BackgroundProlonged lockdown in our country provided us with a unique opportunity to study the interplay of psychosocial impact on pain in surgically treated patients of chronic pancreatitis.MethodsForty-one patients who underwent surgery for chronic pancreatitis in the last 24 months were followed up, of which 27 were enrolled. The data were collected telephonically. Pain was assessed using the numeric pain rating (NPR) scale and depression using Patient Health Questionnaire (PHQ) 9. In patients having recent onset pain during the lockdown, oral tramadol 50 mg and amitryptiline 25 mg were prescribed and reassessed after two weeks.ResultsOf the 25 pain-free patients in February (pre-lockdown), 14 developed pain of varying intensity during the lockdown and were prescribed medications. Twelve out of 14 patients had very good resolution of pain after two weeks of medication.ConclusionsOperated patients with chronic pancreatitis who developed new-onset depression and pain responded well to low-dose anti-depressants in addition to analgesics. This study gives indirect, objective evidence that covert depression leading to pain in chronic pancreatitis is often downplayed and interpreted as poor results of surgery. The current coronavirus disease COVID-19) pandemic has influenced the natural course of various diseases unrelated to the coronavirus, with numerous factors affecting it. Several countries have implemented a lockdown of varying degrees, to decrease the spread of this deadly coronavirus. The prolonged lockdown in our country provided us with a unique opportunity to study the interplay of psychosocial impact on pain in surgically treated patients of chronic pancreatitis. Recurrent epigastric pain of varying intensity and frequency is the most common presentation of chronic pancreatitis and leads to poor quality of life (QOL) in these patients 9 pandemi. During We prospectively analyzed our retrospectively maintained database from April 2018 to March 2020 at the department of surgical gastroenterology, All India Institute of Medical Sciences, Patna. During this period, 88 patients with chronic pancreatitis were evaluated, out of which 41 patients underwent surgery  , in the first week of May (during the lockdown period), and then again after two weeks of medication while still being in lockdown. The pain was measured with 11 points numeric pain rating (NPR) scale. This NPR scale has been validated for various chronic pain syndromes . AssessmEthical clearance was obtained. We tried calling up all 31 patients under routine follow-up but were able to contact only 27 patients.Out of the 27 patients studied, two had pain in the month of February and before the lockdown occurred, but the intensity had increased in the month of May Figure .The rest of the 25 patients were pain-free in February Table .Out of the remaining 25 pain-free patients, 14 developed pain of varying intensity in the month of May. Even though the intensity of pain was variable, the nature of pain was similar in all 14 patients. We prescribed oral tramadol with amitriptyline in all 14 patients. Twelve out of 14 patients had very good resolution of pain after two weeks of medication. Three patients out of 27 had preoperative exocrine insufficiency and were on postoperative enzyme supplementation. None of the other 24 patients had any deterioration of exocrine insufficiency based on symptomatology. Getting data on endocrine insufficiency proved difficult, as most of them couldn't get their blood sugar examined due to the lockdown.Pain is the most common symptom for which patients seek treatment in chronic pancreatitis -2. A tonTraditionally, pancreatic ductal and parenchymal hypertension, as well as pancreatic morphological changes, were considered to be the therapeutic challenges that were dealt with by endoscopic and surgical intervention -13. But Of all the mechanisms, depression leading to pain in chronic pancreatitis has not been studied well -23. TherBased on telephonic conversations, covert depression of various magnitudes was present in all the patients. A noteworthy point in our study was that all the patients were surgically treated for the disease and were having good results. Still, more than 50% of our patient population, who was pain-free before lockdown, complained of typical pancreatic pain after six weeks of lockdown and got excellent results with antidepressants combined with a non-opioid analgesic.It may be inferred that chronic pain leads to poor quality of life in patients, which, in the long term, leads to depression. This depression further propagates the pain, making it a vicious cycle. The addition of low-dose antidepressants could have helped us to break this cycle giving excellent results. It is evident from this study that the correlation between depression and pain is not linear. This study gave us indirect evidence that the mental health of patients is one of the pain pathways of pain, which we end up neglecting the most. We need further research to study this complex interplay between psychosocial aspects and pain.The strength of our study was a very simple observational study design with an opportunity provided by circumstances. The drawback of this study is its small sample size and the indirect inference of the result. But this small study gives us an insight into a problem that deserves more attention from modern medicine.Despite all the currently available therapeutic interventions, the long-term results of pain-free good quality of life is still not possible in chronic pancreatitis. One of the possible causes that has not been given due attention is covert depression associated with chronic pancreatitis. The addition of low-dose anti-depressants may help break this vicious cycle of chronic pain, poor QOL, and depression and provide a good pain-free life.


Polycystic ovarian syndrome (PCOS) is one of the common endocrinopathy noted in women of childbearing age groups. Patients with PCOS have increased cardiovascular risk factors compared with age-matched control; hence, these patients are believed to be at an increased risk for cardiovascular events. Here, we report a case of a young female with PCOS, who presented with atypical back pain in the thoracic region. Initially, her electrocardiogram (EKG) and troponin were normal; hence, it was thought to be a muscle spasm but the back pain continued; repeat EKG and troponin came abnormal suggestive of myocardial infarction (MI). The patient underwent primary percutaneous coronary intervention and was discharged on dual antiplatelet therapy. MI is common in patients with PCOS. MI is the most important differential diagnosis in any patients of PCOS presenting with chest pain or back pain. Early diagnosis and prompt treatment of MI in patients with PCOS prevent adverse outcomes. Polycystic ovarian syndrome (PCOS) is one of the common endocrinopathy noted in women of childbearing age groups, with a prevalence ranging from 4% to 12% globally . HoweverA 36-year-old, Caucasian female, nonsmoker, with a past medical history of PCOS, anxiety, and depression came to the ED with a complaint of back pain in the thoracic region for 10 days. The pain started suddenly after she lifted a typewriter weighing 60 pounds. The pain was throbbing in nature, 5/10 in intensity, radiating to both arms, worsened with any movement, and lasted for several hours. She was taking over-the-counter tylenol with minimal improvement in the pain. She came to the ED as the pain persisted. On arrival, she rated her pain as severe. She was vitally stable and general physical exam was benign. Routine laboratory workup and troponin were within normal limits. She was suspected to have muscle spasm of the back and was treated with stat doses of ketorolac 30 mg intramuscularly, cyclobenzaprine 10 mg orally as well as a lidocaine transdermal patch. She reported improvement in her back pain and was discharged on cyclobenzaprine 10 mg orally three times a day for seven days. After reaching home she started having the back pain again without any improvement with muscle relaxant (cyclobenzaprine). She also reported having a new onset of nausea and one episode of vomiting. However, she did not have a fever, cough, hemoptysis, and shortness of breath. She came to the ED for further evaluation. On detailed discussion, she reported that her father and grandfather had MI in their fifties, and mother died at the age of 24 during childbirth due to unknown reasons.On physical examination, the patient appeared anxious. The temperature was 36.7°C , pulse 121 beats per minute , blood pressure 140/93 mmHg , respiratory rate 20 breaths per minute , and oxygen saturation 96%  while she was breathing ambient air. The body mass index (BMI) was 34.6 kg/m² . There was mild tenderness in the thoracic spine at the T1-T3 level. The remainder of the physical examination was unchanged. Differential diagnosis included musculoskeletal pain, infectious process , aortic dissection, pulmonary embolism, and MI.The details of lab work investigations are shown in Table Blood culture was negative for any growth. Urine drug screening for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, oxycodone, phencyclidine, and propoxyphene was negative.CT angiography of the chest, abdomen, and pelvis was negative for pulmonary embolism, aortic aneurysm or dissection, and contrast-enhanced CT scan of the thoracic spine was negative for epidural abscess, fracture, or malalignment. Electrocardiogram (EKG) was initially normal Figure .Repeat EKG the next day showed sinus tachycardia, and Q-wave in lead III, and V1-V3 Figure .Echocardiogram showed hypokinesis of the left ventricular mid to apical, anterior septum, apical cap, and inferior apical wall.A provisional diagnosis of acute MI was formulated based on ongoing chest pain, dynamic EKG changes, rising troponin I on serial monitoring, and echocardiographic findings. The patient was started on a heparin drip and was medically managed with aspirin 325 mg orally, metoprolol 25 mg orally, and sublingual nitroglycerin 0.4 mg. The patient was transferred immediately to the cardiac catheterization lab for left heart catheterization with angiography. Coronary angiography showed 99% ostial left anterior descending (LAD) artery stenosis, mild luminal irregularities in the left circumflex artery, and right coronary artery (RCA) dominance. There was no stenosis noted in the left main artery and RCA  was placed to the ostial LAD artery without any complications Figure . She was discharged on oral medicines  for secondary prevention. Dual antiplatelet therapy (aspirin and prasugrel) was continued for one year.Polycystic ovarian syndrome is one of the most common endocrine problems in women of childbearing group with a prevalence ranging from 4% to 12% globally . PCOS caMyocardial infarction is the leading cause of death in women worldwide . PostmenThe association of PCOS with metabolic syndrome  further increases the risk of CAD , 7, 9-10As PCOS is associated with a range of reproductive, obstetric, metabolic and psychosocial features, management should focus on multiple aspects like metabolic, reproductive, and psychosocial features , 8. The Polycystic ovarian syndrome is a common and increasingly challenging endocrine problem in women of childbearing age. Despite the association of PCOS with multiple comorbidities, this medical condition is not treated properly due to a lack of awareness and treatment guidelines. Patients with PCOS are found to be at increased risk for MI, stroke, and aortic dissection. The purpose of our case report is to raise awareness regarding the association of PCOS with MI, and our focus as a physician should provide emotional and psychosocial support to the patient. In conclusion, this case suggests an association of PCOS with MI. Further studies are needed to decrease the risk of cardiovascular disease in PCOS patients. Proper evidence-based guidelines are needed for appropriate prevention and management to reduce morbidity and mortality associated with it.


Background and purpose — Pain catastrophizing contributes to acute and long-term pain after total knee arthroplasty (TKA) but currently there are only limited treatment options. This study investigates the effectiveness of patient education in pain coping among patients with moderate to high pain catastrophizing score before TKA. Secondary outcomes were physical function, quality of life, self-efficacy, and pain catastrophizing.Patients and methods — The study was a parallel-group randomized controlled trial including patients with moderate to high levels of pain catastrophizing. 60 patients were recruited from December 2015 to June 2018. The mean age of the patients was 66 (47–82) years and 40 were women. The patients were randomized to either cognitive-behavioral therapy (CBT) based pain education or usual care. The primary outcome measure was pain under activity measured with the Visual Analog Scale (VAS). All outcomes were measured preoperatively, at 3 months, and at 1 year after surgery.Results — We found no difference in the primary outcome measure, VAS during activity, between the 2 groups but both groups had large reductions over time. The CBT-based pain education group reduced their VAS score by 37 mm (95% CI 27–46) and the control group by 40 mm (CI 31–49). We found no statistically significantly differences between the 2 groups in any of the secondary outcomes.Interpretation — Future research is warranted to identify predictors of persistent pain and interventions for the approximately 20% of patients with persisting pain after a TKA. Up to 20% of patients report persistent pain after a total knee arthroplasty (TKA) , proficiency in written and spoken Danish, and informed written consent.The patients were excluded if they had severe depression as diagnosed with the Major Depression Inventory (MDI) or were planning to have a contralateral knee arthroplasty within 1 year after the operation.The patients were included consecutively and randomized 1:1 to either the intervention group or usual care in 7 blocks of 8 persons. Because of high withdrawal rate, we decided to continue including patients and randomized another 16 patients. At the predefined deadline of June 1, 2018 we stopped the inclusion of patients. The physiotherapists and nurses who did the baseline and follow-up testing where blinded for the randomization. It was not possible to blind the patients and the 2 physiotherapists who delivered the patient education.Patients in the control group received usual care. Preoperatively this consisted of a multidisciplinary information meeting for patients and their relatives. Postoperative patients in the usual care group were offered a phone call after 1 week and 3 control visits at the hospital after 2, 4, and 12 weeks.In addition to usual care the intervention group participated in patient education based on CBT. The patient education consisted of 7 individual sessions of approximately 45 minutes, 3 sessions preoperatively and 4 sessions postoperatively. The 1st session was delivered approximately 2 weeks before the operation and the last session was given 3 months after the operation. The patient education was delivered by 2 physiotherapists who followed a manual describing in detail the content of each of the 7 sessions. This ensured that each session was standardized although there was room to discuss individual needs. The physiotherapists observed each other on a regular basis to make sure that they delivered the intervention in the same way. As far as possible the same physiotherapist followed the patient through all the sessions. The patient education covered 3 main components: (1) education in pain and the interaction between cognition and pain perception; (2) training in cognitive and behavioral pain coping skills; and (3) training in how to apply the learned coping skills in real-life situations. For details see the protocol : 0 indicating “no pain,” to 100 indicating “worst pain imaginable” on a mm scale. Pain during activity was measured right after the 6-minute walk test. Secondary outcomes included physical function, quality of life, physiological factors, and pain during rest. The Oxford Knee Score (OKS) was used to measure knee-related pain and physical function. Overall scores run from 0 to 48 with 48 being the best outcome , and data not normally distributed by median (range). In the analysis the intention-to-treat principle was used including all randomized participants. For all outcomes, between-group mean differences, changes over time, and 95% confidence intervals (CI) from baseline to 3 and 12 months were analyzed by a mixed-effects linear regression model with a random person level and systematic effects of time, group, and the interaction between time and group. In the analysis of change in the primary outcome from baseline to 12 months we included VAS during activity at baseline as a covariate. Model validation was performed by comparing observed and expected within-subject standard deviations and correlations and by inspecting QQ plots. We tried to include morphine intake as a covariate, but this did not change the results or conclusions.We filled missing values with mean values as described in the manuals if less than half of the answers were missing in the SF-36 (PF) and if 2 or fewer of the answers were missing in the OKS, the PSEQ, and the PCS. In each questionnaire missing values were filled with mean values between 0 and 5 times.The significance level was set at < 0.05. The statistical analyses were performed using STATA 15  software package.The study was conducted in accordance with the Declaration of Helsinki and the CONSORT statement, and registered in the Danish Data Protection Agency (j.nr. 1-16-02-245-15). All patients gave informed written consent. The protocol was approved by the Central Denmark Regions Committee on Biomedical Research Ethics  and registered at ClinicalTrials.gov (NCT02587429). The study was supported by the Tryg Foundation (grant number: 113944) and the Danish Rheumatism Association (grant number: A3622). None of the funders have any role in the study other than providing funding. The authors have no competing interests. Data is available from the corresponding author on reasonable request.From December 2015 to June 2018, 324 patients were considered for inclusion. 283 patients were screened and 105 of these had a PCS score > 22. We randomized 67 patients but shortly after the randomization 7 patients decided not to participate and 60 patients were measured at baseline and included in the analysis . Of the We found a mean difference of 3 (CI –6 to 11) mm in the primary outcome measure VAS during activity 12 months after TKA between the pain education group and the usual care group (p = 0.6). Mean VAS during activity 12 months postoperatively was 12 mm (CI 5–18) for the pain education group and 9 mm (CI 3–15) for the usual care group . Both grWe found no statistically significantly differences between the 2 groups in any of the secondary outcomes . In bothParticipation in patient education in addition to usual care for patients with a high pain catastrophizing score did not result in better outcomes 12 months after TKA. However, for both groups OKS and VAS during activity improved statistically significantly over time indicating that knee function improves and knee pain reduces after a TKA.Recent research on the effect of CBT on pain severity has shown mixed results and meta analyses show that the effect size on pain is small (Dixon et al. We found no additive effect of pain education based on CBT on pain, physical function, quality of life, self-efficacy, or pain catastrophizing. There may be several reasons for this. 1st, most of the former studies reporting an effect of a CBT intervention on these factors have included patients with knee OA and only a few studies have included patients scheduled for TKA. Cai et al.  found th2nd, based on existing research suggesting that pain catastrophizing is a predictor of persistent pain after a TKA, we decided to use PCS as a screening tool for inclusion of patients. However, recent research has suggested that patients with elevated scores on more than 1 risk factor are more likely to develop prolonged pain and disability, and that multiple psychological factors need to be considered with respect to pain and physical disability in knee OA (Sinikallio et al. We wanted to include the one-third of our TKA population with the highest PCS score. Based on data collected in our department in the years 2011–2013 we defined a cut-off for inclusion at PCS > 22 in this study (Birch et al. Our intervention consisted of only CBT-based pain education and consistent with the study of Riddle et al.  we foundFor the psychological outcomes we expected a larger reduction in PCS and an increase in PSEQ among the patients in the intervention group compared with the usual care group because these issues were emphasized in the pain education. However, this was not the case and both groups achieved similar improvements after 12 months. 3 months after the operation both groups have a PCS score far under 21 points, which is the cuff point for moderate PCS.There are some limitations too. 1st we had to change the number of sessions from 7 to 6 approximately 1 year after we started including patients. This means that not all patients have received the same number of sessions, but they all received the same content and we found no difference in the primary outcome between patients who received 7 sessions and patients who received 6 sessions. Furthermore, because we wanted to design a method of patient education that fits into a hospital setting, it consisted of only 7 sessions contrary to previous studies where the CBT intervention ranged from 10 to 12 sessions (Keefe et al. This study showed that pain education based on CBT was not superior to usual care after TKA in terms of reducing pain or improving physical function, quality of life, self-efficacy, and pain catastrophizing. Future research is warranted to identify predictors of persistent pain and interventions for the approximately 20% of patients with persisting pain after a TKA.The authors would like to thank all the participating patients, nurses, physiotherapists, and secretaries at the University Clinic for Hand, Hip, and Knee surgery and the Department of Physiotherapy and Occupational Therapy, Holstebro Regional Hospital, Hospital Unit West, Denmark.SB, MS, IM, and TBH participated in the conception and design of the study and helped to revise the manuscript. All authors read and approved the final manuscript.Acta thanks Johan Creutzfeldt and Kristian Kjaer Petersen for help with peer review of this study.


At present, information about clinical efficacy and adverse events of controlled release (CR) form of pelubiprofen, a prodrug of 2-arylopropionic acid with relatively selective effects on cyclooxygenase-2 activity, remains scarce. In this study, we sought to determine non-inferiority of pelubiprofen CR 90 mg/day compared to aceclofenac 200 mg/day regarding clinical efficacy and adverse events after a 4-week course of medication in the patients with symptomatic knee osteoarthritis.A total of 191 patients were randomly assigned to take either pelubiprofen CR 90 mg (n = 95) or aceclofenac 200 mg (n = 96). The primary outcome variable was non-inferiority of pain reduction between baseline and week 4 when assessed using a 100 mm pain visual analogue scale (VAS). Pelubiprofen was considered non-inferior to aceclofenac if the upper limit of the one-sided 97.5% confidence interval for the difference in terms of pain VAS was above 15 mm (the average change of pain VAS in the pelubiprofen group-pain VAS reduction in the aceclofenac group). Secondary outcome variables were the changes in 100 mm pain VAS at week 2 versus baseline, K-Western Ontario, and McMaster University Arthritis Index (K-WOMAC) changes at weeks 2 and 4 as compared to baseline, patient global assessment at weeks 2 and 4. The frequency and amount of rescue medicine usage at weeks 2 and 4 were also evaluated as the secondary outcome variable. For safety analysis, adverse events, clinical laboratory tests, vital signs, and physical examinations were assessed and conducted at each follow-up visit.At week 4, the pain VAS values were significantly reduced in both groups receiving either pelubiprofen CR 90 mg or aceclofenac 200 mg as compared to the baseline. However, the pelubiprofen group and the aceclofenac group respectively showed the pain VAS changes of -22 and -21.9 in the pre-protocol set and -20.8 and -21.7 in the full analysis set, confirming non-inferiority. The pelubiprofen CR 90 mg showed a reduced incidence of adverse events compared to the aceclofenac 200 mg (p = 0.005).Pelubiprofen CR 90 mg is as effective as aceclofenac 200 mg with reduced adverse events for the treatment of symptomatic knee osteoarthritis. Osteoarthritis (OA), one of the most common chronic diseases, causes symptoms such as pain and disability of joints in the elderly –3. PatiePelubiprofen, one of the 2-arylpropionic acid drugs, is structurally and pharmacologically related to ibuprofen . PreviouAmong commonly used NSAIDs, aceclofenac is a phenylacetic acid derivative which is structurally related to diclofenac that showed a higher therapeutic index than other NSAIDs with similar analgesic activity , 12. FurTherefore, in the present study, we sought to evaluate non-inferiority of pelubiprofen CR 90 mg compared to aceclofenac 200 mg regarding clinical efficacy and AEs after a 4-week course of medication in the patients with symptomatic knee OA.The patients visited from August 2015 to March 2016 and aged from 35 to 80 years old with symptomatic, primary knee OA were included in this prospective randomized controlled trial. Inclusion criteria were as follows: 1) diagnosis with knee OA according to the American College of Rheumatology (ACR) guidelines; 2) the Kellgren-Lawrens (K-L) grade I-III OA on knee radiographs; 3) stable knee pain for at least 3 months; 4) pain on a visual analogue scale (VAS) score of ≥ 40 mm after the NSAIDs/analgesic washout. This study included both femorotibial knee OA and patellofemoral knee OA patients. K-L grading was performed on the worse grading of the two compartments. Prospective participants were excluded if they had secondary OA, inflammatory arthritis such as RA, a history of surgery  and/or trauma in the knee joint within the previous 12 months, as well as had conditions that could confound the assessment of efficacy of the tested drug, such as tendinitis, bursitis, and fibromyalgia of the lower extremities. Furthermore, the patients with the following conditions were also excluded: a history of opioid use for over 3 months, intra-articular corticosteroid injection or systemic corticosteroid use (> 1500 μg) within the previous 3 months, intra-articular hyaluronic acid injection within previous 2 months, gastric ulcer or gastritis confirmed using endoscopy, genetic galactose intolerance, lactase deficiency or glucose-galactose uptake, contraindication for use of NSAID , need of pain treatment regarding pre- or post-coronary artery bypass graft (CABG), active malignancy, ulcerative colitis, Crohn’s disease, active renal and/or liver diseases, significant hematologic, cardiac, pulmonary diseases, uncontrolled hypertension (systolic pressure ≥ 160 mmHg and/or diastolic pressure ≥ 100 mmHg), and substance dependence . Women of childbearing age who did not agree to use an effective method of birth control, had positive serum pregnancy results, and were lactating were also excluded. All participants signed written consent forms before participating in this clinical study.Power analysis of the designed trial showed that a sample size of 85 patients per group would be needed. To calculate sample size required to evaluate non-inferiority between pelubiprofen CR 90 mg and aceclofenac 200 mg for clinical efficacy, the following conditions were used: statistical power, 1-ß = 0.975; level of significance, a one-sided α = 0.025. We set the non-inferiority margin of the difference between pelubiprofen CR 90 mg and aceclofenac 200 mg to 15 mm of the VAS score ranging from 0 to 100 mm . The samIn a previous study that compared aceclofenac and paracetamol in the management of symptomatic OA of the knee, the range of changes in 100 mm pain VAS score in the aceclofenac group was -18.34 ± 24.86 mm . TherefoThe study was performed in the patients with knee osteoarthritis for 7 months as a multi-center, randomized, double-blinded, parallel-group, phase IV, and non-inferiority study. Researchers from 10 centers participated in this study from August 2015 to March 2016. All study protocols were approved by the institutional review boards of each hospital (DW_PlbCR_401) . This trial was registered with clinicalTrial.gov (NCT02682524). The patients were randomly assigned to one of the two study groups (pelubiprofen CR 90 mg or aceclofenac 200 mg) at the ratio of 1:1. Before the clinical trial, the randomization table  starting from subject number 1) was generated by a statistician. The patients in the pelubiprofen group received pelubiprofen 90 mg  for 4 weeks with an aceclofenac placebo tablet in the morning and evening. The patients in the aceclofenac group received 200 mg of aceclofenac  for 4 weeks with a pelubiprofen placebo tablet in the morning and evening. Acetaminophen was used as the rescue medicine, and the patients were allowed to take one Tylenol ER sustained release tablet (acetaminophen 650 mg) as needed (but up to 3 tablets per day).Fourteen days prior to the randomized assignment, the patients who had previously received NSAIDs, osteoarthritis nutrition, physiotherapy, and oriental medicine remedies had a drug wash-out period, which involved discontinuation of the administration and application of those drugs and therapies. The investigators maintained the double blind and performed the examination; the release of the double blind was considered on a case-by-case basis only in the event of a serious medical emergency, and the double blind was released when the information on the administration group affected the treatment of the patients.After the random assignment, follow-up visits were conducted on the days of baseline (week 0), and at weeks 2 and 4 after the drug administration. At the screening visit, we checked vital signs/weight and performed physical examinations, laboratory tests , creatinine, uric acid, total bilirubin, albumin, prothrombin time (PT), activated partial thromboplastin time (aPTT), urine human chorionic gonadotropin (hCG), urine protein, urine glucose), electrocardiogram (ECG), conventional radiographs and measured 100 mm pain VAS. At the baseline visit, we checked vital signs, performed weight measurements and physical examinations, and measured 100 mm pain VAS and K-WOMAC . During The data obtained from the subjects of the clinical trial were analyzed in three forms: safety set, full analysis (FA) set, and per protocol (PP) set. The safety set included all data from the patients who received at least one drug for the clinical trial. The FA set included all patients for whom the data on primary efficacy evaluation parameters were obtained after the administration of the drugs for the clinical trial among the participants who received the drugs for the clinical trial at least once. The PP set included data from the patients who had completed the drug administration in accordance with the protocol among the participants included in the FA set.All the statistical significance tests were carried out by the two-sided test at a significance level (α) of 5%, and non-inferiority was tested using confidence interval. In the analysis of the demographic data and baseline characteristics data, continuous data were analyzed by independent t–test, while categorical data were analyzed by Chi-square test or Fisher's exact test. We assumed that pelubiprofen met the non-inferiority criterion if the upper limit of the one-sided 97.5% confidence interval for the difference in terms of pain VAS was below 15 mm (average changes of pain VAS in the pelubiprofen group-pain VAS reduction in the aceclofenac group). Additionally, a sensitivity analysis was performed using ANCOVA with factors of treatment group, site as a covariate for evaluating the treatment by center interaction. The differences in the K-WOMAC scale changes between clinical visits were determined using paired t-test. The results of global patient assessment were analyzed using Chi-square test or Fisher's exact test. For the use frequency of the rescue medicine, Chi-square test or Fisher's exact test and independent t-test were used for analysis. For safety confirmation, Chi-square test or Fisher's exact test was used to analyze the difference of the rate of adverse events. Laboratory tests, vital signs, and physical examination results were analyzed using paired t-test or Wilcoxon signed rank test.A total of 191 patients who received the study medication at least once were randomized in the 10 centers . Among tThe study population was predominantly female (73.3% {140 of 191 patients}) with the mean age of 62.1 years . Mean duration of knee OA was 3.2 years. The baseline characteristics were well balanced between the groups for the patients’ age, gender, laterality, K-L grade. The most common comorbidities were hypertension in both groups .In the PP population, the 100 mm pain VAS score of the pelubiprofen group was 57.9 mm at week 0 and 35.9 mm at week 4. The mean change in pain VAS scores was −22.0 mm between weeks 0 and 4. In the aceclofenac group, 100 mm pain VAS score was 56.3 mm at week 0 and 34.4 mm at week 4. The mean change in pain VAS score was −21.9 mm between weeks 0 and 4 , Table 2p = 0.410 and FA population, p = 0.253, respectively), and the one-sided 95% confidence interval  of the change difference met the criteria for non-inferiority. In the change of K-WOMAC scores, no difference in any part and within any study period was observed in both PP and FA sets . Among the drug-related AEs, the pelubiprofen group showed a significantly lower rate of GI AEs than that in the aceclofenac group  (Forty-nine cases of AEs were reported from 35 patients (18.3%). Eleven AEs were reported from 10 patients (10.6%) in the pelubiprofen group, and 38 AEs were reported from 25 patients (26.9%) of the aceclofenac group. Among the 26 drug-related AEs, GI problems were the most frequent . The pelubiprofen group had a significantly reduced rate of drug-related AEs compared to the aceclofenac group (= 0.048) .NSAIDs are the most commonly used medications for pain reduction and function improvement in the patients with symptomatic knee OA. Both safety and efficacy of NSAIDs are essential, as most patients with knee OA use the NSAIDs in the long term. In the present study, we sought to evaluate non-inferiority of short-term use of pelubiprofen CR to aceclofenac regarding clinical efficacy and rate of AEs in the highly selected sample of patients with symptomatic knee OA. The principal findings of this study were that non-inferiority of the pelubiprofen CR to aceclofenac was confirmed in terms of 100 mm pain VAS, K-WOMAC, and global patient assessment after a 4-week course of medication with a reduced rate of drug-related AEs.The efficacy of traditional pelubiprofen 90 mg has been reported to be non-inferior to other control NSAIDs. Shin et al. compared traditional pelubiprofen 90 mg (30 mg three times daily) to aceclofenac 200 mg (100 mg twice daily) in the patients with lower back pain . The autp = 0.09). These findings suggest that further research is needed to confirm the GI safety of the pelubiprofen to treat OA. On the other hand, the CR form of a drug may reduce local gastrointestinal irritation caused by rapid localized dissolution of the traditional form of the drug. However, in a previous study that compared aceclofenac controlled release (CR) (200 mg once daily) to a traditional twice daily aceclofenac dose (100 mg twice daily), the patients with aceclofenac CR showed a higher rate of heartburn (10 of 45 vs. 3 of 45) even when there was no difference in terms of overall GI complications between the two groups [However, despite confirming the reduced GI AEs rate of pelubiprofen CR as compared to aceclofenac in the present study, the rate of GI AEs in pelubiprofen remains a controversial issue. In a previous study in the patients with low back pain, the rate of heartburn and abdominal discomfort were similar between the pelubiprofen and aceclofenac groups . Howevero groups . The auto groups . In conto groups , the CR o groups . Therefoo groups  In the sThe present study has several limitations. First, as we mentioned above, most patients with symptomatic knee OA use NSAIDs in the long term. However, in the present study, the drugs were prescribed only for 4 weeks. In general, NSAIDs are often taken for a long time in patients with arthritis, so a long period of study is needed. Therefore, in further research, it is necessary to evaluate the efficacy and safety of the pelubiprofen CR in the long-term period. Second, in our study, the patients with a higher risk of cardiovascular AEs were excluded. Therefore, we did not determine the safety of the pelubiprofen CR in the patients with increased cardiovascular risk. So studies on the cardiovascular risk of pelubiprofen and its use in patients with high cardiovascular risk are needed. Furthermore, since this study excluded patients with cardiovascular disease as well as many other serious diseases, there is a limitation that this study was conducted only for otherwise healthy patients. So patients with severe disease, as well as cardiovascular disease, included in the exclusion criteria of this study will need further long term studies, too. Third, the criterion for non-inferiority was rather large. However, the mean difference of 100 mm pain VAS between the pelubiprofen group and the aceclofenac group in the PP set analysis was only 0.02 . Therefore, the same outcome could have been achieved in terms of 100 mm pain VAS, although a stricter criterion was used.In conclusion, the results of this clinical trial demonstrated that, in the patients with symptomatic knee OA, pelubiprofen CR 90 mg tablet was not inferior to aceclofenac 200 mg in terms of efficacy and number of adverse events.S1 Protocol(PDF)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.S1 Data(XLS)Click here for additional data file.


The dorsolateral prefrontal cortex (dlPFC) is functionally linked to the descending pain modulation system and has been implicated in top down pain inhibition, including placebo analgesia. Therefore, functions of the dlPFC may be impaired in patients with chronic pain. Postherpetic neuralgia (PHN) is one of several syndromes with chronic neuropathic pain. In the present study, we investigated possible dysfunction of the dlPFC in chronic pain using patients with PHN. In a conditioning phase, heathy controls (n = 15) and patients with PHN (n = 7) were exposed to low (LF) and high (HF) frequency tones associated with noxious stimuli: weak (WS) and strong (SS) electrical stimulation, respectively. After the conditioning, cerebral hemodynamic activity was recorded from the bilateral dlPFC while the subjects were subjected to the cue tone-noxious electrical stimulation paradigm, in which incorrectly cued noxious stimuli were sometimes delivered to induce placebo and nocebo effects. The results indicated that hemodynamic responses to the LF tone in the right dlPFC was significantly lower in patients with PHN compared to the healthy controls. Furthermore, the same hemodynamic responses in the right dlPFC were correlated with placebo effects. In addition, clinical symptoms of PHN were negatively correlated to cerebral hemodynamic responses in the right dlPFC and magnitudes of the placebo effects. The results suggest that the right dlPFC, which is closely associated with the descending pain modulation system, is disturbed in PHN. ChronicThe dorsolateral prefrontal cortex (dlPFC) has been implicated in pain inhibition through effects on the descending pain modulation system . ActivitIn patients with chronic pain, it has been proposed that differential associative learning of conditioned stimuli (CSs) is impaired when CSs are differentially associated with strong/weak and noxious/non-noxious events . These sAccumulating evidence suggests that the dlPFC is morphologically and functionally altered in patients with chronic pain  diagnosed according to the diagnostic criteria proposed by the international association for the study of pain (IASP) were recruited from Department of Anesthesiology at the Toyama University Hospital. There were 4 male patients, 3 female patients, and the mean age of the patients was 67.29 ± 2.62 years (mean ± standard error [SE]). The inclusion criteria for the patients with PHN were: (1) patients who received appropriate antiviral treatment; (2) persistent pain lasting longer than three months after the onset of herpes zoster infection; (3) over fifty years of age. The exclusion criteria for the patients with PHN were: (1) patients had psychiatric disorders; (2) patients had neurological disorder(s) apart from PHN. Fifteen age- and sex-matched healthy controls (HC) who had no neurological or psychiatric disorders  participated in the present study. All participants were right-handed and had no cognitive impairment assessed by the Japanese version of Mini-Mental State Examination (J-MMSE) . This st2.2First, current intensity of electrical cutaneous stimulation (painful stimuli) was determined. A conditioning session was then conducted, where subjects learned the association between two different cue tones and two different intensities of electrical stimulation in a cue tone-shock associative task. Finally, a recording session was conducted to measure the cerebral hemodynamic activity in the PFC during the cue tone-shock association task. The same pairs of cue tones and electrical stimulations as previously used in the conditioning session were presented in 75% of trials. Different combinations of the cue tones and electrical stimulations were presented (mismatch condition) in the remaining 25% of trials.To determine current intensity of electrical stimulation, electrodes were placed on the subject’s back of the left hand, which was not affected by PHN. Electrical stimulation was delivered by 5 Hz sine-wave electrical stimulator . While current intensity was slowly increased, the subjects were instructed to say “yes” when they felt maximum tolerable pain on a scale of 0–100 [from 0 (no pain) to 100 (maximum tolerable pain)]. Two intensities of electrical stimulation were determined based on the individual’s maximum tolerable pain threshold: 50% of the current intensity of the maximum tolerable pain  and 90 % of the current intensity of the maximum tolerable pain . After determination of the stimulus intensity, the subjects received each stimulus at each stimulus intensity before the experiment, and confirmed that both of the stimuli were noxious.During the conditioning session, the subjects completed 20 trials to associate cue tones and the corresponding electrical stimulation. Each trial consisted of the presentation of a cue tone (5 s), electrical stimulation (5 s), and rest (10 s). Low-frequency  and high-frequency  cue tones were associated with WS and SS, respectively; 10 trials of LF cues-WS and another 10 trials of HF cue tones-SS were randomly presented. At the end of each electrical stimulation, subjects were asked to rate subjective pain intensity using a visual analog scale (VAS) [from 0 (no pain) to 100 (maximum tolerable pain)].During the recording session, cerebral hemodynamic activity was measured by NIRS. Each trial consisted of the presentation of a cue tone (5 s), a delay period before electrical stimulation (5 s), electrical stimulation (5 s), and rest (20–30 s). To prevent prediction of cue onset by the subjects, the resting time was pseudorandomly set . A total of 32 trials were performed. These 32 trials were divided into four conditions, including mismatch conditions: LF-WS condition , in which the LF cue tone was associated with WS (correctly cued stimulation); HF-SS condition , in which the HF cue tone was associated with SS (correctly cued stimulation); LF-SS condition , in which the LF cue tone was associated with SS (incorrectly cued stimulation); HF-WS condition , in which the HF cue tone was associated with WS (incorrectly cued stimulation). Thus, the ratio of mismatched cued stimuli vs. matched cued stimuli was 1:3. The matched and mismatched cued stimuli were pseudo-randomly presented. At the end of each electrical stimulation, subjects were asked to rate subjective pain intensity using the visual analog scale.2.3t-test.VAS pain in response to each electrical stimulation (WS or SS) were analyzed using repeated measures two-way analysis of variance (ANOVA) with the cue tone and subject group as factors. To assess placebo effects, VAS pain differences between the LF-SS and HF-SS conditions were computed for each participant, i.e., [(LF-SS) – (HF-SS)]. The placebo data in patients with PHN and HC were compared using the Mann-Whitney U test. To assess nocebo effects, VAS pain differences between the LF-WS and HF-WS conditions were computed in each subject, i.e., [(HF-WS) – (LF-WS)]. The nocebo data in patients with PHN and HC were compared using the Student's 2.4Cerebral hemodynamic activity was measured by two NIRS systems . The NIRS head cap was placed on the heads of the subjects. The 28 source probes and 32 detector probes were placed on the head cap. The 27 detector probes were placed 3 cm away from the source probes, while 5 detector probes were placed 1.5 cm away from the source probes A. The mo2.5As NIRS signals include both cerebral and extra-cerebral hemodynamic components, we applied a multi-distance probe arrangement method to remove the extra-cerebral components from NIRS signals . When thSince Oxy-Hb best reflects brain activity , Oxy-Hb http://www.MRIcro.com) in each subject  in the dlPFC to LF cue tones were analyzed using repeated measures two-way analysis of variance (ANOVA) with ROI and subject group as factors. When HF cue tones were presented, the data did not show normal distribution (see below), and hemodynamic responses to HF cue tone were compared between HC and patients with PHN using the Kruskal-Wallis test.2.6Correlations among NIRS responses in the dlPFC, clinical symptoms , and psychological data (placebo and nocebo effects) were analyzed using simple regression analysis. In these analyses, NRS = 0 was used for the clinical symptoms in the HC subjects.2.7t-test or the Mann-Whitney U test. The chi-square test was used to compare gender between patients with PHN and HC. All statistical analysis was performed using SPSS . The statistical significance level was set at P < 0.05.All of the data are presented as mean ± standard error. All data were tested for normal distribution using the Kolmogorov-Smirnov test. Homogeneity of variance for repeated measures two-way ANOVA was evaluated using Mauchly’s test of sphericity. The baseline characteristics of the subjects  were compared between patients with PHN and HC using the independent Student’s 33.1t-test and χ2 test, P > 0.05).3.2t-test, P < 0.01)  ( < 0.01) B. When W < 0.01) C, repeat < 0.01) D.Fig. 2S3.3We also analyzed mean effect sizes of Deoxy-Hb responses in the dlPFC during each condition of the task. However, no significant differences were observed between the two groups. Data from one sample in HC were removed as outliers based on Kolmogorov-Smirnov test, and the remaining data of Deoxy-Hb were analyzed by repeated measures two-way ANOVA (ROI x subject group). When the LF cue tone was presented, the results indicated no significant interaction between ROI and subject group . There were no significant main effects of ROI  and subject group . When the HF cue tone was presented, the results revealed no significant interaction between ROI and subject group . There were no significant main effects of ROI  or subject group .3.42 = 0.313, F  = 9.12, P < 0.01], where larger pain reduction by placebo effects was associated with larger hemodynamic responses in the r-dlPFC. However, there was no significant correlation between placebo effects and hemodynamic responses to LF cue tone in the l-dlPFC . Furthermore, there were no significant correlations between nocebo effects (VAS pain difference between the LF-WS and HF-WS conditions) and hemodynamic responses to HF cue tone in the r-dlPFC , nor in the l-dlPFC .2 = 0.285, F  = 7.96, P < 0.05]. Spearman nonparametric correlation test also revealed that there was a significant and negative correlation between the clinical symptoms and hemodynamic responses in the r-dlPFC . 2 = 0.233, F  = 6.07, P < 0.05], where larger pain reduction by placebo effects was associated with less clinical symptoms. Spearman nonparametric correlation test also revealed that there was a significant and positive correlation between the clinical symptoms and placebo effects .4Previous studies reported a dlPFC involvement in placebo effects (pain inhibition) in response to CSs associated with safe stimuli (weak or non-noxious stimuli) through its effects on the descending pain modulation system in heathy subjects (see Introduction). It has been proposed that recognition of CSs associated with safe stimuli is impaired in patients with chronic pain, suggesting that such deficits in safe-cue recognition lead to development of chronic pain (see Introduction). These findings suggest that the dlPFC might be disturbed in patients with chronic pain. However, responsiveness of the dlPFC to CSs is unknown in patients with chronic pain. In the present study, we analyzed dlPFC hemodynamic activity during presentation of CSs associated with weak and strong noxious stimuli in the PHN patients with chronic pain, and reported that hemodynamic (Oxy-Hb) responses in the r-dlPFC, which were correlated with placebo effects, were decreased and inversely associated with clinical symptoms in the PHN patients. The present results provide the first report of hemodynamic responses in the dlPFC during presentation of CSs to induce placebo effects in PHN patients with chronic pain.4.1In the present study, patients with PHN showed smaller placebo and nocebo effects. Since placebo and nocebo effects are attributed to associative conditioning to CSs associated with unconditioned stimuli , where a larger reduction of VAS pain (placebo effects) was associated with a smaller clinical pain. Consistently, placebo effects were lower in patients with long-term fibromyalgia pain  and expe4.2In the present study, placebo effects were negatively correlated with hemodynamic responses to the CS associated with WS in the r-dlPFC, where a larger VAS pain reduction was associated with larger hemodynamic responses in the r-dlPFC. These findings are consistent with a previous study using heathy controls, in which responses in the bilateral dlPFC were correlated with placebo effects . FurtherThe present study further indicated that hemodynamic responses to the CS associated with WS in the r-dlPFC were opposite between patients with PHN and HC, which was consistent with smaller placebo effects in patients with PHN than HC. Furthermore, hemodynamic responses to the CS associated with WS in the r-dlPFC were negatively correlated with clinical pain symptoms (NRS). These findings suggest that smaller placebo effects and greater clinical pain symptoms in patients with PHN may be ascribed to functional impairments in the r-dlPFC . It has been reported that there were individual differences in placebo analgesia, which was associated with individual differences in anticipatory activity in the brain, including the dlPFC . FurtherAlthough larger nocebo effects were observed in HC than in patients with PHN, there were no significant correlations between nocebo effects and hemodynamic responses to the CS associated with SS in the r- and l-dlPFC. Additionally, there were no correlations between nocebo effects and hemodynamic responses to the CS associated with WS in the r- and l-dlPFC in the present study. These findings suggest that anticipatory activity in the dlPFC is more closely associated with placebo effects rather than nocebo effects. Indeed, previous studies reported that nocebo effects were associated with other brain regions, such as the medial system of the pain matrix, which includes the insula cortex, operculum, anterior cingulate cortex, etc. .4.3The present study has several limitations. In the present study, all of the patients with PHN had been prescribed medicines, such as tramadol acetaminophen, pregabalin, duloxetine, etc., after infection of herpes zoster. Human neuroimaging studies have reported that the administration of these analgesic medicines affected activity in the pain-related brain regions , but without affecting the dlPFC in chronic pain patients . One patSecond, decreased responses in the dlPFC in patients with PHN may be ascribed to PFC atrophy, which could be a secondary consequence of chronic pain . HoweverThird, we evaluated Oxy-Hb as cerebral hemodynamic responses in the present study, since 1) signal-to-noise ratio of Deoxy-Hb is lower than Oxy-Hb , and 2) Finally, due to technical limitations of NIRS, we did not investigate other deep brain regions involved in placebo analgesia, such as the rostral anterior cingulate cortex, orbitofrontal cortex, nucleus accumbens, periaqueductal gray, etc. . FurtherThis study followed the guidelines set forth by the Helsinki Declaration and was approved by the Ethical Committee for Human Clinical studies at University of Toyama. Written informed consent was obtained from all subjects who participated in this study.All authors have no conflict of interest to report.Daisuke Hibi: Investigation, Visualization, Writing - original draft. Kouichi Takamoto: Investigation, Visualization, Writing - original draft. Yudai Iwama: Investigation, Visualization. Shohei Ebina: Investigation, Visualization. Hiroshi Nishimaru: Writing - review & editing. Jumpei Matsumoto: Writing - review & editing. Yusaku Takamura: Writing - review & editing. Mitsuaki Yamazaki: Conceptualization, Methodology, Supervision, Project administration, Writing - review & editing. Hisao Nishijo: Conceptualization, Methodology, Supervision, Project administration, Writing - review & editing.


Accommodating a patient’s treatment preference has been reported to promote greater responsiveness and better clinical outcomes. The effect of administration route preference (ARP) on the individual analgesic response has not been extensively examined to date. This study aimed to investigate whether ARP-matched treatment, i.e., individualized intramuscular (IM) or oral (PO) analgesic administration according to patient choice, would increase the analgesic effect.In this prospective randomized study, we collected 38 patients with acute low back pain (aLBP) presenting at the emergency room of the Galilee Medical Center  and asked them to report their ARP for analgesics. Regardless of their reported preference, they received either PO or IM diclofenac according to the treating physician’s preference. Pain intensity was self-reported using the numeric pain score (NPS) before and during the first hour after drug administration.p < 0.05.Both groups receiving PO or IM administration reported similar initial pain on admission,  and the same magnitude of pain reduction. However, patients who received the drug in their desired route  had a significantly greater reduction in pain levels (4.05 ± 2.8) as compared with patients who received the undesired route (2.08 ± 1.8), These findings support the hypothesis that individualized ARP-matched treatment in aLBP improves therapeutic outcomes, although further studies with larger cohorts are needed. The American Pain Society guideline #11 on management of postoperative pain advocates avoiding painful administration of analgesic therapy , adherinFosnocht et al.  have estGreater satisfaction and improvement are assumed to operate through mechanisms attributed also to the placebo response, i.e., positive expectation and conditioning through past experience and beliefs . It is cPrior experience, knowledge, and beliefs that shape positive expectations and conditioning are known to be key components in the placebo response  and are Our research hypothesis was that the ARP itself is a therapeutic ritual which can encompass key components of the placebo effect . Thus, administering the same medication in the preferred ARP will increase the analgesic perception, essentially, “if you believe a certain ARP is better, it will be better for you.” The purpose of this study was to investigate our hypothesis that an additive effect will be observed when an analgesic is received in a patient’s ARP, as compared to the same therapeutic agent when received in an undesired method.To test our hypothesis, patients with acute low back pain (aLBP) were studied, as it is a distinct entity with clear diagnostic criteria and commonly encountered in orthopedic practice. It is generally agreed that there is no known specific etiology and that virtually all cases will resolve with time, regardless of treatment , 12. CurDiclofenac is commonly used for the treatment of aLBP and other types of acute musculoskeletal pain. It is effective and can be administered both orally and intramuscularly to the gluteal muscles , making This was a randomized prospective case series performed at the emergency room of the Galilee Medical Center , during evening shifts (15:00 to 23:00) on April and May 2019.Included were literate adults,18 to 80 years old, who presented with acute low back pain (aLBP) defined as non-radicular pain, located in the lumbar spine, of a 1-month duration or less, with no so-called “red flags” suggesting severe organic pathology [athology .Excluded were patients diagnosed differently or having a known sensitivity to diclofenac.Patients, referred to our emergency department for acute low back pain, were enrolled by one of the authors (either SA or MG) and treated by the resident orthopedic surgeon. They were asked for their consent to participate in the study and report their ARP  and their initial numeric pain score .The NPS was chosen as it is a well-established validated measure for self-reported pain in low back pain . The patAll patients received a single dose of either intra-gluteal diclofenac 75 mg  or 100 mg diclofenac, orally . The dosage differences were in accordance with the recommendations in the literature to adjust for differences in the absorption rate between the digestive system where only 65 to 75% of the active ingredient reaches the bloodstream  and the As either IM or PO diclofenac are routinely used at our emergency department in the treatment of aLBP, allocation to receive one or the other  was done according to the usual choice of the treating on-call resident physician, blinded to the ARP noted by the patient. Demographic and medical information was collected using a questionnaire, and NPS (0–10) were collected every 10 min during the first hour following the analgesic administration.The statistical analysis was performed using IBM SPSS .The patients were divided according to their preference  and also according to the actual administration route. The term “matched” being patients where the actual administration route matched their preference whereas “non-matched” being patients in which the actual administration route did not match their preference.t test for the quantitative data) and also utilized nonparametric tests . Both tests, parametric and nonparametric, achieved similar results.Dichotomic or discrete data were described by frequencies and percentages. Continuous variables were described by mean, standard deviation, and range. We compared the groups with parametric tests . Twenty-five patients received IM diclofenac and 13 PO. Both groups were identical in their demographic characteristics . Due of the difficulties in recruitment of patients, we had 16 patients in the non-matched group and 22 patients in the matched group and therefore achieved the power of 72% for our 1-tailed hypothesis   as well as a similar magnitude of pain reduction Patients who preferred and received oral treatment (B.n = 4)Patients who preferred intramuscular injections and received oral treatment (C.n = 12)Patients who preferred oral treatment and received intramuscular injection (D.n = 13)Patients who preferred and received intramuscular injection Patients who were treated according to their ARP’s—whether oral treatment or intramuscular injection (groups A and D in Table n = 16)Patients who received treatment that did not match their ARP’s  and remained significant at 60 min (P = 0.032)  Fig. .Fig. 2Pn = 13) was compared to the group of patients who received oral medication according to their preference (n = 9)  Fig.  with no p = 0.019)and at 60 min (p = 0.032)).In addition to the observed statistical significance, it is also important to note that the difference between ARP-matched and non-matched groups closely matches or exceeds the 2/10 minimal clinically important difference (MCID) in NPS . The meaIt has long been established that patients have distinct preferences, including administration route preferences, and complying with individual preference can lead to greater patient satisfaction and treatment outcomes , 19, 20.Intramuscular administration may augment pain reduction due to activation of descending pain inhibition, as by the pain-inhibits-pain phenomena, in which the pain evoked by the needle activates descending pain pathways –23 supprAs there was no difference in the analgesic effect between the administration method groups when given according to the ARP’s, it can be assumed that it is not the administration method per se which led to the significance of the findings, but rather the ARP matching.In addition to the observed statistical significance, it is also important to note that the difference between ARP-matched and non-matched groups exceeded the 2/10 accepted MCID in NPS for back pain  or the 1Although shared decision-making has been well established as beneficial in patient compliance, satisfaction, and clinical outcomes , 26, 27,Our findings also support shared decision-making regarding treatment and emphasize the importance of considering other factors that shape the experience of pain other than the physiological aspect , 33.Our study has several limitations; the most notable is the small sample size that limited the statistical comparisons which could be performed.Since the treatment given in this study was mostly by orthopedics residents on call, another limitation is the variability of caregivers, the amount of time they had to interact with the patients, and their personal ability to convey compassion and trust—key elements in clinical practice success.Due to these limitations, we cannot argue that the adjustment of the ARP to the treatment given, regardless of the type of treatment or method of administration, is solely responsible for the outcome. To establish this, further studies with larger samples are needed.The findings of our current study support previously published data that treatment based on patient preference improves therapeutic and analgesic outcomes , 26, 27


Over the years, the internet has enabled considerable progress in the management of chronic diseases, especially hypertension and diabetes. It also provides novel opportunities in online anticoagulation management. Nevertheless, there is insufficient evidence regarding the effectiveness of online anticoagulation management.This study explored the effectiveness and safety of warfarin management via the Alfalfa app, so as to provide evidence in support of anticoagulant management through online services.In this retrospective, observational cohort study, 824 patients were included. In the offline group, patients went to the hospital clinic for warfarin management. In the Alfalfa app group, patients reported the dose of warfarin, current international normalized ratio (INR) value, and other related information through the Alfalfa app. Physicians or pharmacists used the app to adjust the dose of warfarin and determined the time for the next blood INR testing. Patients completed INR testing by point-of-care at home or hospital. The primary outcome of the study was the percentage of time in therapeutic range (TTR). Secondary outcomes included minor and major bleeding events, thrombotic events, warfarin-related emergency department visits, hospital admissions, and high INR values.P<.001; 3314/4282, 77.39% vs 2005/4202, 47.72%, P<.001, respectively). Patients managed via the Alfalfa app had lower rates of subtherapeutic , supratherapeutic , and extreme subtherapeutic INR values . Additionally, the Alfalfa app group had lower incidences of major bleeding , warfarin-related emergency department visits , and hospital admissions  compared with the offline group. However, the Alfalfa app group had a higher incidence of minor bleeding than the offline group . There were similar incidences in extreme supratherapeutic INR values  and thromboembolic events  between the two groups.The TTR and percentage of INR values in the range were significantly higher in the Alfalfa app group than in the offline group (79.35% vs 52.38%, Warfarin management is superior via the Alfalfa app than via offline services in terms of major bleeding events, warfarin-related emergency department visits, and hospital admissions. Venous thrombosis, which includes deep vein thrombosis, pulmonary embolism, and cardiogenic stroke, poses a significant burden on the health care system . AnticoaP<.001). However, there was no statistically significant difference in other anticoagulant effectiveness or clinical outcomes between the two groups [Warfarin dose adjustment is usually performed at hospital clinics. For patients living in rural areas, adjustment of warfarin dosages requires transportation, accommodation, and time. Patients with low incomes are willing to risk thrombosis and bleeding in an attempt to reduce costs. Online services such as smartphones, text messages, Bluetooth, and communication platforms may assist in adjusting warfarin doses -6. Our mo groups . Our preo groups . The resRecently, we developed a new warfarin dosage adjustment app named Alfalfa, which is available for installation on a mobile device; the communication between the physicians or pharmacists and the patient is point-to-point. The privacy of the patients is well protected. Meanwhile, personal medical information can be retrieved by the patients or their physicians or pharmacists at any time. As far as we know, apart from Alfalfa, there are only two studies focusing on managing warfarin with the use of mobile apps that can automatically suggest a dose and time for the next blood test based on the patient's INR value ,9. The dWe conducted a retrospective, observational cohort study to explore the effectiveness and safety of warfarin management via the Alfalfa app versus offline warfarin management. Participants were enrolled between December 2016 and March 2019 in Fujian Medical University Union Hospital (FMUUH). Inclusion criteria were patients who (1) received warfarin therapy for at least 3 months, (2) were willing to learn and accept the Alfalfa app or offline warfarin management, and (3) were willing to undergo follow-up. Exclusion criteria were pregnancy; planning to change to other anticoagulants; serious bleeding, thrombotic events, or both in the previous 3 months; and adjustment of warfarin doses by the patients themselves without a physician’s order. The primary outcome of the study, that is, percentage of time in therapeutic range (TTR), was calculated using a standard linear interpolation method . SecondaA warfarin teaching booklet was given to the patients for further reading prior to counseling as part of the standardized education process . Then, tThe protocols of warfarin dose adjustment are determined by the anticoagulation team in the FMUUH. Monitoring is frequently performed at the beginning of warfarin therapy, with at least one visit per week in the first two weeks of therapy, followed by one visit every two to four weeks. The target INR range is 1.7-2.5 for patients with valve replacement and 2.0-3.0 for those with atrial fibrillation and venous thrombosis. Our study protocol was approved by the Ethics Committee of FMUUH (2016KY036).The data automatically recorded in the Alfalfa app included demographic characteristics, indication for warfarin therapy, duration of anticoagulation, target INR range, INR at each report, warfarin dose at each report, bleeding events, thromboembolic events, emergency department visits, and hospitalization A and B. Statistical analysis was performed using Microsoft Excel, version 2019 (Microsoft Corp), and SPSS, version 20.0 (IBM Corp).t test was used for statistical analysis of continuous variables, including age and TTR. A chi-square test or Fisher exact test was used for categorical variables, including sex, conditions, diseases, target INR, result of efficacy, adverse events, and INR results. Continuous variables are expressed as mean (SD), and categorical variables are expressed as quantity (percentage). Statistical significance is set at P<.05.For different variables in the baseline characteristics and results, different statistical methods were used to check the differences. An independent two-sample, two-tailed A total of 824 patients were enrolled and assigned to either the offline warfarin management group (n=399) or the Alfalfa app group (n=425). There were no significant differences in age, sex, conditions, diseases, coprescribed antiplatelet therapy, or target INR between the groups. In the current study, 48.07% of the participants were men . The maiP<.001). Furthermore, the Alfalfa app group had a higher percentage of INR values in range than the offline group . Patients managed by the Alfalfa app had lower rates of subtherapeutic , supratherapeutic , and extreme subtherapeutic INR values  compared to those managed by offline services. There were similar incidences in extreme supratherapeutic INR values  between the two groups , warfarin-related emergency department visits , and warfarin-related hospital admissions  were lower in the Alfalfa app group than in the offline management group. However, the Alfalfa app group had a higher incidence of minor bleeding events than the offline group . There were similar incidences in thromboembolic events  between the two groups . These results were similar to those reported by Prochaska et al, who showed that TTR was significantly higher from telemedicine-based coagulation service than from regular anticoagulation management  [In this study, TTR was significantly higher in the Alfalfa app group than in the offline warfarin management group  . HoweverP<0.001) . Some stP<0.001) -29. ThisOur research findings showed that the Alfalfa app had lower incidences of major bleeding events, warfarin-related emergency department visits, and warfarin-related hospital admissions than the offline warfarin management group. However, the incidence of minor bleeding events was higher in the Alfalfa app group. This finding was similar to the results reported by Blissit et al, who concluded that the incidence of minor bleeding events was higher in the online anticoagulation management group . The topThe studies by Xia et al and Cryder et al showed that there were fewer anticoagulation-related hospital admissions in the online anticoagulation group ,27. MostHowever, the results of this study showed that anticoagulation control may not be completely consistent with the clinical outcomes. For example, the extreme supratherapeutic INR values in this study were distributed close to each other, but the incidence of major bleeding events was lower in the Alfalfa app group. The average TTR of the offline warfarin management group was only 52.38% (<60%). In theory, the incidence of thrombosis should be higher in the offline warfarin management group, but the incidences of thrombosis were similar between the two groups.In recent years, the internet has made considerable progress in the management of chronic diseases, especially hypertension and diabetes. The internet provides novel opportunities in anticoagulation management. Telemedicine breaks geographical and spatial limitations, providing high-quality medical resources for patients living in vast rural and remote areas. Similarly, INR real-time detection technology is convenient for at-home INR detection. This technology allows patients to enjoy high-quality online anticoagulation management services at home.Currently, rural and medically underresourced areas often lack specialist anticoagulant physicians or pharmacists, resulting in a significant risk of bleeding and thrombosis for patients living in these areas. We are conducting a national randomized controlled multicenter study comparing the effects of the Alfalfa app and offline services . If the There were some limitations to this study. First, as a retrospective study, subjects were not assigned to either group; therefore, selection bias may be present. Second, the participants were included from a single center in Southeast China, which may not be representative of all patients with anticoagulation therapy. More prospective, randomized, and multicenter studies are required to confirm our findings.In conclusion, warfarin management in the Alfalfa app group was superior to that in the offline group in terms of TTR, abnormal INR, major bleeding events, warfarin-related emergency department visits, and warfarin-related hospital admissions. Warfarin management via the Alfalfa app may be suitable for patients living in rural and remote areas.


Significant differences between all 18 TPs were found for PPTs (p < 0.0001), and SPP (p < 0.005) scores were found. The most mechanosensitive points were located in the second costochondral junction, the occiput, the trochanteric prominence; the most painful while applying a normalized pressure considering the TP and side were those located in the gluteus, trochanteric prominence, and supraspinatus. The current study describes PPTs and SPP, as assessed with algometry and visual analogue scale, respectively, of all 18 TPs in female patients with FMS. TPs exhibited significant PPTs and SPP differences between TP locations with no side-to-side differences.Fibromyalgia syndrome (FMS) is a condition that courses with chronic pain, fatigue, sleep disturbance, impaired quality of life and daily function. Due to the lack of blood, imaging or histological confirmatory tests, the diagnosis of FMS is based on the presence of widespread pain and presence of tender points (TPs). Our aim was to assess the pain pressure thresholds (PPTs) and subjective pain perception (SPP) of all 18 TPs while applying a normalized pressure in female patients with fibromyalgia. An exploratory descriptive pilot study was conducted in 30 female patients with FMS. Sociodemographic data , clinical characteristics , PPTs , and SPP  of all 18 TPs were collected. A comparative analysis side-to-side  and between TPs was conducted. No side-to-side differences were found ( Fibromyalgia syndrome (FMS) is a condition that courses with generalized chronic pain  associat2 in at least 11 out of 18 tender points (TPs) in musculoskeletal structures and chronic widespread pain with 88.4% sensitivity and 81.1% specificity [Due to the lack of confirmatory diagnosis by using imaging, blood, or histological test, FMS is diagnosed on the basis of the presence of a pain response when applying approximately 4 kg/cmcificity . These ccificity , includicificity .However, there is no evidence of normative pain-pressure threshold scores of TPs in patients with FMS, differences between points, and subjective pain perception after applying a normalized pressure. Therefore, the aims of this study were to assess the pain pressure thresholds of all 18 TPs and to evaluate the subjective pain perception applying a normalized pressure in each point in female patients with fibromyalgia.We hypothesized that we would find both significant pain-pressure thresholds and subjective pain perception after applying normalized pressure differences among all 18 TPs since pain is a complex and multifactorial experience.A consecutive sample of female volunteer patients with fibromyalgia who responded to local announcements from October–December 2019 in the Association of Fibromyalgia “AFINSYFACRO” located in Móstoles (Spain) were invited to participate in this exploratory descriptive pilot study. To be eligible to participate, individuals had to be 35 to 70 years old, and have a diagnosis of fibromyalgia at least 3 months prior to their participation in the study. Exclusion criteria included any recent surgery, skin conditions, neuropathic conditions, being under pharmacological treatment  three days before their participation, or any underlying medical condition . All participants signed a written informed consent prior to their participation. This study was approved by the Institutional Review Ethical Committee of Camilo José Cela University of Madrid (Spain) with identification number (CEI-UCJC-25/06/2019) and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and checklist .2)) and clinical information  and a physical examination including pain pressure thresholds (PPTs) and subjective pain perception (SPP) of all 18 TPs.The data collection was planned before the physical exam. Before the start of the evaluation, an assessor with more that 10 years of experience treating patients with FMS underwent training to standardize the examination techniques and the interpretation of algometry. This assessor performed a standardized history with sociodemographic data . This questionnaire showed an acceptable reliability (ICC = 0.81) and consists of 10 subscales assessing physical function, number of days feeling good, work missed, ability to do work, pain, fatigue, rest, stiffness, anxiety, and depression. The score ranges from 0 to 100, where a greater score involves more disability and severity .The assessment of PPTs in TPs showed a moderate to high intra-examiner and inter-examiner reliability   and is c2 of pressure was applied, increasing at a rate of 1 kg/second. Standardized instructions given to each subject were, “I am going to push on your body at 9 places. If you feel pain, not pressure, say ‘now’ and I will stop”. The assessor recorded algometer readings for PPT at each tender point site on a body chart and calculated the total tender point count.All the procedures were performed by the same assessor calculating the mean of two procedures. A maximum of 4 kg/cmFinally, for assessing the SPP, patients were asked to identify their level of pain in a 100 mm visual analogue scale (VAS), where 0 was absence of pain and 100 was the worst imaginable pain  while apBased on a previous study conducted by Ge et al. assessing the predetermined sites of examination for the same 18 TPs assessed in this study , a minimData were analyzed using SPSS for Windows . Data distribution was assessed by using the Shapiro–Wilk test. Descriptive statistics  were calculated for sociodemographic, clinical, PPTs, and SPP characteristics. A t-test for independent samples was conducted to assess side-to-side differences for PPTs and SPP. Finally, a multiple comparison analysis between TPs for PPTs and SPP was conducted using the analysis of variance (ANOVA) test.From a total of 33 female patients with FMS, 3 were excluded due to the use of analgesics or muscle relaxants the day of the data collection. Thus, 30 women with FMS were finally included in this study. p > 0.05). However, significant differences between TPs were found for both PPTs  and SPP . Although the most painful points were located at TP7 (69.6 ± 19.4), TP8 (68.0 ± 21.5), and TP4 (65.1 ± 21.1), the lowest PPTs scores were found at TP5 (1.28 ± 0.42), TP1 (1.52 ± 0.34), and TP8 (1.61 ± 0.59).This is, to our knowledge, among the first investigations assessing the subjective pain perception of TP while applying a normalized pressure in female patients with FMS. Our data suggest significant PPTs and SPP score differences among the 18 TPs assessed, but we found no between-sides PPTs nor SPP differences for the same TP location. In a decreasing mechanosensitive order, the points were those located in the second costochondral junction (TP5), the occiput (TP1), the trochanteric prominence (TP8), the lower cervical spine (TP2), the knee (TP9), the epicondyle (TP6), the upper trapezius (TP3), the gluteus (TP7), and supraspinatus (TP4), respectively. The most painful perceptions applying a normalized pressure were located in the gluteus (TP7), trochanteric prominence (TP8), supraspinatus (TP4), upper trapezius (TP3), second costochondral junction (TP5), epicondyle (TP6), occiput (TP1), lower cervical spine (TP2), and knee (TP9), respectively, in decreasing order.A correct clinical assessment during FMS diagnosis is essential, and it should include a comprehensive history including self-reported questionnaires related to the FMS impact , functional capacity , life quality , pain characteristics , and psychological features  . Althoug2 to confirm the presence of a TP should be revised, since the PPTs are different for each point and that pressure is more than two times the pressure necessary to induce pain.Our study provides preliminary data of PPT in all 18 TPs in a cohort of female patients with FMS with similar sociodemographic and clinical characteristics. TPs manual palpation and identification can be used to discriminate patients with FMS from healthy subjects . A priorWe also find that the most mechanosensitive points were not the most painful when applying a normalized pressure for each point and side. One likely reason explaining this finding could be the complexity of the experience of pain. Several studies are consistent with the role of psychosocial and biological factors in the development of persistent pain and disability . DemograFinally, we have to recognize some limitations of the current study. First, only female individuals were included to determine the PPTs and the SPP, and our results cannot be applicable to male patients with FMS. Second, our sample size was small, and therefore our results should be considered preliminary normative data of PPTs and SPP; further research with a larger sample size is needed to confirm these findings. Finally, we did not include a control group to compare PPTs and SPP scores. Further research is needed to confirm these pain domains differences for diagnosis purposes.This study describes PPTs and SPP of all 18 TPs in female patients with FMS. TPs showed differences for PPTs and SPP. Our results suggested that the most mechanosensitive TPs were those located in the second costochondral junction (TP5), the occiput (TP1), and the trochanteric prominence (TP8); the most painful while applying a normalized pressure considering the TP and side were those located in the gluteus (TP7), trochanteric prominence (TP8), and supraspinatus (TP4). Thus, no side-to-side differences were found. However, further research with a larger sample size is needed to confirm these findings.


To explore the effect of modular transitional nursing intervention on the improvement of self-management of the patients with cancer pain.This study will be conducted from March 2021 to May 2022 at Affiliated Hospital of Beihua University. The experiment was granted through the Research Ethics Committee of Affiliated Hospital of Beihua University (4348–019). Eighty patients are analyzed in our study. The patients will be included if they are between 18 and 70 years old and are diagnosed with cancer, the pain intensity score on moderate level, the pain lasts for more than 3 days, and the patients who have signed the written informed consent. While the patients will be excluded if they have a documented history of drug or alcohol abuse, and patients with limited performance, and patients have a surgery in the past 3 days. The primary result mainly expresses as intergroup differences in self-management disorders (Barriers Questionnaire-II) associated with the cancer pain. And the secondary results include the quality of life (QOL) and pain intensity. All the analyses are implemented with SPSS for Windows Version 20.0.Table 1A modular transitional nursing intervention appears to reduce pain in cancer patients.researchregistry6262. The nurses and physicians are involved in the management of daily cancer pain, but they often fail to detect and treat the syndromes of pain.,7 The factors associated with the ineffective pain management can be divided into 3 categories, namely, patients, healthcare providers and healthcare system. In the healthcare system, “curing” is more concerned than “caring” for cancer patients, including the management of symptom. Health care providers often lack the knowledge and attention about the management of pain and patients are unwilling to report pain to physician. Fear of drug resistance, drug addiction and worry about the side effects can also affect their intake of painkillers. Despite pain education programs have increased the knowledge of nurse and patient in the management of pain, none of these programs, as far as we know, has improved the pain results.–10 Goldberg et al have explored the educational effects of nurses on topics related to pain. Nevertheless, these interventions did not result in any obvious reduction in patients pain severity.Many cancer patients suffer from a variety of symptoms, which can affect their social and physical functioning.There is increasing evidence of the importance of transitional nursing interventions, nevertheless, the influence of educational interventions that utilize transition preparation for the patients with cancer pain during hospitalization has not been recognized. Hence, the purpose of our investigation is to assess the influence of Self Care Improvement through Oncology Nursing to reduce patients barriers and improve pain management in cancer patients.2This study will be conducted from March 2021 to May 2022 at Affiliated Hospital of Beihua University. The experiment was granted through the Research Ethics Committee of Affiliated Hospital of Beihua University (4348–019) and recorded in research registry (researchregistry6262). Sequence of random numbers is generated by a computer. Sequentially numbered sealed opaque envelopes are used for the concealment of random numbers. All the patients taking part in our experiment are randomly divided into control and study group and each group includes 40 patients.2.1The patients will be included if they are between 18 and 70 years old and are diagnosed with cancer, the pain intensity score on moderate level, the pain lasts for more than 3 days, and the patients who have signed the written informed consent. While the patients will be excluded if they have a documented history of drug or alcohol abuse, and patients with limited performance, and patients have a surgery in the past 3 days.2.2In intervention group, Self Care Improvement through Oncology Nursing program is managed through the specially trained nurses. The counseling courses are divided into 3 modules. The first module, namely, pharmacologic management of pain, introduces a reliable pain evaluation, the use of the pain medications, and the communication about patient pain. The second module, namely the non-pharmacologic management of pain, contains the information about the influence of adjuvant pain managements and gives the patient a CD instructing them to independently perform the progressive muscle relaxation. While the third module (namely the discharge management related to pain) is designed to help the patients cope properly with potential self-management issues associated with pain in the process of transition to the outpatient care. Advice is provided on how to adhere to the self-management methods learned in the first and second modules after discharge. The checklist is provided to ensure appropriate discharge management is implemented. At the aim of ensuring that the consultation is tailored to the personal needs, but standardized in accordance with basic model, we offer an evaluation of the patients skills, knowledge, perceptions and attitudes of resources, and provide the indicative questions. Each question is associated with the intervention, for instance, offer the information on the types of application and the plans of pain medication. In control group, the patients are given care as usual, involving the standard pharmacological treatment of pain, but there is no standardized written material and teaching application, nor other evidence-based management options.2.3 associated with the cancer pain. And the secondary results include the quality of life (QOL) and pain intensity.The primary result mainly expresses as intergroup differences in self-management disorders (Barriers Questionnaire-II)2.4t test. The categorical variables are determined by the χ2 tests. When P is less than .05, it is viewed to be significant in statistics.Through utilizing the software of IBM SPSS Statistics for Windows, version 20.0, all the data can be analyzed . Afterwards, all the data are described with appropriate characteristics such as mean, median, standard deviation as well as percentage. The qualitative parameters for the groups are evaluated by 3Table 4,14 Fourty percentage of patients with the early cancer or intermediate cancer and 90 percent of patients with the advanced cancer suffer from moderate to severe pain, and approximately 70 percent of cancer pain patients do not get enough pain relief. The pain associated with cancer is a main healthcare challenge. Despite the use of strong opioids may be appropriate for the survivors of moderate to severe pain, most of the cancer survivors do not need them for their pain problems. Furthermore, as more than 40 percent of the cancer survivors live more than 10 years, there is an increasing concern about the opioids long-term side effects and the risks of overdose, abuse, and misuse in the cancer survivors.,18 Studies have indicated that the inadequate exchange of information between health care providers, the lack of communication with the patients and their family members in the transition period, and the high incidence of post-hospital adverse events suggest that the inadequate nursing transition from the hospital to family is frequent. Thus, we conduct this investigation to explore the effect of modular transitional nursing intervention on the improvement of self-management of the patients with cancer pain.Our experiment is the first to explore the effects of modular transitional nursing intervention to improve the management of pain and decrease patient barriers for the cancer patients. Pain remains one of the most painful and prevalent symptoms in the cancer patients, especially in the end-stage of this disease.5A modular transitional nursing intervention appears to reduce pain in cancer patients.Beibei Miao finishes the manuscript.Ling Gong collectes data.Wei Liu plans the study design.Yali Sun reviews the study protocolData curation: Yali Sun.Formal analysis: Yali Sun.Funding acquisition: Wei Liu.Investigation: Ling Gong.Methodology: Ling Gong.Writing – original draft: Beibei Miao.


In both groups, the number of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) consumed for managing postoperative pain was compared using the chi-square test and Mann–Whitney test. Our results showed that from postoperative day (POD) 0 to POD 3, the average numerical rating reflecting the postoperative pain was comparable between the two groups . However, at POD 7, opioid consumption in the CLP-treated group  was significantly lower than that in the ASP-treated group . After reaching a stable state by repeated systemic administration, clopidogrel sustained the analgesic efficacy for a certain period. In conclusion, microglial P2Y12 receptors may mediate signal transduction of postoperative nociceptive pain and enhance clinical opioid analgesia.The purinergic P2Y12 receptor regulates microglial activation, resulting in persistence and aggravation of pain in neuropathic and nociceptive pain models. We conducted a retrospective chart review to explore the analgesic potency of the P2Y12 receptor-specific antagonist, clopidogrel, for clinical management of postoperative pain in patients who underwent abdominal surgery. Twenty-seven patients with cardiovascular comorbidities, who underwent laparoscopic abdominal surgery and had ceased aspirin (ASP,  Pain is one of the most frequent symptoms observed in postoperative patients. Postoperative pain not only causes distress but also interferes with cough, breathing depth, and expectoration during the acute postoperative period and can be followed by atelectasis, pneumonia, and hypoxia . FurtherRegarding the mechanisms of severe postoperative pain, central sensitisation is a possible target candidate for exploring novel agents. An emerging concept of central sensitisation states that immune cells  and neurons form an integrated network, in which activation of an immune response modulates the excitability of nociceptive pathways . MicroglBased on this concept, we hypothesised that clopidogrel and its active metabolite may antagonise P2Y12 receptors not only on platelets but also on microglia at the spinal cord level, and thereby suppress pain through microglial inhibition. To the best of our knowledge, no report has documented the intimate relationship between clopidogrel and clinical pain. In this study, we conducted a retrospective chart review to explore the analgesic potency of clopidogrel for managing postoperative pain in patients who underwent abdominal surgery.We retrospectively reviewed the pharmacy and medical records of 27 patients with a history of cardiovascular diseases, who underwent laparoscopic abdominal surgery and were prescribed antiplatelet drugs. Patients taking clopidogrel within 14 days of cessation ; and those taking aspirin  were compared. The purpose of this study was to determine whether clopidogrel affected postoperative pain. Clopidogrel is a specific P2Y12 receptor antagonist, and possibly acts by antagonising microglial P2Y12 receptors, thus exerting an analgesic effect. When postoperative pain was similarly managed in both groups, during the 7 days post-surgery, the total amount of opioids administered was significantly higher in the aspirin group than in the clopidogrel group. This indicated that clopidogrel exerts potential analgesic effects in managing postoperative pain.P2Y12 gene knock-out mice, pain aggravation after microglial activation was not observed [The P2Y12 receptor is expressed on the spinal cord microglia and is responsible for the initial stage of microglial activation, which is known to aggravate neuropathic and nociceptive pain ,9. In P2observed . Previouobserved . Thus, tobserved . In the observed . Previouobserved . Therefoobserved ,15. In aobserved . Thus, tNotably, the P2Y12 receptor affects postoperative pain intensity and/or sensitivity of opioid analgesics through its antagonistic effect on microglia at the spinal cord and/or the PAG. Hence, the microglial P2Y12 receptor in the central nervous system would be a novel candidate for drug development targeting pain relief and/or preventing and treating opioid tolerance. However, this study was conducted as a retrospective chart review with a limited number of patients. To confirm our present findings, a prospective study with a larger number of participants needs to be performed.This study was approved by the Ethical Review Board of the Faculty of Medicine, University of Tokyo (ID: 3678), and was registered at University Medical Information Network (12665). Opt-out consents were obtained from all participants.n = 10), and the other group was given aspirin ; both groups had ceased antiplatelet drug usage 14 days prior to surgery. This time constraint was predetermined, considering the following factors: clopidogrel is a thienopyridine prodrug, whose active metabolite acts as an irreversible antagonist of the P2Y12 receptor. Following repeated clopidogrel administration, inhibition of platelet aggregation reaches a steady state. After clopidogrel administration is discontinued, platelet aggregation gradually returns and completely recovers to baseline values, generally within 14 days. Following a single systemic clopidogrel dose, its serum concentration reaches a peak in approximately 0.5 to 3 h in healthy subjects, disappearing mostly within 24 h. Reportedly, this time course of a single systemic clopidogrel administration in rats is similar to that in humans [We retrospectively reviewed the pharmacy and medical records of 27 patients with a history of cardiovascular diseases who were prescribed antiplatelet drugs and who underwent laparoscopic abdominal surgery during the study period (April 2014 through October 2016). All patients were administered general anaesthesia in combination with epidural anaesthesia. Postoperative pain was treated with a continuous epidural infusion of local anaesthetics  and intravenous fentanyl (10–30 µg/h). In the case of worsening pain, either bolus intravenous fentanyl (10–30 µg/dose) or NSAIDs  were administered. No protocols were available regarding the administration of opioid dosages or NSAIDs, and the attending physicians with expertise in postoperative pain management adjusted opioid or NSAIDs doses for individual patients at their discretion. Patients were divided into two groups based on clopidogrel use: one group was administered clopidogrel  to manage postoperative pain during 7 postoperative days was compared between the two groups. These comparisons were performed using the Mann–Whitney test or chi-square test as suitable, and results with P-value < 0.05 were considered statistically significant.The preliminarily findings of this retrospective chart review suggest that the P2Y12 receptor possibly mediates the signal transduction in postoperative nociceptive pain and enhances opioid-mediated analgesia.