Objectives. The purpose of this double-blind, randomized study was to investigate whether the addition of intra-articular bupivacaine to intravenous parecoxib could improve pain relief in patients undergoing total knee arthroplasty. Methods. A total of 36 patients undergoing total knee arthroplasty were enrolled into our study. These patients were randomly allocated either to a placebo-controlled group or study group. Postoperative pain scores and analgesic consumption were evaluated. Results. Numeric rating scale (NRS) data of bupivacaine group in postoperative room were significantly lower than that of control group   versus 4.5 (3.2–5.8) , p = 0.001). NRS data of bupivacaine group in ward were also significantly lower than that of control group. A significantly lower dose of meperidine was used in the study group postoperatively during the first 24 hours . Conclusion. Intra-articular bupivacaine in combination with intravenous parecoxib may improve pain relief and reduce the demand for rescue analgesics in patients undergoing total knee arthroplasty. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12615000463572). Knee surgeries usually lead to severe postoperative pain , which mAmong these, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain relief , 5. PareIntra-articular drug injections may reduce pain following joint operation . FurtherThe study was approved by the Institutional Review Board of Chang Gung Medical Foundation prior to the start of the trial. Written informed consent was obtained from every participant. A total of 40 patients (of both sexes) were prospectively included in the study. All patients were scheduled for total knee arthroplasty under general anesthesia between December 2012 and March 2013. The inclusion criterion was patients with knee osteoarthritis who were recommended for total knee arthroplasty. Preoperative evaluation for general anesthesia was performed. Exclusion criteria included neuropathic pain or sensory disorder in the knee requiring surgery, coagulation abnormalities, severe renal or hepatic impairment, and chronic opioid use. The neuropathic pain was detected according to the modified painDETECT questionnaire .All participants were randomly assigned to either the control group (preoperative intravenous parecoxib) or the bupivacaine group (intra-articular bupivacaine combined with preoperative intravenous parecoxib) on the basis of a concealed allocation approach. A computerized random number table with no restrictions on the randomization was used to determine this allocation. Numbered, opaque, sealed envelopes containing the randomization schedule were kept by an investigator who was not an assessor of the study. The envelopes were opened immediately before the intra-articular injection. All patients were blinded to their allocation. Parecoxib 40 mg was injected intravenously 1 hour before operation. All enrolled patients received general anesthesia by means of orotracheal intubation with propofol (2 mg/Kg), fentanyl (2 mcg/Kg), and cisatracurium (0.2 mg/Kg). Anesthesia was maintained with sevoflurane. In all cases, fentanyl was not given during the last 30 minutes of surgery. Surgery procedures were performed by the same orthopedic technique. After the closure of the surgical wound, an intra-articular injection of 0.5% bupivacaine 60 mL (300 mg) or 0.9% normal saline 60 mL was given into the joint space. The bupivacaine and normal saline were prepared by the pharmacy and were exteriorly indistinguishable. Hence, both the patients receiving the intra-articular injection and the doctor attending these patients did not know which drug was injected.After operation, the numeric rating scale (NRS) scores, wherein score 0 denoted no pain and score 10 denoted the worst pain, were used for the first time for pain assessment. If the NRS score exceeded 4, an intramuscular meperidine 50 mg injection was given for pain relief. The frequency of assessment was every 4 hours and an intramuscular meperidine 50 mg injection was given if needed. Data were collected by nursing staff who were unaware of the study.The primary outcome was the NRS scores after the operation. The secondary outcome was the amount of meperidine use within the first 24 hours after the operation.t-test was used for analysis. A p value < 0.05 was considered to be statistically significant. All statistical data were analyzed using the SPSS statistical software.Data were collected and expressed as number, percentage, and mean ± standard deviation. The statistical result of pain scores was expressed as mean and 95% confidence interval. Unpaired Student's Forty patients were enrolled in this study. Four of them were excluded. Two patients declined to participate. One patient had a sensory disorder in the knee and required surgery and one patient had severe renal impairment. The CONSORT flow diagram for the study is shown in The basic data and preoperative comorbidities of all the patients are shown in p = 0.001). NRS data of bupivacaine group in the ward were also significantly lower than those of control group  versus 4.5 , p = 0.0002).NRS scores obtained in the postoperative room and in the ward, 24 hours following the operation, are expressed in Tables p = 0.001), indicating that patients under intra-articular bupivacaine intervention had a lower amount of meperidine use within 24 hours following the operation.The total amount of meperidine use is shown in The results of this prospective study suggested that intra-articular bupivacaine (300 mg) in combination with intravenous parecoxib (40 mg) could improve pain relief and reduce meperidine requirements in the management of postoperative pain during the first 24 hours following total knee arthroplasty. Poor control of postoperative pain may lead to a series of adverse effects, including immunosuppression , 13. MulIntra-articular injection of 60 mL of 0.5% bupivacaine was used in the current study. Previous studies have shown that intra-articular infusion of 0.5% bupivacaine at a rate of 2 mL/h for 48 hours produces little or no pain relief . The resSome limitations of this study should be considered. We did not record mobilization data, and pain scores were determined only at rest. The pain rating at rest alone is not very helpful as it is the functional outcome that is of clinical interest. This includes pain during movement, quadriceps strength, and early ambulation. Evaluation of pain during movement is suggested for further study. Furthermore, a pilot study was not performed to calculate the required sample size. In this study, with such a small sample size, the investigation may not have been sufficiently convincing. In addition, a single-bolus dose of bupivacaine was used in this study. A third group with a higher or lower bupivacaine dose to determine the optimal dose/volume of bupivacaine is suggested for a future study.In conclusion, intra-articular bupivacaine in combination with intravenous parecoxib improved pain relief and reduced the demand for rescue analgesics in patients undergoing total knee arthroplasty.


Neuropathic pain following surgical treatment for breast cancer with or without chemotherapy is a clinical burden and patients frequently report cognitive, emotional and quality of life impairment. A preclinical study recently showed that memantine administered before surgery may prevent neuropathic pain development and cognitive dysfunction. With a translational approach, a clinical trial has been carried out to evaluate whether memantine administered before and after mastectomy could prevent the development of neuropathic pain, the impairment of cognition and quality of life.A randomized, pilot clinical trial included 40 women undergoing mastectomy in the Oncology Department, University Hospital, Clermont-Ferrand, France. Memantine  or placebo (n = 20) was administered for four weeks starting two weeks before surgery. The primary endpoint was pain intensity measured on a (0–10) numerical rating scale at three months post-mastectomy.Data analyses were performed using mixed models and the tests were two-sided, with a type I error set at α = 0.05. Compared with placebo, patients receiving memantine showed at three months a significant difference in post-mastectomy pain intensity, less rescue analgesia and a better emotional state. An improvement of pain symptoms induced by cancer chemotherapy was also reported.This study shows for the first time the beneficial effect of memantine to prevent post-mastectomy pain development and to diminish chemotherapy-induced pain symptoms. The lesser analgesic consumption and better well-being of patients for at least six months after treatment suggests that memantine could be an interesting therapeutic option to diminish the burden of breast cancer therapy.NCT01536314Clinicaltrials.gov  Although surgery, radiotherapy and chemotherapy have dramatically increased the life expectancy of patients suffering from breast cancer , these tN-methyl-D-aspartate (NMDA) receptor (r) antagonist, may be an alternative, but serious side-effects limit its clinical use [via its NR2B-subunit [When patients face therapeutic failure with classical drugs, ketamine, a ical use . The effical use –17 but iical use . NMDAr h-subunit . However-subunit . Rather -subunit . Preempt-subunit –27.1472NR2B at spinal and cerebral level, confirming the preventive effect of memantine on central sensitization. This present clinical trial explores the preventive properties of oral memantine on pain and on the cognitive and quality of life impairment up to six months after mastectomy. Considering the poor efficacy of available drugs on post-operative and cancer-induced neuropathic pain, and the risks associated with comorbidity and multiple pharmacy [A recent preclinical study has reported for the first time that memantine administered for four days before surgery in a neuropathic pain model prevents the development of neuropathic pain symptoms and cognitive impairment . Concomipharmacy , this noThe methodology of the study has been detailed in a recent article .http://www.clinicaltrials.gov (NCT01536314). The protocol for this trial and supporting CONSORT checklist  and registered on 16 February 2012 at hecklist  Files arBefore giving informed consent, patients were informed that they would be participating voluntarily and that they could chose to withdraw at any time. Furthermore, the general aims, the different questionnaires and the pharmacological intervention of the study were explained to each participant.Women were included two weeks before mastectomy (Baseline), in the course of their Anesthesiology visit. After clinical examination, pain, cognition, quality of life and sleep questionnaires were filled out and patients were randomized in two parallel groups: memantine (n = 20) or placebo (n = 20). Oral treatment was given for four weeks starting two weeks before surgery (S). Memantine was prescribed according to regional recommendations for Alzheimer disease. Follow-up clinical examination was performed 2 weeks (S+15 days), 3 and 6 months after mastectomy (M3 and M6). Patients were called once a week by phone to collect adverse events. A booklet for monitoring analgesic concomitant medications was completed daily by the patient for six months from the day of surgery.Pain was evaluated with several tools: a (0–10) numerical rating scale (NRS), the Brief Pain Inventory (BPI) , the McGFurthermore, we differentiated neuropathic pain induced by surgery, "surgery DN4" focused on the surgery site, from neuropathic pain induced by chemotherapy, "chemotherapy DN4" focused on "hand and foot" distribution of chemotherapy-induced neuropathy.The treatment group received memantine during one month, starting two weeks before surgery. Memantine was prescribed in increasing doses during the first two weeks before mastectomy and maintained at 20 mg daily during two weeks after surgery.Patients received a daily dose of placebo (lactose) during one month starting two weeks before mastectomy.The drugs used in the study (memantine and placebo) were prepared, conditioned and released in the hospital pharmacy by one qualified person according to good manufacturing principles. The number of tablets in each dispensed container was verified and recounted at the end of the treatment by two persons totally independent of the protocol.The primary outcome was to evaluate by NRS whether memantine, administered two weeks before and two weeks after mastectomy, could prevent pain development at three months post-mastectomy when compared with the placebo group.The secondary outcomes were to evaluate at three and six months post-mastectomy the pain intensity, the analgesic concomitant medications, the impact of treatment on cognitive function, quality of life and sleep and the intensity of cancer chemotherapy-induced pain.The estimated number  of patieOn the day of the visit, inclusion and exclusion criteria were verified and written informed consent was obtained by the physician. After clinical examination and pain assessment, a clinical nurse independent of the protocol obtained the randomization number from the hospital pharmacy and the patient was then randomized in the memantine or placebo group. Treatment allocation followed the order of a predetermined randomization list and was generated using random blocks. In order to maintain blinding, the physician who evaluated pain could not guess allocation at any time and would not meet the patient again in the course of the trial.t-test or Mann-Whitney test when appropriate  for quantitative parameters and using chi-squared or Fisher’s exact tests. For the primary endpoint, results were expressed as effect-size and 95% confidence interval. Concerning the analysis of repeated measures, random-effect models were considered, as it was usually proposed, to study fixed effects  and taking into account between and within subject variability. The normality of residuals was checked for each model. When appropriate, a log transformation was proposed to achieve the normality of dependent variables. Subgroups analyses were planned and were performed with anticancer chemotherapy (yes/no) proposed as fixed effect in previous models. Residual normality was checked for all models. Finally, a sensitivity analysis was carried out to study the attrition bias and to characterize the statistical nature of missing data.Statistical analyses were performed with Stata software . The tests were two-sided, with a type I error set at α = 0.05. Concerning the primary outcome, comparison between the randomized groups was performed using an analysis of covariance with baseline score as a covariate as suggested by Vickers and Altman . ConcernThe investigators pre-screened 207 patients; 104 women refused to participate in the study, 60 did not meet the inclusion criteria and 43 gave written informed consent. These were randomized into the memantine or placebo group. Two patients withdrew before starting treatment and one interrupted the trial because surgery was postponed due to advanced disease. Out of 43 enrolled patients, 40 were analysed .Demographic and clinical data of the 40 participants, including age, previous chemotherapy, type of anticancer agents and axillary dissection are presented in At M3 post-mastectomy, a significant difference in the primary outcome, NRS pain intensity, was recorded in the memantine group compared with the placebo group  while at M6 post-mastectomy no significant difference was observed . The effect size for the main end point was 0.76 .Regarding the secondary outcomes, a significant decrease of pain intensity was reported in the memantine group at M3 compared with baseline  but such a decrease was not obtained at M6 post-mastectomy .Concerning neuropathic pain induced by surgery (DN4 surgery), no significant difference was observed at M3 and M6 post-mastectomy between memantine and placebo groups. In the placebo group, 45% (n = 9) of patients at M3 and 30% (n = 6) at M6 had neuropathic pain while in the memantine group, 35% (n = 7) developed neuropathic pain at M3 and M6 . In the Concerning analgesics, all patients were prescribed non-opioids , with opioids for two days post-mastectomy. At M3, there was a significant difference in neuropathic pain drug consumption (antiepileptics prescribed for pain) between both groups, (six patients in the placebo group (30%) and only one patient (5%) in the memantine group; p = 0.040) . This diIn the McGill pain questionnaire, the affective component was improved at three months  in the memantine group  while noOf the forty patients included in the study (n = 20 in each group of treatment), half of the patients had received chemotherapy before inclusion . In this subgroup, at M3 and M6, pain was significantly less intense in the memantine group  were significantly diminished   .This pilot trial proposes for the first time with the administration of the NMDAR blocker memantine before surgery, a successful therapeutic option to prevent pain and diminish neuropathic pain treatment. Three months post-mastectomy, patients in the memantine group reported significantly less pain than in the placebo group (p = 0.017) and only 5% needed neuropathic pain treatment compared with 30% in the placebo group (p = 0.04). No such a randomised successful intervention preventing neuropathic pain development after surgery has been shown so far in the literature. A number of analgesics have been tested to reduce pain after breast surgery but data of the literature are conflicting and focus on acute rather than long—term residual chronic pain –27.The study also showed that patients coped better with pain, as shown by the beneficial effect of memantine on the emotional component of pain using the McGill pain questionnaire (p = 0.032), and they declared to the physician not to be bothered by pain. However, in both groups, a third of the patients had significant neuropathic pain scores (DN4≥4). This paradox between the presence of pain and the indifference of the patient to it may suggest a sensori-limbic dissociation in the effect of memantine, with features reminiscent of pain asymbolia . Such a This clinical trial does confirm preclinical results where memantine given for several days before surgery has been shown to limit and even inhibit downstream protein expression and phosphorylation of tyrosine 1472 on the NR2B subunit of NMDAr in two structures of the limbic system, the hippocampus and the insular cortex . These cFor the first time, this pilot trial also reports a curative effect of memantine on chemotherapy-induced neuropathic pain at M3 and M6, with a 55% reduction of dysesthesia and paresthesia symptoms in patients who had received chemotherapy before inclusion and had developed chemotherapy-induced typical polyneuropathy with "hand and foot" distribution [Likewise, cognition, sleep and quality of life were also studied in the trial, as these domains are often impaired in cancer patients because of multifactorial and intertwined causes including cancer itself , treatmeSimilarly, assessment of sleep and quality of life, secondary endpoints, did not show any significant difference between both groups. This is certainly linked to the small sample size and the overall short duration of the study. Neuropathic pain is known to affect quality of life, functionality, and to precipitate functional decline especially in vulnerable patients , and futIn conclusion, this innovative trial shows for the first time that pre-surgery memantine may prevent the occurrence of pain three months after mastectomy, and suggests that it may also reduce dysesthesia and paresthesia induced by chemotherapy. Memantine could be a valuable option for patients with breast cancer who are at risk of developing the double burden of post-mastectomy and post-chemotherapy neuropathic pain, both potentially long-lasting types of pain. This pilot trial will help to design future studies and these preliminary results will need to be extended and confirmed over a longer follow-up period, with different memantine dosages and with a larger assessment of pain, cognitive-emotional status and functionality in a larger population.S1 FileCONSORT Checklist of the present study.(DOC)Click here for additional data file.S2 FilePrevention of post-mastectomy neuropathic pain with memantine: study protocol for a randomized controlled trial.(PDF)Click here for additional data file.


Acute pelvic pain is a common reason for emergency room visits that can indicate a potentially life-threatening emergency (PLTE). Our objective here was to develop a triage process for PLTE based on a self-assessment questionnaire for gynecologic emergencies (SAQ-GE) in patients experiencing acute pelvic pain.P < 0.05) by univariate analysis were used to develop a decision tree by recursive partitioning; the remaining third served for validation.In this multicenter prospective observational study, all gynecological emergency room patients seen for acute pelvic pain between September 2006 and April 2008 completed the SAQ-GE after receiving appropriate analgesics. Diagnostic procedures were ordered without knowledge of questionnaire replies. Laparoscopy was the reference standard for diagnosing PLTE; other diagnoses were based on algorithms. In two-thirds of the population, SAQ-GE items significantly associated with PLTEs , 81%-94%) in the derivation set and 83.7% in the validation set. Derivation of the decision tree provided probabilities of PLTE of 13%  in the low-risk group, 27%  in the intermediate-risk group and 62%  in the high-risk group, ruling out PLTE with a specificity of 92.3%; . In the validation dataset, PLTE probabilities were 16.3% in the low-risk group, 30.6% in the intermediate-risk group, and 44% in the high-risk group, ruling out the diagnosis of PLTE with a specificity of 88.6%.A simple triage model based on a standardized questionnaire may assist in the early identification of patients with PLTEs among patients seen in the gynecology emergency room for acute pelvic pain. Acute pelvic pain is the leading reason for gynecological emergency room visits . HoweverIn general emergency rooms, nurses typically prioritize patients to ensure that those with serious conditions are seen first by the emergency physicians. Triage scales such as the Emergency Severity Index  are usedA self-assessment questionnaire for gynecological emergencies (SAQ-GE) recently developed by our group for the assessment of acute pelvic pain in women with gynecologic emergencies has been used to build clinical prediction rules for tubal rupture complicating ectopic pregnancy  and for The study was approved by the French Department of Higher Education and Research (n°06.336) and by the French National Committee for Information Technology and Individual Liberties (n°906253).We conducted a prospective multicenter study in five gynecology departments in the Paris metropolitan area, France. Four departments were in teaching hospitals  and one was in a general hospital (Versailles).From September 2006 to April 2008, all patients at least 18 years of age who presented to study-center gynecological emergency rooms with acute pelvic pain were eligible to complete the SAQ-GE on a voluntary basis. Exclusion criteria were a history of chronic pelvic pain, neurological or psychiatric disease, hemodynamic instability, and no knowledge of French. Patients with a verbal 11-point numerical rating scale (NRS) pain score lower than 1 and those with bartholinitis or breast pain were excluded.The SAQ-GE was developed using a qualitative method  and adviThe SAQ-GE was completed by the patients after appropriate initial pain management and before diagnostic investigations or surgery. The nurses collected the completed questionnaires, which were not made available to the physicians. Thus, in this non-interventional study, all diagnostic and therapeutic decisions were made without knowledge of the questionnaire replies.The final diagnosis was the diagnosis at hospital discharge established based on the physical examination, abdominal and endovaginal ultrasound, routine biology (if needed), computed tomography (CT) of the abdomen and pelvis (if needed), and surgical procedures . The diagnosis of ectopic pregnancy was based on laparoscopy or on an algorithm ,14, withAmong patients who did not undergo emergency laparoscopy, those who were pregnant were followed until a definitive diagnostic was made . In nonpFor the purpose of the study, patients were classified according to whether they had a prospectively recorded diagnosis of PLTE. PLTEs were defined as gynecological or nongynecological disorders causing acute pain and associated with a high risk of complications likely to cause residual impairments, severe morbidity, or death within a short period in the absence of appropriate emergency surgical or radiological treatment . This deWe randomly assessed two-thirds of the patients to the derivation dataset and the remaining third to the validation dataset. All statistical tests were done using Stata 11.0 .P values <0.05 were classified as possible predictors. For each of these variables, we computed sensitivity, specificity, the positive likelihood ratio (Lr+) and negative likelihood ratio (Lr-), and the crude diagnostic odds ratio with their 95% confidence interval (95% CI).SAQ-GE replies of patients with a final diagnosis of PLTE were compared to those of the other patients by univariate analysis using Pearson’s chi-square test or Fisher’s exact test. Variables significantly associated with PLTE with Variables significantly associated with PLTEs by univariate analysis were used for multivariable analysis by recursive partitioning to create a decision tree based on the best combination of variables. The decision tree identified groups at high, intermediate, and low risk for PLTEs based on the sequential Lr values . When a Finally, we assessed the performance of the decision tree in the validation dataset.At the five study centers, 574 of about 992 eligible patients completed the SAQ-GE. Among them, 516 met our inclusion criteria and were entered into the study. A final diagnosis of PLTE was made in 145 (28.1%) patients. Table Table In the validation dataset, the diagnostic performance characteristics of our decision tree were similar to those in the derivation dataset, with most of the validation-dataset values being within the 95% CI for the derivation-dataset values. The PLTE probability was 16.3% in the low-risk group, 30.6% in the intermediate-risk group, and 44% in the high-risk group, ruling out the diagnosis of PLTE with a specificity of 88.6%. Sensitivity of the decision tree was 83.7% in the validation dataset.We built a decision tree for triaging women presenting to the emergency room with acute pelvic pain using a standardized yes/no items from a self-questionnaire. The decision tree relies on three simple items: vomiting, pain upon self-palpation, and sudden onset of pain. It separates three groups of patients, at low, intermediate, and high risk for PLTEs, respectively. Sensitivity of the decision tree was 87.5% .The time to management of gynecological emergencies is the sum of four periods: time from symptom onset to arrival; time from arrival to the first medical assessment; time from the first medical assessment to the diagnosis, which usually required pelvic and endovaginal ultrasonography by a specialist ; (iv) anMost triage tools use clinical decision rules that separate patients into five triage categories depending on the acceptable time to medical management ,23. ThesA rigorous statistical approach was used to develop our decision tree, in contrast to the methods generally used by consensus panels . DecisioThe high predictive values of our model may seem surprising in the light of pathophysiological considerations. Our definition of PLTE encompassed a variety of conditions that differ regarding the pathophysiological mechanisms responsible for pain ,27. Howehttp://www.acem.org.au/media/policies_and_guidelines/G24_Implementation__ATS.pdf). In patients with PLTEs as defined for our study, an earlier and more accurate diagnosis allows the rapid provision of appropriate care, thereby improving patient outcomes in terms of both morbidity and mortality.One limitation of our study is related to our definition of PLTE. This definition was not established by consensus among a panel of experts . NeverthAnother limitation may be overfitting of the decision tree to our data. However, the validation study in the third of our population not used to build the decision tree showed similar diagnostic performance characteristics and substantial overfitting was also prevented by constructing the SAQ-GE in a preliminary study involving different patients and experts.In summary, our decision tree is the first dedicated to the diagnosis of PLTEs with a 87.5% sensitivity. In addition, it relies on only three simple items of a self-questionnaire. We plan to study the extent to which our decision tree decreases time to appropriate management and improves outcomes in patients presenting with acute pelvic pain to crowded emergency rooms.The authors declare that they have no competing interests.CH and AF wrote the manuscript. AF, AD and BF designed the study. AAC, CH and AF collected the datas. CH, AD and AF performed the statistical analysis.


Edema and necrosisof the temporomandibular joint (TMJ) have been described in terms of bone marrow signal abnormalities in magnetic resonance imaging (MRI). However, painful joints often show no such signaling abnormalities, making the diagnosis of TMJ disorders difficult in the clinical setting. An association has been suggested between TMJ bone marrow change and TMJ pain, but even when such change results in slight pain, it may be too slight to be visually apparent on MR images. We hypothesized that fluid-attenuated inversion recovery (FLAIR) can be used to detect such minimal changes. The purpose of this study was to determine whether there is an association between signal intensity on FLAIR images and pain in the TMJ.t test and Pearson’s product-moment correlation coefficient were used for the statistical analysis. A p value of <0.05 was considered statistically significant.The study included 85 TMJs in 45 patients referred to our department for MRI. The signal intensity on FLAIR images was measured. Pain was evaluated based on the visual analog scale. An unpaired Signal intensity on the FLAIR images was significantly higher in painful than in nonpainful TMJs, although a significant correlation was not observed between the signal intensity and the pain score.The results of this study suggest an association between abnormalities in the marrow of the mandibular condyle and pain. They also indicate that FLAIR imaging is a useful tool in the clinical diagnosis of painful TMJs. Pain is a primary concern in patients with disorders of the temporomandibular joint (TMJ) , 2. The MRI is generally performed to obtain proton density- and T2-weighted or T1- and T2-weighted images in patients with disorders of the TMJ. Such images allow for the detection of typical marrow abnormalities such as edema and osteonecrosis in the mandibular condyle. In the clinical setting, however, painful joints showing neither typical bone marrow changes nor other abnormalities are sometimes encountered when attempting to diagnose diseases of the TMJ based on MRI. If there is an association between change in the bone marrow and pain in the TMJ, it is possible that pain may occur even when such change is too small to be visually apparent on proton density- or T2-weighted images.Imoto et al.  used fluThis study investigated 108 joints in 54 consecutive patients with symptoms of TMJ dysfunction. All patients were referred to our department at Tokyo Dental College Chiba Hospital for MRI in 2009. Informed consent was obtained from all patients, and the study protocol was approved by the ethical review board of our institution No. 347). Twenty-three joints in 15 of these patients were excluded from the study as follows: 8 joints in 4 patients referred for MRI after surgery for jaw deformity; 7 joints in 6 patients with osseous change . Twenty-. TherefoImmediately prior to MRI, the patients rated their degree of pain upon occlusion using a VAS in which the maximum and minimum scores were 100 and 0, respectively. The degree of pain was scored separately for the left and right joints. The joints were categorized into a painful and a nonpainful group based on the median score, which was 2. The painful group included the joints with a VAS score of >2, and the nonpainful group included the joints with VAS score of <2. Four patients had both painful and nonpainful joints; each joint was categorized into the painful and nonpainful group, respectively.MRI was performed using a 1.5 T MRI system  and a double-loop array of coils for the TMJ. Corrected sagittal images of the fast-spin echo sequence with FLAIR were obtained in the closed-mouth position . The ROIs were placed over both the condylar marrow and gray matter (GM), which was taken as the reference point  of the condylar marrow was calculated using the signal intensity of the condylar marrow and GM  in the ROIs as follows: SIR = SIC/SIM .t test to compare differences between the two groups. A correlation was also evaluated between the SIR and pain score obtained using the VAS with Pearson’s product-moment correlation coefficient. A p value of <0.05 was considered statistically significant.The statistical analysis was performed using an unpaired p = 0.77).No significant difference in the average patient age was seen between the 41 painful and 44 nonpainful joints (p = 0.012) (Table p = 0.0004), indicating no correlation between the SIR and pain score (Table A significant difference in the mean SIR was seen between the painful and nonpainful joints p = 0.01 Table 2p = 0.0122) Table . Howeverre Table .Table 2DThe patient’s age should not be ignored when evaluating the bone marrow MRI signal intensity. Although the bone marrow is generally hematopoietic and red in youth, it gradually becomes fatty and yellow during development. The signal intensity of the bone marrow in the mandibular condyle thus changes starting after 10 years of age and continuing until age 25 . In T1-wIn this study, the mean SIR on FLAIR images of painful joints was significantly higher than that on FLAIR images of nonpainful joints, indicating a difference in the condition of the bone marrow between the two groups. A correlation between increased protein levels and high signals on FLAIR images has been observed . TherefoThe joints in our patients had no visually apparent marrow change on proton density-weighted and T2-weighted images and appeared as normal bone marrow on MRI examination. According to Larheim et al. , bone maYajima et al.  studied Osteonecrosis and bone marrow edema reportedly show abnormal signal intensity in the bone marrow . Some auIschemia is one cause of pain , and as Although the pathologic processes that result in ischemia are poorly understood, and although it is difficult to reflect such changes at the cellular level, we suspect that ischemic change might be one factor involved in the development of TMJ pain.No significant correlation was seen between the SIR and pain score, although a significant difference in the mean SIR was observed between painful and nonpainful joints. This was probably because of our exclusion of joints with visually apparent MR images. We suspect that a significant correlation would have been found between the SIR and pain score if a substantial number of joints with visually apparent changes had been studied. Further study is needed on this matter.Pain in the TMJ is a symptom of TMJ disorders , 25. A nIn conclusion, the present results suggest an association between abnormalities in the marrow of the mandibular condyle and pain. They also indicate that FLAIR is a useful tool in the clinical diagnosis of painful TMJs and offers a significant advantage over proton density- or T2-weighted images.


Fibromyalgia is characterized by widespread pain and is often accompanied by accessory symptoms. There are limited treatment options for this condition in Japan. Therefore, we conducted a phase III study to assess the efficacy and safety of duloxetine in Japanese patients with fibromyalgia.This randomized, double-blind, placebo-controlled, parallel-group trial was conducted in Japan. Outpatients who met the American College of Rheumatology 1990 criteria for fibromyalgia and whose Brief Pain Inventory (BPI) average pain score was ≥4 were randomized to duloxetine 60 mg or placebo once daily for 14 weeks. The primary efficacy measure was the change in the BPI average pain score from baseline. Secondary efficacy, quality of life (QoL), and safety outcomes were also evaluated. Mixed-effects model repeated-measures (MMRM) analysis and last observation carried forward (LOCF) analysis of covariance were used to evaluate the primary efficacy measure.Overall, 393 patients were randomized to receive either duloxetine (n = 196) or placebo (n = 197). The MMRM analysis revealed no significant difference between duloxetine and placebo regarding the change in BPI average pain scores at week 14. Based on LOCF analysis, a statistically significant improvement in the change in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo. Duloxetine treatment was associated with improved outcomes in nearly all secondary and post hoc analyses. The treatment was generally well tolerated. Somnolence, nausea, and constipation were the most common treatment-emergent adverse events in the duloxetine group. The discontinuation rates due to treatment-emergent adverse events were similar in both groups.Although the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change in the BPI average pain score and most of the secondary outcomes, including analgesia and QoL. Duloxetine treatment was safe and well tolerated. These results suggest that duloxetine treatment could be associated with improvements in pain relief and QoL in Japanese patients with fibromyalgia.NCT01552057. Registered 9 March 2012.ClinicalTrials.gov Identifier:  Fibromyalgia is a disorder characterized by widespread pain. In addition to widespread pain, patients with fibromyalgia frequently experience other troublesome symptoms, such as fatigue, sleep disturbances, and cognitive disturbances; other specific painful conditions such as chronic headache, temporomandibular disorders, and irritable bowel syndrome; and psychiatric comorbid conditions, including anxiety and depression. Furthermore, fibromyalgia often has negative effects on personal relationships, careers, and daily activities –7. AccorIn an epidemiological survey conducted in 2004, the Ministry of Health, Labour and Welfare of Japan reported a prevalence of fibromyalgia in Japan of 1.7 %, accounting for approximately 2 million individuals , which iDiagnostic Guidelines for Fibromyalgia 2013 document [Three agents  have been approved for treatment of fibromyalgia in the United States . Conversdocument , 13. In document . Duloxetdocument , 16. Clidocument –22. FurtIn Japan, duloxetine has been approved for treatment of major depressive disorder and diabetic peripheral neuropathic pain after its efficacy for these conditions was validated in phase III studies , 24. DesThis randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase III trial was conducted in 42 outpatient clinics and hospitals (listed in the Acknowledgments) in Japan between March 2012 and December 2013. An institutional review board for each site (listed in the Appendix) approved the protocol, and all patients provided written informed consent before study commencement. The study was conducted in compliance with the International Conference on Harmonisation Good Clinical Practice guidelines. All monitoring activities for this study were outsourced to SRL Medisearch, Inc., Tokyo, Japan. This study was registered at ClinicalTrials.gov under the identifier NCT01552057 on 9 March 2012. There were no changes to the methods or planned endpoints after study initiation.The criteria used in a previous study of duloxetine  were adoPatients were prohibited from using analgesics and drugs with analgesic effects, including nonsteroidal anti-inflammatory drugs, anticonvulsants, pregabalin, neurotropin, anesthetics, opioids, and adrenocorticosteroids. The use of analgesics for up to 3 consecutive days and for up to a total of 10 days was permitted only for the treatment of adverse events (AEs). Coadministration of acetaminophen at doses up to 1500 mg/day was permitted to treat AEs and as rescue treatment for fibromyalgia, except on the day before efficacy was evaluated after visit 2 and until just before the evaluation. The use of prophylactic aspirin at doses up to 325 mg/day to prevent cardiac events was also permitted. Patients taking mood-affecting drugs such as antidepressants, sedatives, and benzodiazepines were also excluded. Zopiclone and zolpidem were the only hypnotics permitted during the study, as long as their use began before the participant entered the screening phase , without dosing changes. Tender point injections and nerve blocks were to be stopped before visit 1. Non-drug therapies  received at least 14 days before visit 1 were permitted during the study, as long as no changes were made.This randomized, multicenter, double-blind, placebo-controlled, parallel-group phase III trial consisted of four phases. The study lasted 17–18 weeks and included a 1- to 2-week screening phase, a 14-week treatment phase, a 1-week dose-tapering phase, and a 1-week follow-up observation phase . The drug allocation controller confirmed the study drugs were undiscernible in terms of appearance, packaging, and labeling, and mock titration of placebo pills was also performed to maintain blinding. Only the drug allocation controller was aware of the type of drugs being dispensed.The primary efficacy measure was the change in the BPI average pain score from baseline (visit 2) to the end of the 14-week treatment phase (visit 7). The pain score was based on a scale from 0 (no pain) to 10 (pain as bad as patient can imagine).Secondary outcomes included the “worst pain severity,” “least pain severity,” and “pain right now” items of the BPI; pain interference with seven daily activities ; data reported in patient diaries; and scores on the Patient Global Impression of Improvement (PGI-I) and the Clinical Global Impressions–Global Improvement (CGI-I) . Pain inPatients responded to the Fibromyalgia Impact Questionnaire  , 32, conUsing the 36-Item Short-Form Survey  , 34, patUsing the Beck Depression Inventory II (BDI-II) , 36, patSafety was assessed on the basis of the presence or absence and incidence of AEs and adverse drug reactions (ADRs) reported during the treatment phase until the end of the follow-up observation phase. Additionally, laboratory tests , ECG, body weight, and vital signs were measured. The presence or absence of suicidal tendencies was assessed using the C-SSRS.Based on clinical data from three previous studies –22, the The primary efficacy measure was analyzed using a mixed-effects model repeated-measures (MMRM) approach to compare the change from baseline in BPI average pain score at week 14 of study treatment between the duloxetine and placebo groups. The model included treatment, week, and a treatment × week interaction as fixed effects, as well as the baseline pain score and presence or absence of concomitant major depressive disorder diagnosed as covariates. The change in BPI average pain score from baseline to week 14 of treatment was also compared between the groups by analysis of covariance (ANCOVA) with the baseline value and presence or absence of major depressive disorder as covariates. The missing data at week 14 of treatment were imputed based on the last observation carried forward (LOCF) approach. Post hoc ANCOVA was used for additional sensitivity analyses of the primary efficacy measure. In these post hoc analyses, the baseline observation carried forward (BOCF) or worst observation carried forward (WOCF) values were carried forward to impute missing data instead of the LOCF method being used. The proportions of responders were calculated for patients with a reduction in the BPI average pain score of ≥30 % from baseline to endpoint or ≥50 % from baseline to endpoint, and also for patients with a sustained response. Sustained response was defined as ≥30 % reduction from baseline to endpoint in the BPI average pain score with a 30 % reduction from baseline at an earlier visit (at least 2 weeks prior) and ≥20 % reduction from baseline for every visit in between if there were any intervening visits. These proportions were compared between the groups using a Mantel–Haenszel test adjusted for the allocation factors.Unless otherwise noted, the MMRM approach was used to evaluate the differences in the changes in other secondary endpoints from baseline between the duloxetine and placebo groups. PGI-I and CGI-I scores were analyzed using a MMRM model without baseline as a covariate. In post hoc analyses, PGI-I and CGI-I at week 14 were compared between the treatment groups using Wilcoxon’s rank-sum test with the LOCF approach. For SF-36, changes from baseline to week 14 of treatment were compared between the duloxetine and placebo groups using the LOCF ANCOVA approach.Path analysis, which consists of the following two regression models, was performed to estimate a direct analgesic effect relative to an indirect effect on pain reduction through an improvement in depressive symptoms:andY1 is the change from baseline in BPI average pain score, Y2 is the change from baseline in BDI-II total score, X1 is treatment, Z1 is baseline BDI-II total score, and Z2 is baseline BPI average pain score. The direct and indirect effects of the duloxetine were estimated by α1 and α2 × β1, respectively. Then, the contribution (as a percentage) of each effect to the total effect, which was defined as the sum of the direct and indirect effects, was calculated if feasible.where Incidences of AEs and ADRs were compared between the treatment groups using Fisher’s exact test. The AEs and ADRs reported were coded with MedDRA , and the incidences were tabulated for each preferred term by treatment group.n = 197) or duloxetine (n = 196). In the placebo and duloxetine groups, 2 and 5 patients, respectively, were excluded from the FAS and 149 and 166 patients, respectively, completed the study treatment. Although more patients withdrew because of a lack of efficacy in the placebo group , a similar proportion of patients withdrew from each group because of AEs   in the MMRM analysis, a statistically significant improvement in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo when we used the LOCF ANCOVA approach (Table p = 0.0132) than in the placebo group (Table p = 0.0130) or ≥50 % (p = 0.0318) and the sustained response rate (p = 0.0139) in the BPI average pain score indicated that the reduction in pain was significantly greater in the duloxetine group than in the placebo group  was also observed in the total WPI and SS scores  were reported in one patient in the placebo group. One serious AE (liver injury) was reported in one patient in the duloxetine group, and the investigator could not exclude the possibility of a relationship between the AE and the study drug. That patient recovered after discontinuation of the study drug. The number of patients who discontinued treatment because of AEs was similar in both groups, with 15 and 14 patients in the placebo and duloxetine groups, respectively. Somnolence , nausea (4.6 % vs. 21.6 %), constipation (4.1 % vs. 14.9 %), decreased appetite (0.5 % vs. 6.7 %), and dizziness (1.0 % vs. 5.7 %) were significantly more frequent in the duloxetine group than in the placebo group  in the duloxetine group compared with the placebo group.The efficacy and safety of duloxetine in the treatment of fibromyalgia was previously investigated in four randomized, double-blind, placebo-controlled trials in other countries , 20–22. Furthermore, analysis of the change in BPI average pain score from baseline to week 14 using ANCOVA (with missing data imputed by LOCF) showed a significant improvement in the duloxetine group compared with the placebo group. These results are consistent with those of earlier international studies , 21 in wMoreover, in post hoc analyses of the results of our present study, the change from baseline to week 14 in BPI average pain scores was compared when missing data due to discontinuations were imputed using the BOCF or WOCF methods. These results indicate that, with either of the missing data imputation methods, a significant improvement was observed in the duloxetine group compared with the placebo group. In this clinical trial, there were more patients who discontinued the trial because of an inadequate improvement in the BPI average pain score or exacerbation of pain in the placebo group (11.7 %) compared with the duloxetine group (4.1 %). Therefore, the MMRM analysis might introduce a bias toward greater improvement in BPI average pain score in the placebo group than in the duloxetine group.Of the seven pain-related items among the secondary efficacy measures, six  showed a significant improvement from baseline to week 14 of treatment in the duloxetine group compared with the placebo group. Although the superiority of duloxetine over placebo was not demonstrated in the MMRM analysis of the primary efficacy measure, a significant improvement in the duloxetine group compared with the placebo group was observed in the secondary and post hoc analyses and several other secondary efficacy measures. These results suggest that treatment with duloxetine could be associated with improvement in pain relief in Japanese patients with fibromyalgia.Moreover, the 30 %, 50 %, and sustained pain reductions based on the change at endpoint in the BPI average pain score were significantly higher in the duloxetine group than in the placebo group. According to the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations, patients with a clinically relevant reduction in the assessment scale of 30–50 % compared with baseline are considered responders . Therefop = 0.0586) than in patients with a baseline BDI-II score of ≥14 . In patients without major depressive disorder, the reduction in the BPI average pain score was significantly greater in the duloxetine group . Therefore, treatment with duloxetine could be associated with an improvement in patients with very mild depressive symptoms as well as in those without major depressive disorder.The path analysis performed in this study suggested that the direct effect of duloxetine on the reduction of the BPI average pain was smaller than the indirect treatment effect, as evidenced by the improvement in depressive symptoms at study endpoint. The changes in both BPI average pain score and BDI-II score indicated improvements in these symptoms. Because the between-groups difference at the last evaluation was large for BDI-II and small for BPI average pain score, we estimate that the contribution of improved mood  to the whole analgesic effect was high. In the present clinical study, however, the proportion of patients with a complication of major depressive disorder was small compared with the proportions observed in other studies: major depressive disorder was diagnosed in only eight patients (4.2 %) in the duloxetine group and seven patients (3.6 %) in the placebo group in our study. Thus, an evaluation of exactly how much of the analgesic effect of duloxetine was due to its antidepressant effect was considered difficult. A subgroup analysis using LOCF ANCOVA was performed to examine the potential effects of the degree of depressive symptoms  and theFibromyalgia is characterized by widespread body pain as well as a variety of symptoms that affect overall health status and QoL. Therefore, PGI-I and CGI-I scores were assessed for comprehensive evaluation of illness improvement from baseline to 14 weeks of treatment. The SF-36 and FIQ were used, in addition to the BPI pain interference scale, to assess the overall impact of fibromyalgia on health status. Because fibromyalgia is associated with neuropsychiatric symptoms, the BDI-II was used to assess improvement in these symptoms. In this study, illness improvement (PGI-I and CGI-I scores) was significantly higher in the duloxetine group than in the placebo group. The BPI interference scores for mood, relationships with people, and enjoyment of life, as well as the average score for all seven items, were significantly improved in the duloxetine group compared with the placebo group. These improvements in the BPI interference scores are similar to the results of a study conducted in Japanese patients with diabetic peripheral neuropathic pain  who presThe present study suggests that duloxetine treatment could be associated with a reduction in the pain associated with fibromyalgia and the improvement of related symptoms. Because of the wide array of clinical manifestations of fibromyalgia, the disease can considerably deteriorate the QoL of patients. On the basis of the present findings, duloxetine could potentially improve the QoL of patients as well as ameliorate depressive symptoms by improving the symptoms associated with fibromyalgia.Compared with the placebo group, the duloxetine group showed a significant improvement in WPI and a trend toward a numerical improvement in SS, indicating an improvement of clinical symptoms. This result is consistent with the significant improvement in associated symptoms of fibromyalgia and in several items of the QoL assessment in patients who received duloxetine in this study. Moreover, 85.0 % of patients in this study matched the ACR 2010 criteria for fibromyalgia, which is consistent with the findings reported by Usui et al. . The aboGenerally, patient compliance has been found to increase as dosing frequency decreases . CurrentThe results of the present short-term study indicate that there were no significant safety concerns related to duloxetine treatment. Somnolence, nausea, constipation, decreased appetite, and dizziness were significantly more frequent in the duloxetine group than in the placebo group, which is consistent with previously reported AEs among patients with approved indications, such as major depressive disorder  and diabSome limitations of this study should be mentioned: we excluded patients with psychiatric disorders other than depression, and we did not assess the long-term efficacy and safety of duloxetine.Although the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change of the BPI average pain score and most of the secondary outcomes, including analgesia and QoL. No significant safety concerns were reported during the duloxetine treatment. These results suggest that treatment with duloxetine could be associated with improvement in pain relief and QoL in Japanese patients with fibromyalgia.


P = 0.13), mean age (P = 0.54), and baseline visual analogue score (P = 0.21). A repeated measure analysis of variance revealed that the difference between the two treatments was significant (P = 0.0001). The VAS reduction at primary endpoint (30 min after drug administration) was significantly higher in the acetaminophen group than in the morphine group (P = 0.0001). This study demonstrated that intravenous acetaminophen could be more effective than intravenous morphine in acute renal colic patients' pain relief.The aim of this study was to compare the clinical efficacy of intravenous acetaminophen with intravenous morphine in acute renal colic pain management. In this double-blind controlled trial, patients aged 18–55 years, diagnosed with acute renal colic, who met the inclusion and exclusion criteria, were randomized into two groups. First, using the visual analogue scale (VAS), intensity of pain was assessed in both groups. Then, one gram of intravenous acetaminophen or 0.1 mg/kg morphine was infused in 100 mL normal saline to either acetaminophen or morphine group. Intensity of pain was reassessed in 15, 30, 45, and 60 minutes according to VAS criteria. Finally, data from 108 patients were analyzed, 54 patients in each group. No significant difference was observed between the two groups in regard to sex ( Pain is the most common chief complaint in emergency departments . The essSeveral clinical trials compared the efficacy of opioids and NSAIDs in the case of pain relief and adverse effects. Majority of these trials found NSAIDs more effective than opioids or at least as effective as them. Although NSAIDs cause less vomiting, nausea, respiratory suppression, and drowsiness in comparison with opioids, they have potential adverse effects such as platelet dysfunction, nephropathy, and increasing cardiovascular mortality in ischemic heart disease –8.Since NSAIDs and opioids have several side effects, they are unavailable in some emergency departments, seeking new drugs with fewer side effects, and an adequate analgesic property is crucial. One of these alternative drugs is intravenous acetaminophen.Acetaminophen is acetyl-para-aminophenol. It has analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs , 10. IntThe aim of this study was to investigate whether or not acetaminophen could reduce pain score equally to morphine and to observe pain score in longer duration (60 minute) after drug administration.This single-center prospective randomized double-blind clinical trial was performed in emergency department of our hospital with an annual census of approximately 100000 visits per year, October 2012–January 2013. Patients, aged 18–55 years, diagnosed with acute renal colic based on their chief complaint, history, and physical examination, and, or past medical history of renal stone, were enrolled in the study. In all participants, kidney or urinary tract stones were confirmed by ultrasound or CT scan.Exclusion criteria were allergy to morphine or acetaminophen, hemodynamic instability, fever greater than 38°C, evidence of peritoneal inflammation, pregnancy or suspected pregnancy, proven or suspected aortic aneurysm or dissection, use of any analgesic drug up to 6 hours before evaluation, heart failure, renal failure, respiratory failure, liver failure, kidney transplant patients, and opioid addiction.Eligible patients were randomized to receive acetaminophen or morphine in a 1 : 1 ratio using a computer-generated code. The identities of the study drugs were recorded in a document, folded four times, and then covered for allocation concealment. When a patient was enrolled in the trial, a study nurse retrieved one of the drugs from a box. The medication was prepared by the study nurse and administered by the second nurse who was blinded to the purpose of the intervention. The study drugs were identical in color and appearance; therefore, the patients and study physicians were blinded to identity.First, using 10 centimeter visual analog scale (VAS), all participants were assessed for severity of pain (10 = the worst possible level of pain and 1 = painless). Then, in the acetaminophen group, patients received intravenous acetaminophen  with a dose of 1 gram in 100 mL normal saline. In the morphine group, 0.1 mg/kg morphine in 100 mL normal saline was infused. Both drugs were infused during 5–10 minutes.μgr/kg intravenous fentanyl was administered to the patient as rescue therapy. After 60 minutes, patients with pain severity of two units or less were discharged from emergency department. If any degree of pain persisted after min 60, a second 1 μgr/kg dose of fentanyl was administered.All participants in both groups were assessed for severity of pain according to VAS standards 15, 30, 45, and 60 minutes after drug administration, and differences in pain level of 2 or more VAS units were considered significant. After 30 minutes, if severity of pain was equal to or more than 5 VAS units, 1 This study was approved by the ethics committee of our university and was registered in the Iranian Registration of Clinical Trials. Besides, Institutional Review Board approval was obtained before starting the trial. A written consent was obtained from all participants. The study was in accordance with Helsinki Declaration 1975.α = 0.05, β = 0.2, power = 80%, and the final differences between the two groups at least 2 scores on VAS, the sample size was calculated to be at least 20 in each group. Continuous variables were summarized as mean ± SD and categorical variables as ratios. Two-tailed independent t-test was carried out to compare quantitative variables with normal distribution and Chi-squared was done for comparing qualitative ones. A repeated measure analysis was used to compare the differences between the two treatments across the time.To consider Initially, 154 potential study candidates were enrolled; however, 44 subjects did not meet the inclusion and exclusion criteria. Eventually, 110 patients were allocated randomly between the two groups and data from these participants were analyzed .There were no significant differences between subjects of the two groups with regard to age, sex, and baseline VAS .P = 0.0001) (The mean ± SD scores of two groups of patients are shown in  0.0001) .P = 0.0001). There was a significant difference between two groups in terms of rescue treatment by fentanyl in min 30 (VAS ≥ 5), 31% versus 55% in the acetaminophen group and the morphine group, respectively (P = 0.01). Besides, higher percentages of patients were discharged in min 60 (VAS ≤ 2) in the acetaminophen group (90.7%) than in the morphine group (72.2%) (P = 024). Moreover, there were no adverse effects in the acetaminophen group apart from restlessness in 3 patients which was eliminated by slowing infusion rate, while 8 patients in the morphine group had nausea and 6 had vomiting.The VAS reduction at endpoint (30 min after drug administration) was significantly higher in the acetaminophen group than in the morphine group . Besides, in the case of adverse events, two groups showed no significant difference (P = 0.14). The study also showed that intravenous paracetamol had a more pronounced effect than morphine at min 15 [In 2009, in a randomized, double-blind, placebo-controlled clinical trial by Bektas et al., the efficacy of acetaminophen, morphine, and placebo was compared in 146 patients with acute renal colic, and it was concluded that intravenous paracetamol is an effective and safe drug for pain control in acute renal colic patients in emergency departments and is comparable with morphine. The mean reduction of VAS pain intensity score was 43 mm in the paracetamol and 40 mm in the morphine group  in patients with VAS ≥ 5 at min 30. Hence, although pain scores in min 45 and 60 were recorded, the results were confounded by the effect of fentanyl. This could be considered as our study limitation. Another limitation of our study was administrating the acetaminophen during 5–10 minutes, while the recommended method is infusing in 15 minutes. This could be considered as the potential cause of restlessness in acetaminophen group patients.Given the above results, in cases of acute renal colic, intravenous acetaminophen could be considered to be a suitable alternative to other available drugs or as a complement to them, in order to reduce their dosage, leading to less potential side effects, and lower costs. The use of intravenous acetaminophen in management of pain induced by other diseases should also be investigated, in order to extend its uses.


The intensity and quality of pain and anxiety were evaluated using the visual analogue scale, short form and modified-McGill pain questionnaire (SFM-MPQ) and the Spielberger situational anxiety level inventory (STAII) scale, respectively. Patients in all treatment groups had significantly lower pain intensity and anxiety compared with the control group immediately, 5, 10 and 15 min after CTR. There was no statistically significant difference in the SFM-MPQ total scores between the intervention groups. With respect to anxiety score, there was a significantly reduced anxiety level immediately after CTR in the aromatherapy and cold-aromatherapy combination groups versus the cold application group. The present results suggested the efficacy of cold application and aromatherapy with lavender oil in reducing pain and anxiety associated with post-CABG CTR.Post-surgical chest tube removal (CTR) is associated with a significant pain and discomfort for patients. Current treatment strategies for reducing CTR-associated pain and anxiety are limited and partially efficacious. To determine the effects of cold application, inhalation of lavender essential oil, and their combination on pain and anxiety during CTR was investigated. This randomized controlled open-label trial was conducted with 80 patients in the cardiac surgery intensive care unit who had a chest tube for duration of at least 24 hours after coronary artery bypass grafting (CABG). Patients were randomized ( Abbreviations: BMI: Body mass index; CABG: Coronary artery bypass grafting; CTR: Chest tube removal; GC: Gas chromatography; ICU: Intensive care unit; MS: Mass spectrometry; RI: Retention index; SFM-MPQ: Short form and modified-McGill pain questionnaire; STAII: Spielberger situational anxiety level inventory; VAS: Visual analogue scaleInsertion of chest tube following coronary artery bypass grafting (CABG) is a frequent practice aimed at maintaining hemodynamic stability and cardiopulmonary function. Chest tube facilitates drainage of the air, blood and other fluids from the pleural, pericardial or mediastinal cavity and prevents pleural effusion, pneumothorax and hemothorax. Chest tubes are typically removed 24-48 hours after surgery, or when the excess air, blood, or fluid has been properly drained. The tube adheres to the surrounding tissues, and its removal and separation of adjoined tissues is painful for the patient .Cold applications are commonly used as a non-pharmacological method for pain relief. Cold slows down tissue metabolism and nerve conduction velocity locally and also has vasoconstrictive, anti-inflammatory, anti-spasmodic and analgesic effects. The analgesic effects of cold treatment can also be explained by the Melzack and Wall's gate control theory. According to this theory, the stimulus caused by CTR activates fibers within the parietal pleura, chest muscles, and chest tube insertion site. It is believed that activation of these pain transmitting fibers results in a release of various excitatory neurotransmitters. Application of cold may lead to a reduction or reversal of the pain impulse via activating descending inhibitory neurons that block ascending nociceptive nerves originating from the substantia gelatinosa. Reduction of anxiety is another mechanism that can lead to a decreased perception of pain , is a commonly used agent in aromatherapy . Lavendal., 2012; Morris,al., 2012; Sasanneal., 2012; Bagherial., 2012). The anal., 2012; Sasanneal., 2012). It hasal., 2012; Olapoural., 2012; Bagherial., 2012). These al., 2012; Babashaal., 2012).Owing to the contradictory results on the efficacy of conventional pharmacological methods in relieving CTR-associated pain and discomfort, the present research was conducted to examine the effects of cold application, aromatherapy with lavender oil, and combination of both of these methods on the severity of pain and anxiety during CTR. 2 (2 ml/ min); and detector temperature 280 °C.Lavender oil was provided by the Giah Essence Pharmaceutical Company (Gorgan-Iran). The plant material was collected by Dr. H. Soleimani from the Tooskestan region  located at the Southeast Gorgan, Golestan province, Iran. The plant was identified by Mrs. Souzani and a voucher sample (no. 13144) was identified and deposited in the herbarium of the School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Chemical composition of the essential oil was analyzed using Gas Chromatography (GC) and GC-Mass Spectrometry (GC-MS) methods. GC analysis was performed using a Varian CP-3800 apparatus equipped with a FID detector and fused silica column . The operating conditions were oven temperature 50 °C (5 min), 50 °C-250 °C (3 °C /min), 250 °C (10 min); injector temperature 260 °C; split ratio 1:5; carrier gas NGC-MS analyses were performed using an Agilent 5975 apparatus with a HP-5ms column  interfaced with a quadruple mass detector and a computer equipped with Wiley 7n.l library. The operating conditions were oven temperature 50 C (5 min), 50 C-250 C (3 C/min), 250 C (10 min); injector temperature 250 °C; injection volume 0.1 µL; split ration, 1:50; carrier gas Helium at 1.1 mL/min; ionization potential 70 eV; ionization current 150 µA; ion source temperature 250 °C; and mass range 35-465 mui  and the oil on a CP-Sil 8CB column. Identification of individual compounds was made by comparison of their mass spectra and retention indices (RI) with those of authentic samples and those reported in the literature . Quanti2, full consciousness, ability to report pain, experiencing cardiac surgery and CTR for the first time, and having normal vital signs. Exclusion criteria were receiving mechanical ventilation support, continuous infusion of sedatives and analgesics or opioid analgesics during less than 4 hours before intervention, presence of psychiatric disease or any disease that could affect the research question , difficulty in breathing, nausea, vomiting, history of hypersensitivity or dissatisfaction during aromatherapy or cold application, and history of drug addiction or smoking. Eighty ICU-hospitalized patients who had a chest tube for at least 24 hours after cardiothoracic surgery were included in this study. Other inclusion criteria were age > 18 yrs, body mass index (BMI) < 30 kg/ mThis study was a randomized comparative trial with a factorial design that was conducted between December 2014 and March 2015 in the cardiac surgery intensive care unit (ICU) of the Imam Reza Hospital, Mashhad, Iran. Approval for the study was obtained from the Ethics Committee of the Mashhad University of Medical Sciences . Written informed consent was obtained from each participant prior to the study commencement.Eligible subjects were randomized (using random number tables) in an open-label fashion (using a random number table) to one of the following four groups:Group I: applied cold with cooling gel pack .Group II: inhaled lavender essential oil .Group III: applied cold with cooling gel pack and inhaled lavender essential oil .Group IV: did not receive either cold application or lavender oil inhalation . Pain intensity was measured using a vertical visual analog scale (VAS) from 0 to 10 . Numerous studies have used this scale to measure pain severity in CABG patients  was used to evaluate pain quality during CTR. Reliability and validity of the MPQ was previously established by Melzack (1975). The vaOn the first postoperative morning, patients' readiness for CTR was determined by a physician according to the standard criteria. Patients were instructed by the researcher to use VAS, SFM-MPQ and STAII for rating pain intensity, quality and anxiety level. In addition, some information about cold application and inhalation of lavender essential oil was presented to the participants. At 6 am CTR day, an ICU nurse administered 1 gr acetaminophen intravenously to all study subjects. Cold packs were kept in freezer for at least 2 h and then were covered with gauze or special pocket (according to the manufacturer's leaflet) and applied to the area surrounding the chest tube until the skin temperature reached 13 °C.The researcher asked the patients to mark the pain intensity, quality and situational anxiety they felt with the chest tube in place. Pain intensity was measured 10 minutes before, and immediately, 5, 10, and 15 minutes after CTR. Pain quality and situational anxiety of the patients were measured 10 minutes before and immediately after CTR.All patients were reassured that analgesic drugs would be administered as needed. All chest tubes were removed by the same ICU nurse to ensure the reliability of the results. The procedures for the application of cold and aromatherapy are as follows.In the cold application group, cooling gel packs  were used to reduce the body temperature around the chest tube during undressing. The bandage was removed from the chest area and body temperature was measured and recorded by a non-contact infrared thermometer . Then, a single layer of sterile gauze pad was placed around the skin area of pericardial tube insertion  and cooling packs (14×18) were twisted in gauze and placed on top of it.Cold application was terminated when the skin temperature reached 13 °C. After removal of cooling packs, the nurse removed the pericardial tube within 1-2 minutes. The intensity and quality of pain experienced by the patient and the anxiety level were measured and recorded at the time points described above. In the aromatherapy group, 1-2 drops of aromatherapy blend containing lavender essential oil were poured on cotton and fixed at a 10 cm distance from the patients' nose. The patient was asked to breathe slowly for 20 minutes and then pain and anxiety were measured as described above.SPSS software version 11.5 was used to analyze the recoded data. Descriptive statistics were used to summarize demographic characteristics of the study participants. Normality of data were checked using Kolmogorov-Smirnov and Shapiro-Wilk tests. Baseline parameters of the study groups were compared using one-way ANOVA, Chi-square and Fisher's exact tests were used. To compare the efficacy measures among the study groups, one-way ANOVA, Kruskal-Wallis, and repeated measures ANOVA tests were used. Bivariate correlations between anxiety and pain scores before and immediately after CTR were performed using Pearson's correlation coefficient. In all analyses, a two-sided P value of <0.05 was considered as statistically significant.Ninety-three compounds were identified in the lavender oil, representing 99.0 % of the total oil composition Table 1. The maiThe mean age of participants was 54.3 ± 10.9 yrs. The study population consisted of 56.2 % men and 43.8 % women, and distribution of genders among the study groups was similar (P=0.77). All subjects had two chest tubes  after CABG.Mean tube remaining time was 45.9±1.3 hrs, and there was no significant difference among the study groups regarding this parameter (P=0.17). Likewise, the groups were comparable with respect to demographic characteristics including marital status (P=0.23), education (P=0.86), and residential status  (P=0.91), the worst pain experienced in the past (P=0.58) and its description (P=0.33). Baseline characteristics of the study groups are summarized in Table 2P=0.55). Repeated-measures analysis revealed a significant increase in pain severity immediately after CTR, followed by a continuous decreasing trend until the last assessed time point in all study groups (P<0.001). Post-hoc multiple comparisons revealed significantly reduced pain intensity in all intervention groups compared with the control group immediately after CTR, as well as at 5, 10 and 15 min post-CTR time points. However, there was no significant difference among cold application, aromatherapy and cold-aroma groups.The study flow diagram is show in Figure 1P<0.001 [cold and cold-aroma groups] and P=0.020 [aroma group]); however, there was no statistically significant difference between the interventions.The words selected by most of the subjects to describe the present pain endured during CTR were “discomforting” (reported by 37.5 %), “distressing” (22.5 %), and “horrible” (21.2 %). Also, the words selected by subjects to describe pain during CTR, according to the SF-MPQ sclae were “fearful” (70 %), “shooting” (51.2 %), “tender” (51.2 %), “sickening” (48.8 %), “hot or burning” (46.2 %) and “sharp” (30 %). The total SFM-MPQ score in cold, aroma, cold-aroma and control groups were 19.5±5.8, 21.9±7.2, 17.1±9.9 and 29.1±5.5, respectively. All interventions were associated with a reduced total SFM-MPQ score compared with the control group (P<0.001). Post-hoc multiple comparisons revealed a significant difference between the aroma group with cold (P<0.009) and control groups (P<0.007), and also between the cold-aroma group with cold (P<0.001) and control groups (P<0.001).Table 4Bivariate correlations using Pearson's correlation coefficients did not suggest any significant correlation between anxiety and pain scores either before or immediately after CTR. Likewise, there was no significant correlation between age, sleep duration, length of chest tube in the body, duration of chest tube presence in the body and fatigue score with either pain or anxiety score immediately after CTR.Findings of the present study showed that all three types of interventions  could reduce pain and anxiety associated with CTR. However, there was no significant difference among the applied interventions, and combination therapy did not further improve the analgesic and anti-anxiety effects of each intervention. Although numerous studies have shown the efficacy of non-pharmacological methods in reducing pain, to the best of authors' knowledge, this is the first study comparing the effects of cold application and lavender aromatherapy in reducing the pain associated with CTR. In order to eliminate the confounding effect of surgery type and chest tube type on the study outcomes, CTR-associated pain was assessed in subjects undergoing pericardial tube removal following CABG. L. angustifolia. The volatile oil of the herb had 19 compounds representing 90.4 % of the oil composition, and the main components were linalool (39.5 %), terpinen-4-ol (7.3 %) and linalyl acetate (32.4 %). Recently, Tayarani-Najaran et al.  studiedal. (2014) identifIn previous studies, lavender oil was shown to be useful in reducing the pain associated with migraine, cesarean section, and needle insertion into a fistula in hemodialysis patients . In thiThe MPQ words selected most frequently by subjects in this study were “fearful”, “shooting”, “tender”, “terrible” and “stinging”. In earlier studies on CTR, the frequency of selection of “terrible” from the MPQ varied considerably. Sauls (2002) found tIn the literature, there has been only a few studies related to anxiety associated with CTR. Mimnaugh et al. (1999) also reAs a limitation, this study was performed on a relatively small number of subjects and was limited to patients who underwent CABG surgery. Whilst this inclusion criteria increase the homogeneity of the study population, it will make generalizability of findings difficult. Moreover, the subjective nature of efficacy measures might have introduced bias into the results, though the effect of such a potential bias could be minimized by the randomized design of the study. Finally, this study was performed in an open-label fashion because the nature of interventions made it impossible to design appropriate placebo.In conclusion, the findings of the present randomized controlled trial suggested that cold application, aromatherapy, and cold application in combination with lavender oil inhalation could be used as non-pharmacologic interventions to relieve pain associated with CTR. Given the simplicity and inexpensive nature of such approaches, their application in clinical practice could be suggested to the nursing staff. However, before routine application, confirmation of the present findings in larger scale trials, and in CTR-associated pain of non-CABG subjects is recommended. This study was financially supported by the Research Council at the Mashhad University of Medical Sciences, Mashhad, Iran.The authors have no competing interests to disclose.


Low back disorder is the most common problem in the entire spinal axis. About two-thirds of adults suffer from low back pain (LBP) at some time. Pain generators in the lumbar spine include the annulus of the disc, the posterior longitudinal ligament, a portion of the dural membrane, the facet joints, the spinal nerve roots and ganglia, and the associated paravertebral muscle fascia. There is no doubt that the facet joint is a potential source of chronic LBP. Facet joints are true synovial joints that have a joint space, hyaline cartilage surfaces, a synovial membrane, and a fibrous capsule. Two medial branches of the dorsal rami innervate the facet joints. If conservative measures fail in the treatment of facet joint pain, pulsed radiofrequency (PRF) of the medial branches can be administered.The aim of this observational study was to evaluate the efficacy of PRF in the treatment of lumbar chronic facet joint pain.In this prospective observational study, we selected 300 patients who suffered from lumbar facet joint pain, were referred to the Pain Therapy Department, and underwent PRF treatment of the lumbar medial branches. We analyzed patients with facet joint pain that was unresponsive to conventional treatment, with a positive response to diagnostic medial branch block, who underwent PRF of the lumbar area for 18 months at San Giovanni Hospital of Rome.Three hundred patients were eligible for the study. After 1 month, 62% of patients (186 patients) reported good pain relief ; 8.6% (26 patients) reported excellent pain relief (95% CI 0.07-0.09); 20. 4% (61 patients) reported poor pain relief (95% CI 0.18-0.22), and 9% (27 patients) reported no pain relief (95% CI 0.08-0.099). The average pain numeric rating scale (NRS) score before the procedure was 6 (range 4-9), decreasing to 2 after the procedure (range 0-4). SF-36 physical and mental parameters improved significantly after the treatment [≥ 1 standard deviation (SD)]. Results after 6 months were similar to those obtained after 1 month.This study suggests that PRF treatment of the lumbar medial branches provides good pain relief for at least 6 months in 70% of patients who suffer from lumbar facet joint pain. Low back disorder is the most common problem in the entire spinal axis. About two-thirds of adults suffer from low back pain (LBP) at some time . Pain geOsteoarthritis is a chronic, degenerative joint disease that primarily affects middle-aged and older adults . OsteoarIf conservative measures fail in the treatment of facet joint pain, pulsed radiofrequency (PRF) of the medial branches can be used . The mecPRF and continuous radio frequency (CRF) originate from the same underlying physical laws but differ in space, time, and strength of the resultant fields. PRF is characterized as having typically stronger E-fields than CRF and temperature spikes above the average thermal background that can reach 45-50°C. In a frequently adopted practice of holding the average T background at or somewhat below about 42°C, PRF also differs from CRF, in that the spatial extent of continuously elevated temperatures is much less than with CRF . Van ZunPRF is supposed to be less destructive and more reversible than CRF . FurtherCosman, Sluijter, and Rittman , 11 formHeat is the rapid thermodynamic spread of energy of all tissue excitations down to the molecular level, characterized by a global parameter T. Tissue disruption by high E-fields would be more specific than by heat. The E-field induces charges in tissue and produces forces on charged molecular structures, causing them to distort and dislocate. E-field gradients produce dielectrophoretic forces on charged objects, causing stress, distortion, and movement.Complete reduction can be reached if the nociceptive input is generated in a small, contained area, which occurs when pain radiates from facet joints.The aim of this observational study was to evaluate the efficacy of PRF in the treatment of lumbar chronic facet joint pain.Patients who underwent PRF of the lumbar area over 18 months at San Giovanni Hospital of Rome were analyzed. Patients with chronic LBP with sheer nociceptive characteristics and symptomatology that was related to facet joint syndrome and unresponsive to conventional treatment, such as medications and physical therapy, were included in the study. Patients with contraindications to the treatments, such as bleeding disorders, infectious diseases, and neurological impairments, were excluded. Patients were informed about the PRF, which provides relief of pain in many patients with chronic zygapophyseal joint arthropathy.All patients who entered the study had been extensively investigated  by the referring physician. They presented with a history of a minimum of 6 months of pain in the lumbar area. Three hundred patients met the inclusion criteria; all of them had been assessed by numeric rating scale (NRS) and SF-36 and reported a positive response to diagnostic block of medial branches .In each patient, we treated 3 medial branches that were related to the painful area. Treatment was performed on an outpatient basis. All procedures were performed by fluoroscopy, with the patient in the prone position, using AP, lateral, and oblique views. A 22-gauge needle, 100-mm RF electrode, and active 5-mm tip were used. The cannula tip was placed using the “tunnel vision,” per van Kleef et al. . Once thThree hundred patients entered the study. Median age was 68 range 45-86), and there were 142 males and 158 females. Pain relief was defined by patients at 1 and 6 months after the procedure. Sixty-two percent of patients (186) reported good pain relief ; 8.6% (26 patients) reported excellent pain relief (95% CI 0.07-0.09); 20.4% (61 patients) reported poor pain relief (95% CI 0.18-0.22); and 9% (27 patients) reported no pain relief (95% CI 0.08-0.099) . Median 5-86, andVarious studies have analyzed the efficacy of CRF treatment of the medial branch -20. ClinA retrospective study by Mikeladze et al.  of 114 pTekin et al.  performeThe use of PRF for the management of patients with zygoapophyseal joint pain was documented in 2 studies , 29. A tOur study was observational, enrolling 300 patients, which is adequte to analyze the efficacy and safety of a technique, such as PRF; however, the limitation of our study is that it was not a randomized controlled trial. There are ethical problems regarding the use of placebo in a controlled trial for patients who suffer from moderate to severe pain; moreover, more findings are needed to carry out a randomized controlled trial, as Gallagher  and othePRF is not a substitute for CRF under conditions for which thermal RF has an acknowledged and proven efficacy, but PRF is an attractive procedure on several accounts; in fact, PRF is supposed not to be neurolesive. This study suggests that PRF of the lumbar medial branch provides good pain relief 1 month after PRF in 70% of patients, whereas there was a recurrence of pain in 30% of patients. The results after 6 months were similar to those obtained after 1 month. In our experience, PRF is an effective and relatively safe technique, useful for treating facet joint pain that is refractory to conservative treatment. If the pain returns, PRF may be repeated safely. Further studies are needed to evaluate the parameters of PRF, especially temperature. Randomized controlled studies are recommended to compare CRF and PRF.