knee replacement surgery patients. Etoricoxib has demonstrated efficacy in many painful conditions, including a previous study that demonstrated efficacy in patients undergoing total knee or hip arthroplasty . Its phaThis study provides additional information on the efficacy and safety of etoricoxib in a large patient sample treated for 7 days postoperatively and followed for 21 days after the first dose; two doses of etoricoxib (90 and 120 mg) were evaluated against both an active comparator (ibuprofen) and placebo, as well as assessing both static pain and pain on movement. The hypothesis of this trial was that etoricoxib 90 and 120 mg would provide superior efficacy compared with placebo and would be non-inferior to ibuprofen.This study (Sponsor Protocol #098) was registered at clinicaltrials.gov (NCT00820027). It was conducted at 63 sites globally, including in the United States 13 sites); Europe ; Costa Rica (1 site); and Asia Pacific  from December 30, 2008 to December 13, 2010. All patients gave written informed consent prior to initiation of the study, and the protocol and all amendments were approved by local institutional review boards (IRBs). The specific institutional review boards that approved the study are provided in  in the recovery room.Patients were excluded if they were allergic or intolerant to study medications; had a recent history of chronic drug abuse/dependence; had received an investigational agent/device (within 4 weeks); or were morbidly obese. Patients with certain cardiovascular  and gastrointestinal conditions  were also excluded.This was a randomized, double-blind, placebo- and active-comparator-controlled, multiple-dose study performed under in-house blinding in patients undergoing unilateral total knee replacement surgery to evaluate the tolerability and efficacy of etoricoxib. The first dose of study medicine  was administered post-operatively in the recovery room and prior to 6 p.m. on the day of surgery. To maintain the blinding, all therapies were given 3 times a day (with 1 active dose of etoricoxib and 2 doses of placebo), to mimic the total daily dosing frequency of ibuprofen.At the time of the first post-operative dose of study medication, patients were connected to a patient-controlled analgesia (PCA) device and morphine was self-administered for at least 24 hours, as needed to control pain. The PCA device was set to deliver 1 mg morphine with a 6-minute lock-out period and a maximum total dose of 40 mg in 4 hours. If the dose was inadequate, the dose could have been titrated incrementally up to 2 mg for a maximum total dose of 50 mg in 4 hours. Patients were disconnected from the PCA device when it was no longer needed; defined as a time lapse since the last PCA morphine dose ≥2 hours and a patient’s pain intensity reported as ≤4 (0-to-10-point NRS). After disconnecting the PCA device, patients could supplement their analgesia with 2 oxycodone 5 mg tablets up to 4 times a day (daily maximum of 80 mg oxycodone), through Day 7, in addition to their study medication.On Days 2 and 3, the first dose of study medication was given approximately 24 and 48 hours after the initial dose taken on Day 1, respectively. Patients received their second and third doses of ibuprofen 600 mg or matching placebo every 8 hours from the time of the first dose. On Days 4 to 7, patients were switched to a first dose of study medication at 8 a.m, with second and third doses of ibuprofen 600 mg or matching placebo given every 6 hours, (i.e. 2 p.m. and 8 p.m.). There were 10 study visits: Visit 1 (screening visit within 21 days of surgery date); Visit 2 (postsurgery predose); Visit 3 (randomization); Visit 4 was for database purposes only and was not a separate clinic/hospital visit; Visits 5–9 ; Visit 10 (one day after last dose of study medication).Knee replacement surgery was performed according to local practice, but anesthesia was standardized using either general or spinal anesthesia. General anesthesia consisted of isoflurane, sevoflurane, or desflurane and nitrous oxide. Spinal anesthesia consisted of up to 15 mg bupivacaine with no spinal opioids. All patients received 4 mg of ondansetron IV during induction to prevent postoperative nausea and vomiting. Propofol was allowed at a dose of 2 to 3 mg/kg and fentanyl was not to exceed a cumulative intra-operative dose of 10 ug/kg or a total cumulative dose of 500 ug, whichever was less. Infiltration of the wound with any local anesthetic agent, including intra-articular analgesia, was not permitted.Patients were allocated at random based on a computer-generated randomization schedule by an Interactive Voice Response System (IVRS) on the day of admission for surgery, to 1 of the 4 treatment options. The active medications and placebo were identical in appearance, size, shape, and taste, ensuring proper blinding of patients, investigator study staff, and sponsor staff, throughout the study duration. Patients were required to stay in hospital for at least 72 hours from the first dose of study medication.The co-primary endpoints were Average Pain Intensity Difference at Rest (as measured on a 0- to 10-point NRS) over Days 1 to 3 and Average Total Daily Dose of Morphine over Days 1 to 3. Other endpoints included Change from Baseline in Average Pain Intensity at Rest (0- to 10-point NRS) over Days 4 to 7, Average Total Daily Dose of Morphine Consumed over Days 4 to 7, and Change from Baseline in Average elicited Pain Intensity at Knee Flexion over Days 1 to 3 and over Days 4 to 7.The objectives of this study were to 1) demonstrate that the analgesic effect of etoricoxib 90 mg or 120 mg, administered once daily, is superior to placebo for the treatment of pain following total knee replacement orthopedic surgery (primary objective); 2) to demonstrate that the analgesic effect of etoricoxib 90 mg or 120 mg, administered once daily, is non-inferior to ibuprofen 1800 mg; and 3) to assess the safety and tolerability of repeated doses of etoricoxib administered over a total 7-day time period in patients treated for pain following total knee replacement orthopedic surgery.To address these objectives, the primary hypotheses were that: 1) the Average Pain Intensity Difference at Rest over Days 1 through 3 in patients treated with etoricoxib 90 mg or 120 mg would be superior to placebo; 2) the Average Total Daily Dose of Morphine on Days 1 through 3 in patients treated with etoricoxib 90 mg or 120 mg would be less than in patients treated with placebo; and 3) etoricoxib 90 mg and 120 mg would be generally safe and well tolerated. The secondary hypothesis was that the Average Pain Intensity Difference at Rest over Days 1 through 3 in patients treated with etoricoxib 90 mg or 120 mg would be non-inferior to that of ibuprofen 1800 mg. Ibuprofen was included in the study as an active comparator; therefore, there was no planned statistical comparison for ibuprofen compared with placebo.Patients rated their pain at rest while in a supine position. During the treatment period, patients recorded Pain Intensity at Rest at 4 pre-specified time points on Days 1 to 3 and at 2 pre-specified time points on Days 4 to 7.Patients rated Pain Intensity with Knee Flexion, on a 0- to 10-point NRS; a baseline measurement on the knee that underwent joint replacement was taken prior to administering the first dose of study medication. The Pain Intensity with Knee Flexion assessment was done 2 hours after the first dose of study medication on Days 1 to 3 and once between 12 to 4 pm on Days 4 to 7. Knee flexion was performed passively, to 90 degrees.The Average Total Daily Dose of Morphine  used during Days 1 to 3 was a co-primary endpoint and the average Total Daily Dose of Morphine  used during Days 4 to 7 was a tertiary endpoint for the study. The total included all doses of morphine (delivered by PCA and IV bolus), oxycodone 5 mg, and any other opioids.The Recovery Index (RI), a 49-item questionnaire, was included to monitor patient recovery postoperatively. The Opioid Side Effects Scale is a 22-item subscale of the RI-49 that was used to assess patient tolerance of opioid side effects. Patients completed the RI Scale on Days 2 to 7 at bedtime. Patients also completed the RI Scale at the discontinuation visit if they had not completed the RI Scale in the past 12 hours.Other efficacy endpoints included Average Pain Intensity Difference at Rest (0- to 10-point NRS) over Days 4 to 7, Average Total Daily Dose of Morphine  over Days 4 to 7, Average Elicited Pain Intensity Difference at Knee Flexion (0- to 10-point NRS) over Days 1 to 3 and Average Elicited Pain Intensity Difference at Knee Flexion (0- to 10-point NRS) over Days 4 to 7.Post hoc responder analyses were conducted to provide further insight on the effect of etoricoxib compared with placebo by evaluating the level of improvement achieved from Days 1 to 3 and from Days 4 to 7, consistent with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for reporting on clinical trials [l trials . PercentIn order to explore the consistency of the treatment effects with respect to baseline pain intensity (moderate versus severe pain) and type of anesthesia  patients received for the surgery, subgroup analyses were performed for the 2 co-primary endpoints.Safety and tolerability were assessed through physical examination, vital signs, laboratory tests . In addition, this study was subject to a prespecified blinded, adjudication procedure for potential thromboembolic, investigator-reported serious cardiovascular AEs.Safety assessments were summarized using a tiered approach . Tier 1 The study plans called for 713 patients to be randomized in a fully concealed manner  to 1 of 4 treatments in a 9:9:9:4 ratio: etoricoxib 120 mg (n = 207), etoricoxib 90 mg (n = 207), ibuprofen 1800 mg (600 mg TID) (n = 207) or placebo (n = 92), with a total of 776 ultimately randomized. For the co-primary endpoint of Average Pain Intensity at Rest over Days 1 to 3, this sample size was predicted to have > 99% power  to detect a significant difference between etoricoxib and placebo of 2 points, with an assumed standard deviation of 3.08. For the second co-primary endpoint, Average Total Daily Dose of Morphine over Days 1 to 3, the study was powered at 93% to detect a 25% reduction in morphine use  between etoricoxib and placebo doses.For the non-inferiority comparison of etoricoxib  to ibuprofen 1800 mg with respect to the average pain intensity difference over Days 1 to 3, with an assumed standard deviation of 3.08, the sample sizes were predicted to have 91% power  to declare that etoricoxib was at least as effective as ibuprofen 1800 mg, given a non-inferiority bound of 1 point on a 0–10 NRS.To preserve the experimental-wise type-I error rate for the co-primary and secondary hypotheses, the comparisons of the 2 etoricoxib doses with placebo were conducted in a step-down manner. Etoricoxib 120 mg was compared with placebo with the co-primary endpoints first, and, only if it was shown to be superior to placebo at the 5% critical level (2-sided) for each of the 2 co-primary endpoints was the 90-mg dose compared with placebo, also at the 5% critical level for each of the co-primary endpoints (2-sided). Because both co-primary endpoints had to be significant  in order to declare that an etoricoxib dose  was superior to placebo, no multiplicity adjustment was needed for the co-primary endpoints for the given dose. This step-down testing procedure controls the type-I error rate at 5% for the testing of both doses against placebo for the co-primary hypotheses. The secondary hypothesis of the non-inferiority of an etoricoxib dose to ibuprofen 1800 mg was conducted with regard to the Average Pain Intensity Difference at Rest (0- to 10-point NRS) over Days 1 to 3 only if that same etoricoxib dose was shown to be superior to placebo with respect to both of the co-primary endpoints at the critical 5% level.The Full Analysis Set (FAS) population, including all randomized patients who received at least 1 dose of study medication and had at least 1 post-randomization measurement, was used for the primary efficacy analysis. The Per-Protocol (PP) population was used as a supportive analysis.A longitudinal data analysis (LDA)  was usedA Cox proportional hazards regression model was used to analyze time to last dose of morphine administered via PCA device; between-group comparisons were assessed by risk ratios . Time-to-event endpoints were plotted using Kaplan-Meier curves.The All Patients as Treated (APaT) population was used for safety analysis and included all randomized patients who received ≥1 dose of study drug and had a change from baseline in laboratory measurements.For the responder analyses, the differences between each dose of etoricoxib and the comparators and between the two doses regarding the percentages for patients achieving a ≥20%, ≥50%, and ≥70% improvement from baseline based on the Pain Intensity at Rest over Days 1 to 3 were tested separately using the Miettinen and Nurminen method, an unconditional, asymptotic method with α = 0.050 (2-sided) . For thea priori were considered Tier 1 safety endpoints and were subject to inferential testing for statistical significance. P-values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2) were provided for between-treatment differences in the percentage of patients with events; these analyses were performed using the Miettinen and Nurminen method [The analysis of safety results followed a tiered approach; the tiers differed with respect to the analyses performed. Safety parameters or AEs of special interest that were identified n method .Of the 925 patients screened for the study, 776 patients met the study inclusion criteria and were randomized to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen (N = 224)  were superior to placebo  and also non-inferior to ibuprofen 1800 mg daily. In the co-primary endpoint of change from baseline in Average Pain Intensity at Rest over Days 1 to 3, the improvements seen for the 2 etoricoxib dose groups (120- and 90-mg) were similar (Table Both etoricoxib doses (120 mg and 90 mg) were superior to placebo in the co-primary endpoint of average total daily dose of morphine over Days 1 to 3 (p < 0.001); morphine consumption was 31% and 34% less per day, averaged over the first 3 days, in patients treated with etoricoxib 120 mg and 90 mg, respectively, vs. placebo .Averaged over Days 4 to 7, both etoricoxib dose groups  showed nominally significant greater reduction from baseline as compared with placebo on Pain Intensity with Knee Flexion.There were no notable differences observed when comparing etoricoxib doses  with ibuprofen 1800 mg in average change from baseline in Pain Intensity at Knee Flexion over Days 1 to 3; however, greater differences between etoricoxib 120 mg and ibuprofen were observed over Days 4 to 7 in favor of etoricoxib 120 mg  . Figure Patients who had severe pain at baseline had a greater improvement from baseline than those who began the study with moderate pain at baseline. However, the ranking of improvement among the active treatments (etoricoxib and ibuprofen) and placebo were consistent across these subgroups Figure A.Patients who received general anesthesia reported higher levels of baseline pain at the time of randomization. Further, the improvement from baseline was also larger for patients receiving general anesthesia as compared with those who had spinal anesthesia; this was true across all treatments and the rank of the treatment differences from placebo for the 3 active treatment groups (etoricoxib and ibuprofen) was also consistent across the anesthesia subgroups Figure B.Interestingly, there was no important difference in the amount of morphine consumed based on baseline pain severity Figure C. There The incidence of clinical AEs was generally similar among the placebo, etoricoxib , and ibuprofen groups; overall, few serious AEs 2.3%) and drug-related AEs (4.5%) occurred and few patients discontinued (4.8%) for any reason, including safety or tolerability. There was a numerically higher percentage of patients with opioid-related AEs in the placebo group compared with the active treatments. The etoricoxib 120 mg group also had the lowest proportion of patients with bleeding-related AEs among the treatment groups  in 1 patient in the placebo group. Two patients in the etoricoxib 90 mg group and 2 patients in the etoricoxib 120 mg group had cardiovascular events; in both groups, there was a patient with a pulmonary embolism and a patient with acute myocardial infarction. No confirmed thromboembolic events occurred in the ibuprofen group. Of note, both patients with myocardial infarction had pre-existing risk factors.The LS mean score for the Recovery Index Opioid Side Effects Scale showed that both etoricoxib doses  were consistently lower (patients reported less opioid-related side effects) than those on placebo, over the 7 days of the study; the LS mean scale scores were similar between the 2 etoricoxib dose groups and ibuprofen 1800 mg group Figure .Etoricoxib is a selective COX-2 inhibitor that has shown efficacy in the treatment of acute pain . This raIn this trial, patients were provided with morphine through a PCA pump on the first day and opioids on subsequent days; etoricoxib 90 mg, etoricoxib 120 mg, ibuprofen 1800 mg, and placebo were provided to these patients in addition to the PCA pump and opioids. Although patients were able to titrate morphine use to the level of desired pain relief in all treatment groups, patients given etoricoxib demonstrated significantly lower pain intensity than patients given placebo and standard opioid-based analgesic treatment. Additionally, consumption of opioids was reduced in association with a reduction in patient-reported opioid negative consequences. The etoricoxib  groups were non-inferior to ibuprofen 1800 mg/day for both the pain and morphine consumption endpoints . The benefits of etoricoxib were observed consistently across multiple endpoints, including Pain Intensity at Rest, Pain Intensity with Knee Flexion, Total Daily Dose of Morphine consumption, and Opioid Side Effects Scale scores.The results reported here are consistent with the level of pain relief reported in a recent meta-analysis of previous trials of selective COX-2 inhibitors with a total of 571 patients; the reduction in pain scores in the meta-analysis on a 0–10 visual analog scale ranged from -0.40 to -1.31 over the first 24 hours and 0.01 to -1.04 from 24 to 48 hours . The difThe results of the present trial confirm the results of an earlier, smaller trial examining the 120-mg dose of etoricoxib in the treatment of patients after knee or hip surgery; in that study, etoricoxib was superior to placebo and similar to the traditional NSAID, controlled-release naproxen sodium 1100 mg . These tAs a methodologically interesting point, the benefits of etoricoxib became more evident beyond the first 2 days after surgery; the period of Days 4 to 7 demonstrated greater separation from placebo as compared with Days 1 to 3. This finding may have been due to the very high pain burden early postoperatively, and the larger requirement for morphine; the differences in reduction of pain intensity between etoricoxib and placebo increased as the use of opioids decreased. The improvements from baseline in Pain Intensity at Rest for both etoricoxib groups  were numerically but not statistically greater than that of placebo on Day 1, when morphine use was the greatest. However, these differences increased over time for both etoricoxib groups, compared with placebo, over Days 2 to 7, as the pain burden and the subsequent morphine use declined. Morphine consumption was approximately 15% less for both etoricoxib groups , compared with placebo, on Day 1, increasing to approximately 25% less on Day 2 and between 34% to 55% less on Days 3 to 7 in the etoricoxib groups. This pattern of greater separation from placebo over time was also observed in the Average Pain Intensity with Knee Flexion endpoint, an endpoint that also increased the pain stimulus as compared with assessing pain at rest. The etoricoxib 120-mg group showed greater reduction from baseline in average Pain Intensity with Knee Flexion compared with ibuprofen 1800 mg over the Day 4 to 7 interval.post hoc responder analyses consistent with IMMPACT recommendations. These analyses demonstrated greater separation for the Average Pain Intensity with Knee Flexion endpoint among patients who achieved >70% pain improvement for etoricoxib 120 mg vs. etoricoxib 90 mg, ibuprofen, or placebo.This trial was conducted prior to the recommendations by the IMMPACT group for the evaluation of pain in trials . We therSubgroup analyses demonstrated that both subgroups of patients, those with severe pain and those patients with moderate pain, achieved a reduction in Pain Intensity at Rest as well as having a reduction in morphine consumption with etoricoxib as compared with placebo. Baseline pain was higher in patients with general anesthesia compared with spinal anesthesia; this observation may be important for future research with analgesic compounds as increased baseline pain may improve assay sensitivity and better identify any treatment differences. In this study, a higher proportion of patients had spinal anesthesia; with regard to assay sensitivity over Days 1 to 3, a larger difference from placebo was observed for general anesthesia for the endpoint of LS Geometric Mean Morphine Consumption.The incidence of clinical AEs was generally similar among the placebo, etoricoxib , and ibuprofen groups. There were no notable differences in serious AEs or discontinuations from AEs. Thromboembolic events are known perioperative complications of total knee replacement surgery, with preventative therapy recommended in most guidelines -23. Thesad libitum for pain control, achieving the simultaneous reduction in pain intensity at rest and a reduction in opioid use, with less patient-reported opioid negative experiences, reinforces the tenets of multimodal care and suggests that adding etoricoxib to standard opioid therapy has distinct, measureable advantages compared with an opioids-alone approach.Bleeding-related AEs and wound infection AEs were similar among both the placebo and the treatment groups. The evaluation of patient reporting of adverse experiences related to opioids, as measured by patient-reported Recovery Index Opioid Side Effects Scale demonstrated an important reduction in opioid-related AEs in the active treatment groups compared with the placebo group, documenting the intended benefit of multimodal pain care postoperatively. Because patients were permitted to use morphine/oxycodone This was a multicenter study conducted in several countries; research has recently shown increasing the number of countries and sites increases the study variability, leading to different estimates of treatment effectiveness in osteoarthritis patients . In the Nevertheless, the present trial is an important contribution to the literature for NSAIDs and selective COX-2 inhibitors in the post-operative setting due to several unique aspects. It is among the largest single trials conducted to evaluate acute pain in a postoperative setting over a period of 7 days with a 21-day follow-up period; notably, it is larger than a recent metaanalysis of all prior trials combined . The 49-In summary, in the treatment of pain following a unilateral total knee replacement, etoricoxib, at doses of 90 mg or 120 mg, administered postoperatively and then daily for the next 6 days on a background of opioid use resulted in greater pain control in this study as compared with placebo , as evidenced by improvements in pain intensity at rest as well as leading to a reduction in opioid use, with its attendant reduction in patient-reported adverse experiences from opioids. The improvements in the etoricoxib 120- and 90-mg groups were non-inferior to the ibuprofen 1800 mg group. Importantly, it was found that both etoricoxib 90 mg and 120 mg doses had a similar tolerability and safety profile to placebo with better patient-reported tolerability on the opioid side effects scale.AEs: Adverse events; ANOVA: Analysis of variance; APaT: All patients as treated; FAS: Full analysis set; IMMPACT: Initiative on methods, measurement, and pain assessment in clinical trials; LDA: Longitudinal data analysis; LS: Least squares; NRS: Numerical rating scale; NSAIDs: Non-steroidal anti-inflammatory drugs; PCA: Patient-controlled analgesia; RI: Recovery index.LC, SS, AM, DKC, SPC, DP are or were employees of Merck and may own stock or stock options in the company. NR has received lecture and consulting fees from Sintetica. EV has received lecture and consulting fees from Merck and has received payment for development of educational presentations from Merck. HM’s institution has received grants from Research Concepts GP LLC.RN: Collected or assembled data; wrote sections of the initial draft and provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript. EV: Collected or assembled data; wrote sections of the initial draft and provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript. PMP: Conceived, designed or planned the study; performed or supervised analyses; interpreted the results; wrote sections of the initial draft and provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript; obtained funding and provided administrative, technical, or logistic support. HSM: Collected or assembled data; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript; provided study materials or patients. LC: Performed or supervised analyses; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript; provided statistical expertise. SS: Conceived, designed or planned the study; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript; reviewed drafts of manuscript and provided feedback. AM: Interpreted the results; wrote sections of the initial draft; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript; provided administrative, logistical, and technical support. DKC: Conceived, designed or planned the study; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript. SPC: Conceived, designed or planned the study; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript. DAP: Performed or supervised analyses; interpreted the results; provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript. All authors reviewed and approved the final version of the paper.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/300/prepubList of Investigators and Independent Ethics Committees.Click here for file


Chronic kidney disease is common and patients with many co-morbid conditions frequently have to undergo surgical procedures and, therefore, require effective pain management. The pharmacokinetics of various analgesic agents are not well studied in patients with chronic kidney disease and the risk of accumulation of the main drug or their metabolites, resulting in serious adverse events, is a common scenario on medical and surgical wards. It is common for these patients to be cared for by 'non-nephrologists' who often prescribe the standard dose of the commonly used analgesics, without taking into consideration the patient's kidney function. It is important to recognize the problems and complications associated with the use of standard doses of analgesics, and highlight the importance of adjusting analgesic dosage based on kidney function to avoid complications while still providing adequate pain relief. Illustrative clinical scenario:- an example to illustrate the problem.2 of 60, pO2 of 86 and oxygen saturation of 95%. His mental state improved transiently with intravenous naloxone, confirming opioid effect. How could this situation have been prevented while effectively providing pain relief?A 63-year-old man with diabetes and end stage renal disease on maintenance continuous ambulatory peritoneal dialysis was admitted to the hospital with gangrene of the left foot and underwent left below-knee amputation under spinal anesthesia. Postoperatively, he was given meperidine (Demerol) 50–75 mg intramuscularly every 3 hr, as required, by the orthopedic surgeon, but this was found to be ineffective in controlling pain. The anesthetist ordered morphine 10–15 mg intramuscularly or subcutaneously every 3 hr as required (pro re nata) in the evening. He received 325 mg of meperidine in the first 24 hr and additional 200 mg of meperidine next day  and 55 mg of morphine within the first 48 hr after surgery. 48 hr after surgery, he was found to be confused and somnolent. On examination the patient was drowsy and somnolent, but arousable with twitching of arms, and complained of mild pain at the stump site when awakened. He had labored breathing with a respiratory rate of 8 breaths per minute. An arterial blood gas showed pH of 7.19, pCO1 and is regularly accompanied with various co-morbidities. Often these patients with various co-morbidities undergo operative procedures and require analgesics. The most-responsible physician providing the care to these individuals during their hospitalization is often a non-nephrologist. Opioids are commonly used in the management of post-operative pain, and often a standard dose is used by the health-care providers without taking into consideration kidney function2. In North America, morphine and meperidine (Demerol) still remain the commonly used parenteral agents, and acetaminophen with codeine (Tylenol #3) a commonly used oral agent for management of post-operative pain in patients with3 and without renal failure. Prolonged central nervous system and ventilatory depression due to morphine and other opioids have been known for over a century in patients with kidney failure10 and the various contributing factors are outlined in11, but also in patients without kidney disease13. It is important to highlight the issue of central nervous system (CNS) and respiratory depression with opioid analgesics in patients with CKD and formulate strategies to prevent these complications, while providing effective pain relief.Chronic kidney disease (CKD) is common14 i.e., ischemic pain from peripheral vascular disease, neuropathic pain of polyneuropathy (diabetes), bone pain from osteoporosis or dialysis-associated amyloidosis, and musculoskeletal pain that may or may not be related to kidney disease. Post-operative pain is often nociceptive, whereas chronic pain may be nociceptive, neuropathic or mixed. It is also important to recognize that depression is common in CKD15 and that it may complicate the management and patient’s ability to cope with pain16.In addition to the post-operative pain, patients with CKD may have underlying chronic pain that is often multi-factorial17.Assessment of pain requires detailed history to elucidate the cause of pain, its location, nature , intensity and its impact on physical, social and emotional functioning18. Acute pain results from direct stimulation of sensory neurons, called nociceptors. Nociceptors have two types of axons, the rapidly conducting thinly myelinated Aδ fibers that mediate the initial phase of acute pain that is extremely sharp pain, and the more slowly conducting unmyelinated C fibers mediate the second phase of acute pain that is more prolonged and less intense following injury. Nociceptors can be stimulated by mechanical, thermal, chemical and inflammatory stimuli18.Acute pain is a protective and an adaptive response to injury, whereas chronic pain or the persistence of pain beyond the healing phase is a maladaptivePain lasting longer than 3 months or beyond the duration required for complete tissue healing is called chronic pain. It may be nociceptive, resulting from prolonged tissue injury with persistent activation of nociceptors, neuropathic resulting from a lesion or a process affecting the somatosensory system or mixed processes.19.Pain intensity may be measured by one of the major pain rating scales including verbal, numerical and visual analogue scales. However, a numerical rating scale comprising of a range of numbers from 0 to 10, is the most widely used system in clinical practice and is generally based on a subjective 10-point scoring system, where 0 denotes the absence of pain and 10 the worst pain imaginable17. In addition, assessment of concomitant medications and co-morbidities is important when selecting analgesic agent(s). Adjuvant analgesics and non-pharmacological methods of pain control are important to consider in such circumstances17. We review the strategies to manage acute pain in CKD with main focus on the use of opioids since most of the challenges occur in the use of opioids in CKD.Effective pain management requires a multifaceted approach with an understanding of the type , underlying cause, assessment of intensity and duration of pain20  step-wise approach was proposed for pain management in patients with CKD20  and thisgesics’ .Box 1. Opiate: Naturally occurring alkaloid i.e., morphine or codeine.Opioid: Any natural or synthetic compound that has morphine-like properties.Balanced analgesia: Principle of combining different classes of analgesics to optimize efficacy while minimizing side-effects.Co-analgesic: A drug administered alongside opioids enabling a reduction in opioid dose.Adjuvant: A substance that helps and enhances the pharmacologic effects of an agent .Acetaminophen: Has potent analgesic and antipyretic properties and is effective in various acute and chronic painful syndromes. It is the analgesic of choice in the elderly and in patients with kidney disease22 and should be considered in all patients (except in patients with hepatic insufficiency) experiencing pain, regardless of pain level, until pain is relieved or up to a maximum dose of 3,000 mg a day23 or 2.6 g/d in high-risk patients24 . It often does not require dose adjustment in CKD but some authors recommend increasing dosing interval from every six to eight hours when GFR is <10 mL per minute25. Acetaminophen is underutilized in the peri-operative period and when prescribed it is often in an "on demand" basis rather than "by the clock"17. We suggest consider prescribing at least half of total daily dose “by the clock” (opinion MSP) e.g., Acetaminophen 500 mg four times a day and remaining dose could be given “on demand” or in combination with other agents.Anti-inflammatory agents: Nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclo-oxygenase (COX-2) inhibitors block prostaglandin synthesis and, when used as co-analgesic, reduce opioid need by 30–50%. However, because of their gastro-intestinal and cardio-renal side effects, they should be avoided for prolonged use in CKD, as these agents may decrease renal blood flow and may precipitate acute renal failure and can cause life-threatening hyperkalemia. However, if used, it should be for short term management (3 to 7 days) of acute pain and consider short-acting agents26 with careful monitoring of renal function and serum potassium.Adjuvant analgesics are medications with a primary indication other than pain that may possess analgesic activity or modify pain response. These are often helpful for management of chronic neuropathic pain. Examples include cabamezapine, gabapentin, and pregabalin. These agents are not required for management of acute pain. However, CKD patients may have associated underlying chronic neuropathic pain that could affect acute pain response or management. Therefore, some patients may already be taking these agents for control of their 'chronic pain’ and these agents may be stopped inadvertently in the peri-operative period. If this is the case, adjuvant analgesics should be resumed when possible, with considerations being taken for the possible drug-drug interactions when prescribing opioid analgesics for acute pain. It is important to understand that the dose of these agents (adjuvants) may also need to be reduced because of renal dysfunction.28. In addition to CNS and respiratory depression, constipation is a common side effect that is important to identify and manage, especially in patients on peritoneal dialysis, as constipation is the common cause of catheter malfunction29, and appropriate laxatives should be used in conjunction with treatment.The relative potency of commonly used opioids is shown inMorphine: Morphine is the most studied opiate in kidney disease. It is primarily an agonist at the µ-receptors with pain relief at µ1-receptors, and causes respiratory depression and constipation through its agonist action at µ2-receptors14. Morphine is metabolized in the liver to several metabolites30. Of these diamorphine and morphine-3-glucuronide (M3G) do not bind to opiate receptors, whereas normorphine and morphine-6-glucuronide (M6G) do, with M6G being approximately 10-fold more potent than morphine31. All metabolites are excreted in the urine along with about 10% of the parent compound. M6G accumulates in kidney failure and causes CNS and respiratory depression32. M6G crosses the blood brain barrier (BBB) slowly, and once it crosses the BBB, the CNS effects may be prolonged and may persist after stopping morphine or after hemodialysis, as the M6G slowly re-equilibrates across the BBB back into systemic circulation6. Transport of M6G across the BBB is an active process mediated by 170-kd P-glycoprotein. P-glycoprotein is an ATP-dependent carrier system that acts as an efflux pump to transport chemicals or metabolites from endothelial cells to vascular compartment and inhibition of this results in an increase of M6G in the brain34. The analgesic and respiratory depressant effects are related to serum concentrations of both morphine and M6G31. A dosage reduction of 25%, 50% and 75% is recommended in patients with mild (stage 3), moderate (stage 4) and severe kidney failure (stage 5) respectively. However, 20–25% of patients may tolerate the full dose of morphine without ill-effects because ofA118G polymorphism36.Meperidine: Normeperidine, an active metabolite of meperidine, is neurotoxic and accumulates in renal failure and may cause a range of neuroexcitatory effects ranging from irritability to agitation to seizures37. Although normeperidine is removed by hemodialysis38, its regular administration iscontraindicated in patients with any degree of renal failure39.(Dextro)Propoxyphene: It is no longer available in North America and its metabolite norpropoxyphene is excreted by the kidneys and accumulates in renal failure39. This results in CNS and respiratory depression, cardiac conduction disturbances and hypoglycemia. Both the parent drug and its metabolite are not removed by hemodialysis and iscontraindicated in patients with renal failure39.Hydromorphone: Hydromorphone is an analogue of morphine with shorter duration of action and with excellent efficacy in moderate to severe pain. It is five to seven times potent than morphine. It is eliminated by both hepatic (60%) and renal routes40. Hydromorphone doesn’t accumulate in renal failure because of its rapid conversion to its less-potent metabolite hydromorphone-3-glucuronide (H3G) that accumulates in renal failure but is effectively removed by hemodialysis41. However, typical opioid adverse effects have been reported in patients with renal failure42, but experience suggests efficacy without excess toxicity, if monitored carefully43.Codeine/Dihydrocodeine: Codeine is metabolized by the liver to a variety of active metabolites  that are renally excreted44. The half-life of codeine is prolonged 5-fold in hemodialysis patients45. Codeine and its metabolites accumulate in renal failure and can cause hypotension and CNS and respiratory depression47. A similar elimination pathway is proposed for elimination of dihydrocodeine, although this has not been fully evaluated39. Dihydrocodeine can cause prolonged narcosis after therapeutic doses in patients with acute48 or chronic renal failure49. Therefore, these agents should be used with caution in patients with renal failure. A reduction in dose by 50% is suggested for codeine in renal failure45 and chronic use should be avoided.Oxycodone: Oxycodone is a strong opioid with a higher oral bioavailability. It is metabolized by the liver to active metabolites – noroxycodone and oxymorphone50. Approximately 19% of the drug is excreted unchanged in the urine. The clearance of oxycodone and its metabolites is reduced in renal failure50 and results in an increase in plasma concentration by 50% and prolongation of its half-life by an hour50. There is lack of consensus of its use in CKD because of varied case reports of toxicity and good tolerance. When required, use cautiously and start with a lower dose51.Buprenorphine: Buprenorphine is a long-acting semi-synthetic partial agonist with the advantage of having less respiratory depression and hypotension53 but has a ceiling effect55. There is no significant difference in the clearance of the drug in patients with normal or impaired renal function. It has limited oral bioavailability because of an extensive first-pass metabolism. Sublingual, transdermal or parenteral administration is required. It is extensively metabolized by the liver with less than 30% renal excretion. The metabolite norbuprenorphine may accumulate in renal failure that has minor analgesic activity. Buprenorphine is 96% protein bound so is not dialyzable56.Fentanyl, Alfentanil, and Sufentanil: Fentanyl, Alfentanil and Sufentanil are potent opioid receptor agonists, with a rapid onset of action and shorter duration of action. Fentanyl is rapidly metabolized in liver to inactive metabolites. Less than 10% of the parent drug is excreted in urine with no significant accumulation in CKD, but there is considerable inter-patient variability in fentanyl pharmacokinetics when given as a continuous infusion or via transdermal route. However, no dosage modification is necessary in patients with renal failure when fentanyl is given as a bolus. However, prolonged sedation is observed in critically ill patients when fentanyl is given as a continuous infusion, as its half-life increases to 25 hr39 due to saturation of its distribution sites, independent of renal function. Accumulation of fentanyl may occur when given by infusion39 or transdermal patch. Its clearance may be altered in advanced kidney disease57 and prolonged sedation and ventilatory depression have been observed in patients with end stage renal disease following fentanyl infusion39. Fentanyl is highly protein bound (80–86%), has a high volume of distribution, and removal by hemodialysis is negligible59. Opioid-naïve patients should not be initiated on transdermal fentanyl because of its variable absorption.Tramadol: Tramadol is an opioid analgesic that also inhibits serotonin and noradrenaline reuptake. It is extensively metabolized by the liver and 30% of the parent drug and 60% of active metabolites are excreted in the urine60. It is effective for both nociceptive and neuropathic pain and has the advantage of less sedation and respiratory depression compared to other opiates. A common side effect is nausea. A rare but important side effect is seizures, especially in patients taking medications that lower the seizure threshold, like selective serotonin reuptake inhibitors (SSRI). In addition, tramadol may precipitate serotonin syndrome61  in patients taking SSRI62. In advanced CKD, the elimination half-life of tramadol may double60 and the dose should be decreased to 100 mg every 12 hr in patients with eGFR of 30 ml/min and 50 mg every 12 hr when eGFR is <10 ml/min. Tramadol is significantly removed by dialysis and should be administered after hemodialysis on dialysis days63.Methadone: Methadone is a synthetic opioid with five to 10 times the potency of morphine, is highly protein bound (70–87%) and has a half-life of 30 hr. Approximately 20% after a single dose is excreted unchanged and about 30% as inactive metabolites in the urine39. There is a 3-fold increase in the excretion of metabolites on chronic dosing, suggesting enhanced metabolism64. The removal by hemodialysis is insignificant65. Although in 2 patients with CKD the plasma concentrations were no higher than patients with normal renal function66, there is a well-described risk of accumulation and toxicity with methadone, even in patients with normal renal function, so experienced specialist supervision is warranted. A dose reduction of 50% to 75% is suggested in patients with renal failure, but it is difficult to use in patients with CKD because of its long half-life and wide inter-individual variation in clearance65. In some countries, methadone may require a specialist in pain management with a special license to prescribe it, and that may limit its use in acute pain management. However, methadone should not be used in opioid naïve patients.67 in patients with CKD with68 and without dialysis43. The general principles of pain assessment and management should be adopted and analgesia should be prescribed incorporating the modified WHO analgesic ladder20 in patients with CKD, with close and frequent monitoring for side effects of drug or its metabolite accumulation. The nephrologist and a pharmacist should be involved in the management of these patients. The non-opioid analgesics should be used early and ‘by the clock’, rather than ‘on-demand’, and the need for opioid analgesics should be re-evaluated every 24–48 hr, as most patients may tolerate the prescribed initial dose of the opioid analgesics, with toxic effects often emerging after 48 hr, when the parent drug and its metabolites starts accumulating. Vigilance in nursing is also required to monitor for early effects of opiate toxicity.Patients with CKD have a high burden of co-morbidities that modulate pain response, and when these individuals undergo operative procedures, standard orders for pain control can be written without taking into consideration the patient's kidney function. Unfortunately, the data on the effects and tolerability of various analgesic agents are limited in such individuals and, given the lack of data, the recommendations are mainly based on expert opinionBox 2. Before prescribing analgesics, consider kidney function to avoid toxicity that may occur from accumulation of the parent drug or their metabolites.The general principles of pain assessment and management should be adopted and analgesia should be prescribed incorporating the modified WHO analgesic ladder.Co-analgesics like acetaminophen should be considered “by the clock” rather than “by demand”.Do not write standing (or long-term) orders for opioids. Reassess the need and the dose of opioids every 24–48 hr.Avoid fentanyl transdermal patch in opioid-naïve patients. I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The manuscript is improved. However, the authors have not responded to my comment regarding adjuvant medications . The authors have still not provided a statement 'that a dose reduction may be required for patients with renal insufficiency' within the revised article. The authors only refer to drug-drug interactions and do not mention that adjuvant medications require dose adjustments with a clinical disease such as renal insufficiency. This problem is independent from any drug-drug interaction. It is important that this point is addressed by the authors in order to improve this articleI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The first clinical scenario includes meperidine as a drug used in the patient. The use of meperidine has significantly been reduced in the USA and is monitored as a negative finding when used in patients over 60. Thus hospitals have made efforts to reduce or eliminate its use except in treatment of rigors and given in low doses only. I am not sure if this would be the best scenario to start the article, although its issues with renal insufficiency are substantial.I would refrain from the use of the word 'narcotic' in your discussion in favor of the word opioid.In the discussion regarding 'adjuvant medications' there is no mention that nearly all these medications require dose adjustments in renal insufficiency. Since the article focuses on this topic, I believe it should be included beyond just mentioning that some patients may be using these medications.The last sentence in the 'Acetaminophen' section gives specific dosing recommendations to give half of the daily dose followed by round the clock dosing.  Is this opinion or should a reference be included?Since propoxyphene is no longer available, I would consider eliminating it from the discussion.  I am unsure if it is still being used in other countries.  If so, I guess I would leave it in.The Codeine/Dihydrocodeine paragraph makes no mention of the active metabolite morphine from codeine. Discussion of other drugs in this section refer to actual names of metabolites. Given that morphine was discussed earlier in the document, including this information is important in my view.The chart indicating % amounts in the column headed by eGFR/ml rates does not really say that the percentages indicate a percent dose reduction.  It should be made more clear even though obvious to me.  The methadone section says that it requires a special license to prescribe. This is not entirely true. The special license is only required when treating opioid addiction. If methadone is used for pain control, no special license is needed. I would also include that methadone is not to be used in opioid naïve patients as you do with the fentanyl patch.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. I approve this article. However, on table 3 and figure 1, oxycodone with acetaminophen is considered step 2 of  the WHO analgesic ladder but oxycodone by itself is considered step 3. I would change this.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Laparoscopic donor nephrectomy (LDN) is now a well established method for kidney procurement from living donors. In our centre, LDN is currently offered only to donors suitable for a left nephrectomy. The aim of this study was to investigate the incidence of testicular pain and swelling following LDN.A total of 25 left-sided LDN male patients were assessed in a prospective structured interview together with a control cohort of 25 male patients who had undergone left-sided open donor nephrectomy (ODN).Data were collected on testicular pain, swelling, numbness, urinary symptoms and sexual dysfunction from all 50 patients (100% response rate). Of the 25 LDN patients, 11 (44%) experienced ipsilateral testicular pain and/or swelling. In most instances, pain was of immediate onset, mild to moderate in severity, lasted for a few days to several weeks and was associated with testicular swelling (10 of 11 cases). However, testicular pain and/or swelling were not apparent in ODN patients, with only 2 of 25 (8%) experiencing mild testicular pain, 1 of whom also had swelling.Testicular pain and swelling following LDN is a common problem. It is underreported in the literature and should be included in the differential diagnoses of testicular pain and swelling. Further investigation is required to confirm our findings. A large number of men are referred with testicular pain and/or discomfort to general surgical and urological outpatient clinics. Although the differential diagnoses of testicular neuralgia include testicular trauma, carcinoma, torsion and infection, many such patients have no definite cause identified and are reassured accordingly.The number of patients requiring renal replacement therapy is increasing steadily worldwide. While transplant remains the best treatment for renal failure, the supply of donor organs has remained constant over the last decade. In order to redress this imbalance, over the last few years there has been rapid expansion in the use of live donor renal transplantation in Europe and North America.The advent of laparoscopic donor nephrectomy (LDN), first described over 15 years ago,We report our experience of patients undergoing LDN, a now well established method for the procurement of kidneys, and donors’ post-operative symptoms including testicular pain and swelling. In our early experience of LDN, several patients have complained of significant testicular pain and swelling. We therefore reviewed our LDN patient group specifically to look at the incidence and severity of testicular pain and swelling post-operatively, and in doing so endeavoured to shed more light on this underreported but clinically significant problem. We investigated whether testicular pain and swelling are indeed more common following LDN and whether there was a causal link between LDN and symptoms of testicular pain and swelling.A total of 54 left-sided LDNs were undertaken over the study period from February 2005, 25 of which were in male patients. For anatomical reasons, all were harvested on the left side using a totally transperitoneal laparoscopic approach. All procedures were undertaken by one very experienced laparoscopic surgeon, without any learning curve required. The maximum intra-abdominal pressure was 12–15mmHg. The left colon was mobilised medially from the splenic flexure to the pelvic brim. Each kidney was retrieved intact with an envelope of Gerota's fascia. The gonadal vein was divided early at mid-ureter level and the ureter was divided late, immediately prior to vascular stapling. The ureteric pedicle was used for retraction to facilitate dissection. The renal vein was divided medial to the entrance of the gonadal and adrenal veins. Each kidney was retrieved in a bag through an 8cm skin creased incision at the left iliac fossa.An equal number of consecutive left-sided ODN male donors from the same unit was used as a control cohort. All 25 ODNs in the control cohort were performed using a mini open nephrectomy approach with an 8–10cm anterior incision extending from the tip of the 12th rib. Gerota’s envelope was dissected off the kidney prior to its delivery, and both the adrenal and gonadal veins were divided at their junction with the renal vein. The ureter was divided early and the renal vein divided medial to the entrance of the gonadal and adrenal veins as in the LDNs. The ureteric pedicle was not used for retraction at any stage, with minimal dissection of the retroperitoneum along the length of the ureter.Patient demographics were collected from a prospectively maintained database kept in the department. All 50 patients were interviewed post-operatively with an identical patient proforma . Data weOverall, information from 25 LDNs and 25 ODNs was analysed. The mean donor ages in the LDN and ODN cohorts at the time of surgery were 41 years (standard deviation [SD]: 7 years) and 42 years (SD: 11 years) respectively. Data were collected from all patients in the LDN and ODN groups (100% response rate).Of the 25 LDN patients, 11 (44%) experienced testicular pain and/or swelling. One of the eleven patients experienced testicular swelling alone for seven weeks. Pain was ipsilateral (left) in all 25 cases, occurring immediately after the operation and lasting for up to four weeks. In 4 of the 10 patients with testicular pain, the pain had persisted for more than 3 years. The mean pain score was 4.6 (SD: 2.0). Five of the ten individuals who experienced new onset post-operative ipsilateral testicular pain had a past history of vasectomy and/or inguinal hernia repair surgery.Swelling typically lasted from a few days to several weeks after the operation. The mean duration of resolved testicular swelling was 8 days (SD: 6 days). However, 6 of 10 patients had persistent testicular/scrotal swelling that had remained since the LDN procedure. There was no past history of scrotal swelling or pain in these individuals.Testicular pain and swelling following LDN was not associated with any urinary symptoms or sexual dysfunction. There was no recorded dysuria, incontinence, retention, erectile dysfunction or fertility problems. LDN patients did not give any history of numbness or paraesthesia in the scrotum or inguinal region.All of the 25 ODN patients received a left-sided ODN. Testicular pain and swelling were not apparent, with only two patients experiencing ipsilateral mild testicular pain. In one case, pain occurred immediately after the operation and resolved within two weeks of surgery. The other case was that of immediate post-operative testicular pain and swelling that had persisted since the ODN procedure .Table 2Since the introduction of LDN at our institution, approximately a third of all nephrectomies are performed using this technique. At present, LDN is offered only to donors suitable for left nephrectomy in view of the longer left renal vein. It is our intention to perform LDN for right kidney procurement in the near future.Our standard practice with LDN is to divide the gonadal vein early up to the mid-ureter level. The ureter is then divided late, immediately prior to vascular stapling, and the ureteric pedicle is used for retraction to facilitate renal dissection. This technique may well contribute to the subsequent testicular neuralgia following LDN.It has been our experience that a considerable number of male donors who have received LDN complain of testicular pain and swelling following their operation. This investigation was undertaken in an attempt to elucidate whether testicular pain and swelling were more common for LDN patients and also whether there was a causal link between LDN and these symptoms.et al noted that 10% of their 145 male patients undergoing left-sided LDN complained of testicular pain.et al demonstrated a 1% incidence of testicular pain in their LDN cohort of 381 patients, the vast majority (95%) of whom had received left-sided procedures.et al showed a 3% incidence of ipsilateral testicular pain in 70 patients treated at their centre following LDN,A study in 2003 by Kim et al,et al found a significant reduction in renal blood flow and function when employing LDN in pigs.et al also demonstrated that reduction in renal blood flow during LDN could be avoided by adequate peri-operative intravascular volume expansion, which in turn may reduce the incidence of orchialgia post-operatively.Other plausible explanations as to the cause of testicular pain have been suggested by Kim We believe that division of the gonadal vein at the mid-ureter and retraction of the ureteric pedicle during dissection in LDN may contribute to post-operative testicular pain and swelling. Furthermore, extensive mobilisation of the left colon may damage the neural plexus supplying the testis and may also disrupt the lymphatic drainage.We have found no reports of ipsilateral testicular pain or swelling following right-sided LDN. This may be attributed to the fact that in right-sided LDN, the gonadal vein is not divided and less extensive mobilisation of the right colon is required, thereby preserving the neural plexus and lymphatic drainage. Similarly, testicular pain and swelling is not frequently reported in laparoscopic nephrectomies of either side for other aetiologies. In such cases, the gonadal vein is not divided and the renal vein is divided lateral to the insertion of the gonadal vein. In addition, the ureter is divided early during the procedure, thus avoiding the retraction of the ureteric pedicle for the duration of surgery as in LDN.Our study has demonstrated that approximately half of patients undergoing LDN for donor renal transplantation experience significant ipsilateral testicular pain. Most complain of associated scrotal swelling and in a notable proportion of these patients pain and swelling last for several weeks and sometimes up to several years. The pain has been sufficient to compromise a return to activities of daily living and consequently has a major impact on post-operative quality of life. The improved post-operative recovery intended with the advent of laparoscopic surgery would therefore be diminished in these patients. The fact that some patients are still experiencing testicular pain in excess of a year post-operatively remains to be confirmed in further studies and, if confirmed, may even be a contraindication to LDN in the future.Further investigation may also attempt to define the incidence of post-operative testicular pain and swelling following LDN for other indications such as benign disease, chronic infection and trauma. To our knowledge, these symptoms have not been reported as a complication of LDN for indications other than donor renal transplantIn general surgical and urological clinics, testicular pain and swelling are frequently observed presenting symptoms with numerous differential diagnoses. Since it is now becoming a widely performed procedure, LDN must be borne in mind asan increasingly common cause for such symptoms.


To describe acupuncture and chiropractic (acu/chiro) use among 11,960 chronic musculoskeletal pain patients enrolled in a Pacific Northwest Health Maintenance Organization (HMO).We identified 119,732 HMO members with chronic musculoskeletal pain from electronic medical records data. Patients were contacted by mail and invited to complete an online survey. Those not responding were either contacted by email or mailed a paper copy of the survey. Survey questions included items related to diagnosis, acu/chiro utilization and payment, and communication about acu/chiro use with HMO clinicians.Of 119,732 patients invited to participate, 11,960 completed the survey. Self reported pain diagnoses included back pain (65%), joint pain (56%), arthritis (53%), extremity pain (53%), neck pain (37%), muscle pain (30%), headaches (21%), fibromyalgia (13%), and abdominal or pelvic pain (10%). Participants were predominantly caucasian (90%) and female (58%), with mean age of 59 years. Roughly a quarter of participants  reported acupuncture use, while slightly more participants  reported chiropractic use. Of those using acupuncture, 39% did not discuss acupuncture use with their HMO clinician, and 82% paid out-of pocket for at least a portion of the care. Of those using chiropractic services, 38% did not discuss chiropractic use with their HMO clinician, and 91% paid out-of-pocket for at least a portion of the care. The most common reason given for out-of-pocket payment to acu/chiro providers was that insurance coverage didn’t cover such care or required a co-payment. Patients with a self referral acu/chiro benefit were more likely to use acu/chiro than those without such coverage (p<.0001), but were not more likely to communicate acu/chiro use to HMO clinicians (p=.13).Acu/chiro use is prevalent among HMO patients with chronic musculoskeletal pain. However, such use frequently is not reported to HMO clinicians, even by patients having a self referral acu/chiro benefit.


Objective. To compare the efficacy and tolerability of etodolac versus etodolac in combination with eperisone in patients of Osteoarthritis knee. Patients and Methods. A prospective, randomized, open label, parallel group, comparative study was conducted in 60 patients of knee OA over a period of 2 months. Thirty patients received etodolac 600 mg once daily and 30 patients received eperisone 50 mg thrice daily in addition to etodolac 600 mg once daily for 8 weeks. Efficacy assessment was done on the basis of improvement in mean scores of spontaneous pain on Visual analog scale (VAS), pain on movement, functional capacity, joint tenderness, swelling, erythema on Likert scale, and patient's overall arthritic condition on a five-point investigator scale at the end of study period as compared with the baseline scores. Assessment of tolerability was done by recording the occurrence of adverse events. Data was analyzed using Chi square test and students t-test. Results. All the enrolled patients completed the study and were compliant to the treatment regimens that they were allocated to. Both the treatment groups showed a statistically significant improvement in all the efficacy parameters at the end of 8 weeks as compared to baseline (P < 0.05) with no statistically significant difference between the groups. Adverse events were few and mild in nature. Conclusion. Combination of etodolac and eperisone is as effective as etodolac alone in patients of OA knee. Thus, it is concluded that additional use of muscle relaxant has no adjuvant value in patients of OA knee and is not recommended. The study is registered with the Clinical Trial Registry of India vide registration number CTRI/2013/03/003442. Osteoarthritis (OA) is the most common chronic joint disease with a prevalence of 22%–39% in India, accounting for 30% of all joint disorders . SymptomEtodolac is a USA FDA-approved NSAID of the pyranocarboxylic acid group. It is being increasingly used in treatment of OA on account of its potent analgesic and anti-inflammatory activity. It has some degree of COX-2 selectivity over COX-1, so frequency of gastrointestinal adverse effects is less . It alsoEperisone hydrochloride is a beta-amino propiophenone derivative established as an effective centrally acting muscle relaxant. It relieves muscle ischemia and reduces pain . The recJoint pain of OA knee is localized deep ache that worsens on activity. Apart from synovitis, stretching of nerve endings in the periosteum, microfractures in subchondral bone, joint instability leading to stretching of joint capsule, and muscle spasm may also be source of pain . AdequatCTRI/2013/03/003442. A total of 60 patients who met all the inclusion criteria and had none of the exclusion criteria were enrolled after obtaining written informed consent , then visit 2 (after 4 weeks), and visit 3 (after 8 weeks) by using Likert version of 5-point scale where “0” represents “none,” “1” is “mild,” “2” is “moderate,” 3 is “severe,” “4” is “extreme” . InvestiPrimary safety endpoint was sedation. Complete physical examination and laboratory evaluation, including blood chemistry profile and urinalysis was done at the baseline and final visits. All the adverse events reported by all patients were noted at follow up visits.α value of 0.05 at 90% power, the sample size for each group was calculated to be 22. Assuming dropouts and withdrawals (at about 15%–20%), it was decided to enroll 30 patients in each group.Sample size was calculated considering the pain intensity on VAS as the primary efficacy parameter. To detect a difference of 1 in VAS score between the two groups, assuming a standard deviation of 1 and t-test. All other efficacy endpoints were analysed using unpaired t-test for difference between the groups and paired t-test for within group analysis. Chi square test was used for categorical variables.Data are presented as mean ± S.D. The primary efficacy endpoint was analysed using unpaired students The demographic and baseline clinical characteristics of study patients were similar between the two groups .P < 0.001). In the etodolac group pain score on VAS decreased from 7.43 ± 0.63 to 2.40 ± 1.14 and in the combination group VAS score decreased from 7.37 ± 0.61 to 1.93 ± 0.84 (Both the treatment groups showed a significant reduction in VAS score for spontaneous pain from baseline across time at the end of 8 weeks (3 ± 0.84 .In all the secondary efficacy parameters like pain on movement, joint tenderness, swelling, joint erythema, functional capacity, and overall assessment scores, significant improvement was seen within the groups as compared to the baseline. However, there was no significant difference between the groups .Both treatments were well tolerated; adverse events reported were few and mild in nature. No abnormalities were found in the lab investigations. Sedation was seen in 3 patients on the combination therapy, whereas it was not reported by any patient in etodolac group. There was no significant difference in the incidence of adverse events in the two treatment groups .Osteoarthritis is becoming increasingly prevalent worldwide because of the combination of an ageing population and the epidemic of obesity. Although NSAIDs form a major part of the pharmacological therapy of osteoarthritis knee, we could not find any published literature about the role of muscle relaxants in such patients. Therefore, the present study was conducted to explore the potential use of muscle relaxant as adjuvant analgesic in patients of OA knee. It was concluded from the results of our study that both etodolac alone and etodolac in combination with eperisone hcl were effective in OA knee, with each treatment group showing significant improvement in all efficacy parameters throughout the study. Both the drugs were well tolerated and systemically safe as none of the study participants discontinued drug treatment during the entire study period. Moreover, eight weeks is a sufficiently long duration to establish effectiveness of a treatment, and since multiple parameters were tested but none of them showed a significant difference between the groups, so it was also concluded that additional use of muscle relaxant does not provide superior pain relief over NSAID use alone in patients of OA knee, and use of combination is not recommended. But at the same time, we can't rule out the possibility that the therapeutic effect of etodolac may be too good to overshadow any advantage of eperisone so that the advantage of the latter is masked. Our study results are in conformity with results of a double-blind study of benorylate and chlormezanone in musculoskeletal disease wherein the authors concluded that there is no advantage in adding chlormezanone in patients of OA of hip or knee, but there was a significant improvement in pain relief in patients with neck pain . Our stu


Although disease progression of osteoarthritis has been well documented, pain pathophysiology is largely unknown. This study was designed with two purposes: 1) to characterize patients with knee pain predominantly originating from intra-articular structures and 2) to describe the location and pattern of their pain.103 patients with medial knee osteoarthritis underwent an intra-articular injection of local anesthetics (joint block). At least 70% pain relief was defined as positive for the joint block, while less than 50% as negative. Pain characteristics in patients positive for joint block were evaluated in detail using a knee pain map.Sixty three knees (61%) were positive and 33 knees (32%) were negative. Patients negative for the joint block were significantly higher age, suffered for longer time, and complained more diffuse pain. Although pain at anterior medial area during walk was the most common finding, pain characteristics differed among different knee areas.The characteristics of joint pain are widely variable even in patients with similar radiological features. Extra-articular sources are not negligible especially in older patients with a long history of diffuse pain. Differences in pain characteristics among knee areas should be taken into account when examining the pain source. Knee osteoarthritis (OA) is a major public health problem across the world. Population based studies revealed that symptomatic knee OA is present in 20-30% of the elderly population aged >65 years . Inclusion criteria were American College of Rheumatism clinical criteria  between joint block-positive and negative patients. p = 0.016), suffered knee pain for longer time (p = 0.024), and complained more diffuse pain (p = 0.003). Neither radiological severity nor clinical score were associated with block effects . All patients underwent the diagnostic joint block and main sources of knee pain were examined. Sixty-three patients (61%) had positive response to the joint block, while thirty-three patients (32%) were regarded as negative. Seven patients who had a 50-70% pain reduction after joint block were excluded from the analysis. Table Among patients in the positive group, the highest prevalence (82%) of pain during walk was observed at anterior medial area (area 4), followed by pes anserinus area (area 8) 32%) and anterior lateral area (area 6) (30%)  was the most common finding in patients with medial knee OA. This pain was observed during walk rather than during extension-flexion, which might reflect increased load at medial compartment in genu varum. On the contrary, popliteal pain (area 12) was observed during extension-flexion of the knee rather than during walk, which might reflect impingement of torn meniscus and capsular contracture. In addition, pain at anterior medial area was usually accompanied by tenderness, while popliteal pain was not. It is possible that the presence of tenderness only reflects the superficial location of painful structures. However, knowing the pain characteristics at each knee area is helpful in evaluating pain in knee OA during daily practice.Several authors used diagnostic blocks with a criterion of 50% pain relief for knee joint (Choi et al. The strength of this study is detailed pain assessment using joint block. However, there are several limitations in our study. Firstly, a placebo response might have been involved because of our single uncontrolled block. For an ideal prevalence study, a placebo controlled or comparative local anaesthetic study will be necessary. Secondly, intra-articular injection was performed blindly. Although the superolateral approach is reported as the most accurate approach for intra-articular knee injection (Hermans et al. In conclusion, our results suggest that the characteristics of joint pain are widely variable even in patients with similar radiological features. Although the main source of pain in medial osteoarthritis knees is intra-articular structures, extra-articular sources are not negligible especially in older patients with a long history of diffuse pain. Differences in pain characteristics among knee areas should be taken into account when examining the pain source of knee osteoarthritis.


Nephrolithiasis is a relatively common problem and a frequent Emergency Department (ED) diagnosis in patients who present with acute flank/abdominal pain. The pain management in these patients is often challenging.To investigate the most effective dose of morphine with the least side effects in emergency renal colic patients.150 renal colic patients who experienced a pain level of 4 or greater, based on visual analog scale (VAS) at admission time were included. Pain was scored on a 100 mm VAS . When patients arrived at ED, a physician would examine the patients and assessed initial pain score, then filled a questionnaire according to the patient information. Patients were assigned to receive 2.5 mg morphine sulfate intravenously. We monitored patients’ visual analog scale (VAS), and adverse events at different time points (every 15 minutes) for 90 minutes. Additional doses of intravenous morphine (2.5 mg) were administered if the patient still had pain. (Max dose: 10 mg). The cumulative dose of morphine, defined as the total amount of morphine prescribed to each patient during the 90 minutes of the study, was recorded. Patients were not permitted to use any nonsteroidal anti-inflammatory drugs as coadjuvant analgesics during the study period. Subjects with inadequate pain relief at 90 minutes received rescue morphine and were excluded from the study. The primary end point in this study was pain relief at 90 minutes, defined as either VAS<40 or decrease of 50% or more as compared to the initial VAS. The secondary objective was to detect the occurrence of adverse effects at any time points in ED.The studied patients consisted of 104 men and 46 women with the mean age of 43 ±14 years . There was no statistically significant difference between the mean age and gender differences in pain response. Rescue analgesia at 30 minutes were given in 54.5% receiving morphine. The average time to painless was 35 minutes. But there were no statistically significant differences between the mean age and gender differences in pain response (P > 0.05). Older patients responded sooner to morphine than the young. Most of the patients had a pain score of 90 -100 (77.3 %) at the beginning that was reduced to 29.4% during the 30 minutes follow up. During the first hour, we found that 94.7% of the patients had no pain or significant pain reduction and only 2.1% of the patients still had pain.We conclude that there were no significant differences among the gender, time of admission and side - effects in renal colic patients in response to morphine. Pain is one of the most common reasons of emergency admission; it places burden on both patient and medical care system. Pain control is incomplete in most situations, especially in emergency settings. Pain management in emergency department (ED) is paramount -7. NephrTheoretically, higher doses may lead to more unwanted effects especially in patients with severe pain. Thus titrated and appropriated dosage is important.There have been many trials aimed at reducing the side-effects of opioids; however, this study was designed to evaluate the effect of admission time and gender on side-effects of morphine sulfate, focusing on pain score in patients with renal colic in ED.After receiving approval from the Ethical Board Committee of the Baqiyatallah Medical Sciences University (BMSU) and written informed consent, this study was conducted in the Emergency Department of the Baqiyatallah Hospital, one of the referral training hospitals in Tehran, I.R. Iran.150 renal colic patients (18-75 years old) who experienced a pain level of 40 or higher, based on visual analog scale (VAS) at the admission time were included. Pain was scored on a 100 mm VAS . Patients were excluded from the study if they had allergy to study drugs, chronic opioid use, significant CNS myocardial, renal, or hepatic impairment, pyelonephritis or fever ≥ 38 degree centigrade, pregnancy and breast feeding and if they were hemodynamically unstable (BP ≤ 90 mmHg or MAP decreased ≥ 30% baseline) or any contraindications to anaesthesia. When patients arrived at the ED, a physician assessed the patients and initial pain score, and then filled a questionnaire according to the patient information. Data collected included age, sex, localization/severity of pain, symptoms, medical history and chemical lab tests and urine analysis in selected patients. Patients were assigned to receive 2.5 mg morphine sulfate intravenously. We monitored patients’ VAS and adverse events at different time points (every 15 minutes) for 90 minutes.Additional doses of intravenous morphine (2.5 mg) were administered if the patient still had pain. (Max dose: 10 mg). The cumulative dose of morphine, defined as the total amount of morphine prescribed in each patient during the 90 minutes of the study, was recorded and used to compare the efficacy of the treatment in the 2 groups. Patients were not permitted to use any nonsteroidal antiinflammatory drugs as coadjuvant analgesics during the study period. Subjects with inadequate pain relief at 90 minutes received rescue morphine and were excluded from the study. The primary end point in this study was pain relief at 90 minutes, defined as either VAS < 40 or decrease of 50% or more as compared to the initial VAS. The secondary objective was to detect the occurrence of adverse effects at any time points in ED. Sample size was based on the power analysis from similar studies. Statistical analysis was performed using the Statistical Package for Social Sciences software . Results were expressed as mean (SD), mean (range), median (inter-quartile range), or the number of patients. A P-value of less than 0.05 was considered statistically significant.The studied patients consisted of 104 men (69.3%) and 46 (30.7%) women with a mean age of 43 ± 14 years . The peak of renal colic was seen during 7 p.m. to 5 a.m. Most of the cases came at : 4-5 a.m. (18.7%), 10-11 a.m. (6.7%) and 7-11 p.m. (34%) . Most reNausea (18.3%), nausea and vomiting (22.7%) were the most frequent side effects in ED. No patients in either group had respiratory depression and hypotension. No patients in either group had urinary retention during 90 minutes follow up in ED ; 108 subjects (36%) had a history of at least one episode of previous renal colic. Rescue analgesics at 30 minutes were needed in 54.5% receiving morphine. The average time to painlessness was 35 minutes . The oldIn this study, most of the patients had a pain score of 90 -100 (77.3%) at the beginning that was reduced to 29.4% during the 30 minutes follow up. During the first hour, we found that 94.7% of the patients had no pain or significant pain reduction and only 2.1% of the studied population still had pain .Our study showed a male predominence (65%) in renal colic population compatible with similar studies. The age distribution was also similar to previous investigations . The pea


Tonsillectomy is one of the most common surgeries in the world and the most common problem is post-tonsillectomy pain and bleeding. The relief of postoperative pain helps increase early food intake and prevent secondary dehydration. One method for relieving pain is peritonsillar injection of epinephrine along with an anesthetic, which has been shown to produce variable results in previous studies. Study Deign: Prospective case-control study. Setting: A tertiary referral centers with accredited otorhinolaryngology-head & neck surgery and anesthesiology department. Patients under 15 years old, who were tonsillectomy candidates, were assigned into one of three groups: placebo injection, drug injection before tonsillectomy, and drug injection after tonsillectomy. The amount of bleeding, intensity of pain, and time of first post-operative food intake were evaluated during the first 18 hours post operation. The intensity of pain in the first 30 minutes after the operation was lower in the patients who received injections, but the difference was not significant during the first 18 hours. The intensity of pain on swallowing during the first 6 hours was also lower in the intervention groups as compared with the placebo group. The amount of bleeding during the first 30 minutes post operation was lower in the two groups who received injections, but after 30 minutes there was no difference.Injection of epinephrine and bupivacaine pre- or post- tonsillectomy is effective in reducing pain and bleeding. The treatment also decreases swallowing pain in the hours immediately after surgery.  Tonsillectomy is one of the most common surgeries in the world. Despite advancements in surgical and anesthetic techniques, bleeding and pain are still the most common complications of tonsillectomy . Since pConsidering the inconsistent results of previous studies and the low cost of this technique, we evaluated the effectiveness of peritonsillar injection of epinephrine and bupivacaine on decreasing pain and bleeding after tonsillectomy. Patients who were referred to Imam Reza Hospital for tonsillectomy and were under 15 years old were eligible for this double-blind clinical trial. Patients with a history of previous disease or coagulation problems were excluded. After obtaining written informed consent from the patients’ parents, study subjects were assigned into one of three groups: one control group who received placebo injections of saline and two case groups who received injections of medication either pre- or post-operation. The required study sample was calculated to be 11 patients for each group, but for increased precision and to account for possible subject loss, we enrolled 24 patients in eachgroup. Patients in the control group received 4 ml normal saline and patients in the case groups received 4 ml of a solution of bupivacaine (0.5%) and epinephrine (1/200000 concentration). The 4 ml of either saline or drug solution was divided into 2 doses and one dose was injected into each of the upper and lower regions of the tonsils. The surgeon, recovery technician and ward nurses were blinded to the medication type and only completed a study questionnaire based on the patient’s condition. The same surgeon and anesthesiologist performed all the surgeries and the method of anesthesia, dosage of injected medication, and method of surgery were similar for all the subjects. Patient information collected included age, gender, duration of surgery, and amount of bleeding during surgery. The amount of bleeding was estimated based on the number of cauterization, bloody sponges that were collected and the surgeon’s satisfaction with surgical field quality was also graded in a 5-item Likert scale . The patThis study was approved by the Ethics Committee of Mashhad University of Medical Sciences, all parents were fully informed about the study protocol and a signed informed consent was obtained from each of them.The distribution of the age and gender of the subjects was similar between the three groups . The meaThe intensity of pain based on the FPRS in the 30 minutes after entering the recovery room was higher in the control group compared with the two other groups (P=0.02) but the difference between the two intervention groups was not significant . The intensity of pain during the remaining post-operative hours was not significantly different between the groups. Swallowing pain at 2, 4, and 6 hours post-operation was less in the intervention groups compared with the control group (P<0.05) but there was no statistically significant difference between the two intervention groups (P>0.05) . In the remaining hours after surgery, the intensity of swallowing pain was similar for all the groups (P>0.05). The intensity of earache and the time of starting oral intake of food/liquid did not show any statistically significant differences. The amount of post-operative analgesic used was similar between the groups and was 250 ml of acetaminophen syrup. The sleep condition during first post-operation night has been shown in .4, which is similar to the pain relief during the first 30 minutes post-operation, observed in our study. Only a few studies have investigated pain relief over 5 days post-operation, such as the study by Park et al. in 2001 where ropivacaine was administered with or without clonidine. The results of the study indicated that the treatment resulted in pain relief at Days 0, 3 and 5 after surgery  but the amount of bleeding was different between the groups. Similarly, in another double-blind study on 80 adults who underwent tonsillectomy, no differences were reported in pain relief between two patient groups who received injections of ropivacaine pre- or post-operation. However, a reduction in immediate postoperative pain was reported in the two groups who received the injection compared with the control group . RegardiLocal injection of epinephrine with bupivacaine in the peritonsillar area before tonsillectomy can decrease bleeding during surgery and administration of the drugs either pre- or post-operation reduces immediate bleeding. Pre- or post-operative injection of epinephrine with bupivacaine also reduces immediate post-operative pain, and decreases swallowing pain in the hours immediately after surgery; therefore their use will help to keep patients calm and recommence oral food intake as soon as possible.