The current gold standard treatment for acute postoperative pain after major abdominal surgery is multimodal analgesia using patient controlled analgesia delivery systems. Patient controlled analgesia systems are expensive and their routine use in very low income countries is not practical. The use of ultrasound in anaesthesia has made some regional anaesthesia blocks technically easy and safe to perform. This study aimed to determine whether adding an ultrasound guided transversus abdominis plane block as an adjunct to the current parenteral opioid based regimen would result in superior pain relief after a trans abdominal hysterectomy compared to using parenteral opioids alone.Thirty-two elective patients having trans abdominal hysterectomy were recruited into a prospective randomised double-blind, controlled study comparing a bilateral transversus abdominis plane block using 21 ml of 0.25 % bupivacaine and 4.0 mg dexamethasone with a sham block containing 21 ml 0.9 % saline. Sixteen patients were allocated to each group. Anaesthesia and postoperative analgesia was left to the attending anaesthetist’s discretion. Primary outcome was visual analogue scale for pain at 2 h and 4 h. Secondary outcomes were time to first request for analgesia, visual analogue scale for comfort and bother. The data were analysed using the Statistical Package for Social Sciences (SPSS version 16).There was no statistically significant difference in the demographics of the two groups regarding weight, height, physical status and type of surgical incision. There was a statistically significant difference in visual analogue scale for pain at 4 h during movement with lower pain scales in the test group (p = 0.034). Women in the control group had an average pain free period of 56.8 min (median 56.5 min) before requesting a rescue analgesic compared to 116.5 min (median 103 min) in the study group. The between group difference in the average total analgesia duration was statistically significant at the 0.05 level (p = 0.005).The addition of a bupivacaine–dexamethasone transverse abdominis plane block to intramuscular opioid does produce superior acute post-operative pain relief following a hysterectomy. However a single-shot block has a limited duration of action, and we recommend a repeat block.Trial registration: Clinical trials registration was obtained PACTR201501000965252.http//www.pactr.org/ATMWeb/appmanager/atm/atmregistry?_nfpb=true&_windowLabel=BasicSearchUpdateController_1&BasicSearchUpdateController_1_actionOverride=%2Fpageflows%2Ftrial%2FbasicSearchUpdate%2FviewTrail&BasicSearchUpdateController_1id=965. The trial was registered on the 12th Dec 2014 Patients usually suffer significant pain after abdominal surgery, with the major source of pain being the anterior abdominal wall and the abdominal viscera . The curPostoperative analgesia at Harare Central Hospital (HCH) and Parirenyatwa group of hospital (PGH) in Zimbabwe consists of parenteral opioid administration with a general preference for intramuscular pethidine 3-h per rising need (prn), with morphine intramuscular being rarely used due to misconceptions that overestimate and overemphasise the risk of adverse effects and addiction . PatientA positive development is the advent of ultrasound use in anaesthesia, which has made a variety of regional anaesthesia blocks possible that may offer technically simple, safe and better alternative analgesic regimen or adjuncts . A transThe aim of this study was to determine whether adding a regional anaesthesia technique, an ultrasound-guided TAP block, as an adjunct to the current parenteral opioid based regimen would result in superior pain relief after a trans-abdominal hysterectomy compared to the use of parenteral opioid alone.This study was carried out at HCH and PGH. Ethical clearance to conduct the study was obtained from the Joint Parirenyatwa Hospital and College of Health Sciences Research Ethics Committee [JREC: 185/13] and the Medical Research Council of Zimbabwe [MRCZ/B/571] and Clinical trials registration was obtained from the Pan African clinical trials registry PACTR201501000965252. Data were collected between 20 September 2013 and 31 March 2014.The participating subjects were patients admitted at PGH and HCH for elective open trans-abdominal hysterectomy. The patients were American Society of Anesthesiologists (ASA) physical status grade I–III, aged between 18 and 60 years and gave consent. Exclusion criteria were as follows: history of local anaesthetic allergy, patients receiving drugs which could result in opioid tolerance, inability to understand study protocols, obesity BMI >35, weight <40 kg and patients who were unable or unwilling to give informed consent. Written informed consent was obtained in their language as well as an English translation made available from all participants.This was a prospective, randomised, double blind, controlled study. The hypothesis was that adding a Bupivacaine–Dexamethasone transversus abdominis plane (TAP) block to currently practised traditional im Pethidine 3 h (prn) as prescribed by the anaesthetist as part of a multimodal postoperative analgesic regimen produces superior postoperative pain relief compared to using Pethidine alone in patients who underwent TAH. A power calculation with an α value of 0.02 and a β value of 0.1 based on a difference in the proportion of patients with moderate to severe pain of 20 % with standard deviation of 15.2 % would require a sample size of 15 in each group. Including a non-response rate of 1 % a sample size of 32 patients (16 per group) was needed to obtain 90 % statistical power of the results. Thirty-seven patients were recruited, five were excluded from the study leaving 32 who were finally included. Three were excluded because they were postponed for lack of theatre time, and of the other two, one could not be done because blood was not reserved for surgery if needed. The remaining patient had the planned procedure changed. See Fig. Randomisation was carried out using sealed opaque envelopes with coupons labelled S for the control group and T for study group. The coupons were generated and sealed in envelopes before data collection was commenced. After obtaining written consent from the patient, she was asked to pick an envelope. An independent anaesthetic assistant prepared the injectate using clearly written instructions depending on the group the patient picked and supplied this to the investigator with the label ‘injectate’ written on it.Sixteen patients were allocated into the control group [SHAM], they received a Sham TAP block using 21 ml 0.9 % normal saline on each side using the ultrasound guided posterior TAP block. The other 16 patients were allocated into the test group and received 20 ml 0.25 % bupivacaine plus 1 ml dexamethasone [4 mg] on each side. The TAP block was performed at the end of surgery before reversal of muscle relaxation and anaesthesia. Patients were blinded as to which group they had been allocated into. The investigator and staff involved in the assessment of the patient postoperatively noting the time to first analgesic request and assessment of the different visual analogue scale [VAS] were also blinded to which group the patient was allocated to.All patients received a general anaesthetic as prescribed by the attending anaesthetist. An intravenous induction with either sodium thiopental or propofol, intubation with suxamethonium or atracurium, maintenance of anaesthesia with isoflurane, intravenous morphine analgesia and reversal with neostigmine and atropine was done. Standard monitoring used intraoperatively included electrocardiography [ECG], non-invasive blood pressure [NIBP], capnography, pulse oximetry and urine output. The prescribed postoperative analgesic regimen was intramuscular pethidine given 3 h prn and nurse controlled. To make the data collection convenient patients were kept in the recovery room until their first request for analgesia. NIBP, ECG and pulse oximetry were monitored in recovery.The primary outcome measured was adequacy of postoperative pain relief, as assessed by a VAS for pain at 2 and at 4 h after surgery. Pain was assessed at rest and during standardised movement [knee flexion]. Secondary outcomes measured were: total analgesic duration, noted as the time from block application to the time to first rescue analgesic request by the patient, patient comfort as assessed using a VAS comfort and VAS bother which assessed if patients were bothered by their surgical wounds. Patients were instructed preoperatively on the use of the VAS.t test for independent groups was used to test the hypothesis and also check relationships on continuous variables. Categorical variables were expressed as percentages and frequencies, and compared using the Chi square analysis. A p value <0.05 was considered to be statistically significant.The data were analysed using, the statistical package for social sciences (SPSS). Descriptive statistics were used to report measures of central tendencies for quantitative variables. Student’s Table Table The box-and-whisker plot in Fig. Shin et al. in their study, the pain scores during movement were superior in the TAP group at 4 h postoperatively compared to the control group. This implies that addition of a TAP block to the postoperative analgesic regimen improved dynamic pain relief . SimilarThis study was conducted to determine whether or not the addition of a bilateral ultrasound guided TAP block to our current postoperative analgesic regimen would provide superior pain relief in women undergoing elective TAH. We found that a TAP block intervention did improve pain relief in the immediate postoperative period as shown by the longer analgesic duration in the study group. The duration of analgesia in the study group was almost double that of the control group. Patients in the study group were pain free early postoperatively in the recovery unit, however there was no significant between-group difference in pain scores at rest or during movement at 2 h post intervention. This implies that a single shot TAP block has a limited duration of effect. The use of continuous catheter technique by infusion or intermittent injection of local anaesthetic into the TAP may be used to prolong the analgesia from of a block .In a similar study by Marais et al. 2014 the researchers found that there was no statistically significant difference between the two groups in pain scores at rest or during movement. They attributed this to the use of intravenous opioid PCA as the primary postoperative analgesia, which is an effective analgesic regimen . HoweverMost studies reported on in the literature were performed in the setting of multimodal analgesic regimen using intravenous opioid, paracetamol or NSAID PCA, oral and per rectal paracetamol and NSAIDs as part of the enhanced recovery programs . IntraveVarious drugs have been used as adjuvants for single shot regional anaesthetic blocks to improve quality and increase the duration of block. These drugs include clonidine, opioids, ketamine, neostigmine, adrenaline and glucocorticoids . RegionaUltrasound guided TAP block is easy to perform, with real time ultrasound images. There is usually an initial steep learning curve to the use of the ultrasound machine and performing the in plane needling techniques, but once these are mastered, a TAP block is one of the easy blocks to perform .In the literature cases of procedure complication under ultrasound guidance are scanty. There is one report of liver trauma and peritoneal inflammation in a patient who had undergone inguinal hernia repair . The othThe limitations of this study were the lack of strict control on the administration of the postoperative analgesia as it was nurse controlled. Bias could arise from the lack of standardization of the postoperative analgesia administration.This study investigated the utility of adding a regional anaesthetic technique, a TAP block as part of a prn opioid analgesic regimen in a low resource setting.The study showed that compared to using traditional methods of prn opioid analgesia alone, the addition of an anaesthetist performed ultrasound-guided bupivacaine–dexamethasone transversus abdominis plane block as part of a multimodal analgesic regimen does produce superior acute postoperative pain relief following a TAH.We recommend the routine use of a bupivacaine–dexamethasone TAP block as part of a wider multimodal analgesic regimen after a TAH. However, a single-shot TAP block has a limited duration of action; a repeat interval TAP block could prolong the analgesic effect in the ward. However this has not been tested in our study.


Touch plays a significant role in human social behavior and social communication, and its rewarding nature has been suggested to involve opioids. Opioid blockade in monkeys leads to increased solicitation and receipt of grooming, suggesting heightened enjoyment of touch. We sought to study the role of endogenous opioids in perception of affective touch in healthy adults and in patients with fibromyalgia, a chronic pain condition shown to involve reduced opioid receptor availability. The pleasantness of touch has been linked to the activation of C-tactile fibers, which respond maximally to slow gentle touch and correlate with ratings of pleasantness. We administered naloxone to patients and healthy controls to directly observe the consequences of µ-opioid blockade on the perceived pleasantness and intensity of touch. We found that at baseline chronic pain patients showed a blunted distinction between slow and fast brushing for both intensity and pleasantness, suggesting reduced C-tactile touch processing. In addition, we found a differential effect of opioid blockade on touch perception in healthy subjects and pain patients. In healthy individuals, opioid blockade showed a trend toward increased ratings of touch pleasantness, while in chronic pain patients it significantly decreased ratings of touch intensity. Further, in healthy individuals, naloxone-induced increase in touch pleasantness was associated with naloxone-induced decreased preference for slow touch, suggesting a possible effect of opioid levels on processing of C-tactile fiber input. These findings suggest a role for endogenous opioids in touch processing, and provide further evidence for altered opioid functioning in chronic pain patients. C-tactile fibers are normally more activated by slow gentle touch than by fast touch and send a signal to the brain that contributes to the perception of pleasantness. This paper shows that people with the chronic pain condition fibromyalgia perceive less difference between fast and slow gentle touch in terms of its intensity and pleasantness, suggesting reduced C-tactile fiber processing and/or differences in opioid signaling. Our paper is also the first demonstration in humans that opioids affect how touch feels. In healthy individuals, blocking opioid binding tended to increase touch pleasantness, whereas in fibromyalgia patients it decreased perceived intensity. This suggests a role for endogenous opioids in touch perception, and provides new evidence that opioids function differently in chronic pain.Touch plays a strong role in social communication and bonding. In mammals, activities such as licking, grooming, and sensual caress seem to be intrinsically rewarding. Primates, for instance, appear to spend more time grooming others than is necessary for hygiene . These bThere is evidence in animals that the rewarding nature of social touch involves opioidergic mechanisms. Indeed, there are opioid receptors throughout the brain, and they are especially concentrated in brain areas related to pain and affect . In addiThe involvement of opioids in human appreciation of CT-targeted touch is unknown. In the current study we examined ratings of the pleasantness of slow touch  and fast touch  in a group of participants with fibromyalgia (FM), a chronic pain condition in which opioidergic abnormalities have been shown , and comt(50) = 0.34; p = 0.74; t(50) = 1.21; p = 0.23; t(48) = 3.14; p = 0.003) and depression (t(48) = 4.15; p = 0.0001) than controls on the Hospital Anxiety and Depression Scale  and 24 chronic pain patients diagnosed with FM . Participants ranged in age from 18 to 64  and all le HADS; ; Table 1le HADS; . The meale HADS;  and was Chronic pain patients were included if they had had widespread chronic pain for at least 1 year prior to study participation with an average daily intensity at least 4 of 10. FM diagnosis was confirmed through medical records. All participants were excluded for smoking (>10 cigarettes per week), excessive alcohol use (>7 drinks/week or 5 drinks in 1 setting), recreational drug use, pregnancy, or breastfeeding, major medical or psychiatric conditions (past or present), recent use of opioids, and MRI contraindications. Non-opioid medications used to treat FM at the standard doses in the community were permitted. Healthy controls were excluded if they had taken any pain medication other than an over the counter NSAID or acetaminophen within the last 1 month or for >1 month on a continual basis within the last 6 months.−1) brushing and three trials of fast (30 cm s−1) brushing  in alternating order, beginning with slow brushing. Brushing was performed with a 2-inch-diameter watercolor brush . Subjects rated both touch intensity and pleasantness/unpleasantness on 17 cm visual analog scales (VAS). Anchors for the intensity scale were no sensation (0) and very intense (4). A 17 cm VAS was also used for the affective scale, but in order to emphasize the difference between intensity and affective ratings, numeric anchors were 10 and −10, with the corresponding words of very pleasant and very unpleasant  to receive saline or naloxone in a double-blinded and counterbalanced manner. A maximum dose of 10 mg naloxone, a dose used clinically to reverse the effects of opiates, was administered to one-half of the subjects during an fMRI scan conducted for a separate part of the larger study. To achieve a constant plasma level throughout the MRI phase, a bolus dose of naloxone  or saline was first administered via an intravenous line, followed by an intravenous infusion dose of 0.08 mg/kg/h naloxone  or an infusion of saline, starting immediately after the bolus injection and continuing for ∼40 mins. Participants were asked to guess which drug they had received and were not better than chance. The brushing task was conducted before the MRI scan (before drug infusion) and again ∼10 min after completion of the infusion and concurrent scan. The half-life of naloxone is 30–80 min with an average of 64 ± 12 min McEvoy.t test, p = 0.09; 0–10 scale). The average level of discomfort in patients was also minimal, both pre-drug (0.71 ± 1.57) and post-drug , with 19 of 24 patients reporting no discomfort at all.The unrelated fMRI study involved the rating of painful heat stimuli. Participants received two blocks of painful heat stimuli, one before and one during drug infusion. A topical placebo manipulation to decrease pain on a small area on the leg was administered. The control spot on the leg was not affected by placebo, so we believe that our arm-brushing task was similarly unaffected. Further, the placebo analgesia was small and the response of patients and controls did not differ (data to be reported elsewhere). Most patients were free of clinical pain during testing (20 of 24 subjects pain-free before drug and 17 of 24 pain-free after drug). Ongoing clinical pain scores were on average 0.69 ± 0.17 pre-drug and 1.33 ± 2.46 post-drug  and drug  on pleasantness rating change scores (from before to after drug administration). We also investigated the effect of drug administration on average pleasantness ratings within the naloxone and saline conditions separately. The same analyses were conducted for ratings of intensity. Finally, we analyzed the effects of group, drug, and pre-post drug change in slow–fast preference  on change in overall touch pleasantness. Slow–fast preference was calculated as each subject’s average slow brushing pleasantness rating minus average fast brushing pleasantness rating.Participants’ VAS ratings were measured independently with a ruler by two experimenters blind to drug condition and patient group. Ratings were averaged across trials separately for slow and fast brushing intensity and pleasantness. All analyses were conducted in JMP (SAS Institute). A two-factor ANOVA was conducted to test the effect of speed (slow vs fast) and group  on baseline pleasantness ratings and separately on baseline intensity ratings. Significant effects were followed up with post hoc Tukey’s; p values <0.05). In contrast to healthy subjects, chronic pain patients did not rate either the pleasantness or intensity of slow and fast brushing differentially . Whereas pain patients differed from healthy subjects in the differential perception of slow and fast brushing, pain patients did not differ from healthy subjects in their average ratings of intensity or pleasantness . There was no effect of age on either intensity or pleasantness ratings for either healthy subjects or pain patients  when included as a continuous covariate in the ANOVA. However, higher depression scores significantly predicted higher pleasantness ratings, whereas higher anxiety scores significantly predicted higher intensity ratings.Healthy participants rated slow brushing of the skin as more pleasant than fast brushing, but less intense  = 0.48, p = 0.51ad; When we compared changes in pleasantness and intensity ratings from before to after naloxone or saline administration, we found that naloxone altered pleasantness ratings in the healthy subjects and altered intensity ratings in the chronic pain patients. In healthy participants who received saline, changes in touch pleasantness and changes in preference for slow brushing were positively correlated. Under naloxone, this correlation was abolished and a trend toward a negative correlation was found . ChronicIn the current study, chronic pain patients with FM exhibited a blunted preference for CT-related touch pleasantness and touch intensity, compared to healthy matched participants. In addition, we demonstrated for the first time that opioid-blockade by naloxone altered touch perception, and did so differently for chronic pain patients than for healthy individuals. These findings suggest that opioids contribute to affective touch perception, and suggest abnormalities in the role of opioids in touch processing in patients with chronic pain.d = 0.51 for pleasantness and d = 0.57 for intensity, medium effect sizes by conventional criteria. In contrast, the mean effect size for placebo analgesia, a popular and meaningful topic of research, is d = 0.15 , but increase the overall valuation and liking of social touch.d = 0.97). Our dose of naloxone was low; a larger dose might show larger effects on patients’ ratings. It is not clear how opioids would become involved in touch intensity in chronic pain patients, but this effect may point to altered functions of the opioid system in FM patients, or to a change in function of CT fibers in chronic pain. Indeed, there is some evidence that in painful conditions, CT fibers may change their role from signaling pleasant touch to be involved in allodynia  that was not observed in healthy participants. Intensity ratings decreased by ∼5% on our rating scale but constituted a large effect size by conventional criteria , whereas in chronic pain patients with FM it significantly decreased overall touch intensity. These findings provide the first direct support in humans for the hypothesis that opioids have a role in CT-mediated affective qualities of touch. Our findings also provide further evidence for opioid abnormalities in patients with FM. The patients showed no preference for CT-optimal touch at baseline, and opioid blockade affected touch intensity rather than pleasantness, suggesting altered processing of CT input. These findings have significance in the understanding of human touch, as well as sensory processing in FM. More research is needed to determine whether abnormal touch perception and abnormal effects of opioids in fibromyalgia are related to the causes or consequences of chronic pain.


Purpose. To evaluate and compare the subjective sensations reported by patients during first and second cataract extractions. Methods. Consecutive patients undergoing bilateral sequential cataract extraction using phacoemulsification were recruited. Following cataract surgery, patients completed questionnaires designed to evaluate subjective sensations, including anxiety, eye bulges, pain, and light sensitivity. Changes in painful sensations experienced by patients between the two surgeries were also recorded. Comparisons were also performed for each subjective sensation between different age groups . Results. A total of 127 patients were included in the final evaluation. Statistical comparison of the results showed that there were significant differences in perception of anxiety, eye bulges, and pain scores between the first and second cataract surgeries (P < 0.05). However, there was no statistically significant difference for light sensitivity scores between the two surgeries (P = 0.555). The differences in anxiety, perception of eye bulges, pain, and light sensitivity scores between both the surgeries showed no correlation with age . Conclusions. Our research confirms the common observation that patients with bilateral cataracts often report more ocular discomfort during the second surgery. There are, therefore, additional factors that should be considered upon treating patients with bilateral cataracts, and the provision of preoperative counseling could play an important role in providing adequate patient care. Phacoemulsification cataract surgery is the most commonly used and effective surgical method for the treatment of cataract to improve a patient's visual function and quality of life –3. ShortSubjective sensations, such as ocular pain and light sensitivity, are known to occur during phacoemulsification surgical procedures , 6. It hThis study was approved by the institutional ethics committee of the Central Hospital of Wuhan and followed the tenets of the Declaration of Helsinki. Patients affected by bilateral cataracts were eligible for this study. Patients were enrolled if they underwent phacoemulsification cataract surgery at the Central Hospital of Wuhan  between January 2015 and September 2015. The first surgery was performed in the eye with a higher-grade cataract or otherwise poorer vision. The other eye was operated on within approximately 1 month, based on the patient's choice. All patients who had uneventful phacoemulsification under topical anesthesia using proparacaine 0.5% (Alcaine®) with the placement of an intraocular lens in the capsular bag were included. A preoperative mydriatic was administered, and the pupil size remained at more than 6 mm throughout the operation. All surgeries were performed under the same conditions. The exclusion criteria were cataract with glaucoma, high intraocular pressure, lens dislocation, and posterior capsular rupture during surgery that prolonged the procedure by 10 min or more. The procedures were fully explained to each patient, and each patient provided written informed consent.All procedures were performed by a single surgeon using the same phaco machine  between 9:00 and 12:00 am. The surgical technique was clear corneal phacoemulsification through a 3.2 mm incision located between sectors 10 and 12. In all cases, foldable intraocular lenses were implanted using the dedicated injector. Only sutureless cases were included in the final evaluation. The operation time was recorded by an assistant doctor, as the time from the opening of the side port incision to the removal of the lid speculum. After the cataract surgery, patient questionnaires were used to evaluate subjective sensations. Every patient was accompanied to the recovery room and asked to grade the pain they experienced during the procedure using the Numerical Rating Scale (NRS) with scores from 0 to 10, where 0 means no pain, 1–3 mean mild pain, 4–6 mean moderate pain, and 7–10 mean severe pain , 15. AnxThe data was collected using a structured study form and a questionnaire. The following patient data was collected and analyzed: patient age and sex, concomitant diseases, operative time, anxiety score, eye bulges score, pain score, and light sensitivity score. For each score, subgroups were also assigned and compared based on patient age .U test was used to estimate the differences in each score between the first and second surgery. For the comparison of parameters in different age subgroups, a chi square test with a 5 × 4 contingency table was used. Correlation between subjective sensation and age was assessed using Spearman's correlation test. Statistical analysis was performed using SPSS PASW Statistics version 18.0 software . P values less than 0.05 were considered statistically significant.All data were recorded in Microsoft Excel spreadsheets and analyzed using the Kolmogorov-Smirnov test for normal distribution. Continuous variables were expressed as the mean ± standard deviation for those displaying normal distribution or otherwise using the median. A Mann-Whitney A total of 132 consecutive patients were enrolled in this study. However, 5 patients gave up treatment before undergoing the second surgery. Hence, 127 patients (60 men and 67 women) aged between 43 and 93 years (median 70 years) were included in the final evaluation. Patient demographic characteristics and concomitant diseases are recorded in P = 0.317). All the scores that were obtained did not follow a normal distribution ; therefore a Mann-Whitney U test was used to estimate differences of these parameters between the first and second surgery. The comparative analysis of anxiety, eye bulges, pain, and light sensitivity scores between the first and second phacoemulsification cataract surgeries is shown in P = 0.001, P = 0.049, and P = 0.011, resp.). Patients experienced less anxiety, a greater number of eye bulges, and pain during the second cataract surgery compared to the first surgery. However, differences in the scores for light sensitivity between surgeries were not statistically significant (P = 0.555).The average operation time was 11.5 ± 1.9 min for the first surgery and 11.7 ± 1.8 min for the second surgery. The difference between operation times was not statistically significant . Additionally, the differences in anxiety, eye bulges, pain, and light sensitivity scores between the first and second surgery had no correlation with age .The comparative data for the different age subgroups  for anxiety, eye bulges, pain, and light sensitivity score are shown in Our analysis shows that 33 (26.0%) patients reported more pain during the first cataract surgery compared to the second surgery. Fifty-three (41.7%) patients reported more pain during the second cataract surgery than during the first surgery, while 35 (27.6%) patients reported the same pain score during both surgeries. Six (4.7%) patients reported no pain during both the first and the second surgeries. The numbers of patients in the different age groups who reported changes in painful sensation score between the first and second surgeries are presented in In clinical practice, it is a common observation among ophthalmic surgeons that patients with bilateral cataract often report more pain and discomfort during the second consecutive eye surgery. Previous studies have investigated this observation and have also reported an increase in pain in the second surgery relative to the first , 9, 10. Eye bulges, which reflect sensitivity to intraocular perfusion pressure, were also found to increase in severity following the second cataract extraction. There are most likely multiple factors that contribute to the sensitivity of the eye to perfusion pressure. We propose that this observation might be related to factors such as the lens nuclear hardness, concomitant diseases, type of lens opacity, inflammatory cytokines, and psychological factors. These may be the same factors that contribute to ocular pain. Our study found no correlation between patient age and differences in eye bulges and pain score between the first and second surgery, which implies that intraoperative perception of discomfort is unaffected by age.It is well known that psychological factors, such as mental stress, are present beforehand and influence patient responses to cataract surgery. The degree of mental stress most likely contributes to the degree of pain reported by patients. It is also likely that patients often have more mental stress before their first cataract surgery . AdditioWe have discussed the role of subjective psychological factors in patients' perception of pain during second cataract surgeries. However, objective molecular mechanisms, for example, sympathetic irritation in the second eye resulting from surgery in the first, might also contribute to this phenomenon. Zhu et al. reported that expression of MCP-1, a pain-related inflammatory chemokine, is significantly increased in the aqueous humor of the contralateral eye following first cataract surgeries. This suggests that there may be a sympathetic ophthalmic type uveitis in the contralateral eye after surgery, which may explain why phacoemulsification of the second eye is more painful . Not allPatients undergoing cataract surgery can experience a wide range of subjective sensations. Light sensitivity is one example. Some studies have also reported that patients can see instruments and movement within their visual field during surgery, and in some cases, where vision is lost completely during surgery, light sensitivity was still present for each patient –24. HighIn conclusion, our research confirms the common observation that patients with bilateral cataract often experience more pain or ocular discomfort during the second consecutive cataract surgery, compared to the first procedure. The differences in subjective sensations, such as anxiety, eye bulges, ocular pain, and light sensitivity, between the first and second surgeries were not significantly related to patient age. During cataract surgery, the management of patient discomfort is important, not only for the patient's psychological well-being but also for influencing the surgical outcome. Therefore, the role of several factors that can influence patient comfort is a necessary additional consideration for surgeons treating patients who are undergoing consecutive surgeries for bilateral cataracts.


Neuropathic pain is one of the key features of  Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies.PubMed and Embase were searched up to September 2014 for relevant articles on treatment of neuropathic pain in FD.Seven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8. Carbamazepine appeared most beneficial: complete pain relief in 5/25, partial relief in 17/25, and no benefit in 3/25 patients. Phenytoin resulted in complete relief in 1/27, partial relief in 12/27 and no benefit in 6/27 patients. In 8 patients a significant reduction in the frequency of pain attacks was described. Gabapentin caused partial relief in 6/7 and no relief in 1/7 patients. Little evidence was reported for SSNRI’s or treatment combinations. Adverse-effects were reported in all treatment strategies.Only for carbamazepine, phenytoin and gabapentin there is evidence of effectiveness in neuropathic pain due to FD, but comparison of effectiveness between these drugs is lacking. In routine clinical practice adverse-effects may discourage use of carbamazepine and phenytoin in favor of second-generation antiepileptic drugs, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies. Fabry disease FD, OMIM 301500) is a rare X-linked inherited lysosomal storage disease caused by a deficient or decreased activity of the lysosomal enzyme α-galactosidase A, as a result of a mutation in the GLA gene. The consecutive accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in lysosomes of several cell-types results in kidney, heart and nervous system complications . Patient01500 is 2+ levels in peripheral sensory neurons and pain was shown [Neuropathic pain is one of the key features of the classical phenotype of the disease and has been shown to start on average at an age of 9 years in male patients and 16 years in female patients , but hasTwo types of pain often co-occur in classical FD: chronic pain in hands and feet and severe episodic pain attacks, also referred to as ‘Fabry crises’ , 11. Then = 53) of whom 51 % uses pain medication, chronically. In a post-marketing registry study, 71 % of patients used analgesics, 36 % used anticonvulsants and 23 % used NSAIDs [Treatment of neuropathic pain in FD starts with preventive measures and lifestyle changes, such as avoiding precipitating factors . Conservative therapy includes rest, holding icepacks, or administration of acetaminophen during febrile periods. Apart from these measures, additional pharmacological pain management is often necessary. A wide range of pain medication has been reported in the treatment of neuropathic pain in patients with FD. Gold et al.  report od NSAIDs . Furtherd NSAIDs . Despited NSAIDs . The curd NSAIDs . NeverthPubMed and Embase were searched from 1947 until September 2014 for relevant studies and reports on pain management strategies for neuropathic pain in FD. Key terms used were ‘Fabry disease’ and ‘pain’, including alternative notations. Also, ClinicalTrials.gov was searched to identify additional published or unpublished data. Additional reports were identified by hand searching the reference lists in the retrieved papers.We included clinical trials, case series and case reports on the effect of pain medication in children as well as adults with FD and neuropathic pain. Studies on the effect of ERT on pain and reviews were not included in this review. Furthermore, studies lacking data on outcome were excluded. Articles reporting only on analgesics (acetaminophen and NSAIDs) were excluded, because these are known to be ineffective in the treatment of neuropathic pain in FD and the renal involvement due to FD makes NSAIDs unsuitable for chronic use in these patients. Title and abstract of all identified studies were read. If considered relevant, full text was read and analyzed. Data on pain severity and number of patients treated, drug and dosing regimen, study design, study duration and follow up, outcome measures and results, withdrawals and adverse events were extracted by one author (YS). As primary outcome we recorded chronic pain reduction after any treatment period as assessed in each study. Pain reduction was classified as complete relief of pain, partial relief of pain and no effect on the scale used in each study. As secondary outcome measures we recorded i) reduction of the frequency of pain attacks as reported by the patient, ii) any pain related outcome indicating improvement or worsening, iii) treatment withdrawals due to lack of effect, and iv) any (serious) adverse event while on treatment.The search provided 728 articles , most often as mono-therapy . Patients used carbamazepine dosages of 100-600 mg/day, or 0.8-15.9 mg/kg/day. Complete relief of pain was described in 5 of the 25 patients on mono-therapy , 61, 67,In a study by Filling-Katz, 5 of 7 patients on carbamazepine therapy had a history of phenytoin use . PhenytoOne study published in 1962 described the use of pethidine in 2 male patients, in whom partial pain relief was achieved with 500-700 mg/day IM . Anothern = 27 patients) reported on adverse effects. In this study 1 patient suffered from dizziness, drowsiness and headache [Three out of 20 studies including 4 patients reported on adverse effects of carbamazepine. Dose-related autonomic complications were reported in 2 patients, and necessitated dose reduction in 1 patient and discontinuation in the other . Carbamaheadache . Furtherheadache . Few advheadache .This systematic review of the literature on neuropathic pain management in FD clearly demonstrates that currently available effectiveness data are mainly derived from case reports and small observational studies. This is disappointing when considering the high prevalence of chronic pain in patients with FD and the fact that analgesics are frequently prescribed by caregivers. Apparently, most physicians treating patients with FD have local procedures, based on either treatment protocols for painful neuropathies not specific for FD, or personal experiences. Of these drugs, anti-epileptics, including carbamazepine, gabapentin and phenytoin appear to be prescribed most often.Based on this review we conclude that there is class IV evidence that carbamazepine and phenytoin are effective in the treatment of FD neuropathic pain, although it remains unclear to which extent. This is in agreement with previous reviews reporting on drug use for neuropathic pain in FD , 68. ForAs is evident from this review, the literature does not provide an answer to the important pragmatic question which drug should be prescribed for the treatment of neuropathic pain in FD. In addition, there is no sound evidence in which order drugs should be evaluated. Clinical practice has shown that most patients may achieve good results with carbamazepine or phenytoin. Phenytoin, however, is known to be associated with a number of potentially troublesome adverse events, including neurologic and hematologic effects . In addiVice versa, other commonly prescribed drugs in patients with FD  may increase the serum concentration of phenytoin and carbamazepine by inducing CYP enzymes . In womeLittle has been reported about the use of dual serotonin and norepinephrine reuptake inhibitors such as venlafaxine and duloxetine in treating neuropathic pain due to FD. Duloxetine has shown consistent effectiveness in painful diabetic peripheral neuropathy, with effectiveness sustained for 1 year in an open-label trial . UnfortuMost of the medications we have discussed provide only partial pain relief, and adverse effects may limit dose escalation. Hence, in clinical practice, it would make sense to use 2 or more medications in combination in order to achieve either an additive beneficial effect or a reduction in the adverse effects associated with the use of a high dose of a single drug. However, little evidence is available to support the use of such combinations. Recently, combination therapy is advised if at least two monotherapies failed to relieve pain in FD . A treatSince conditions that cause neuropathic pain in children are relatively uncommon, data on general neuropathic pain treatment in children are limited by small numbers and few randomized controlled trials, leaving clinicians with many unanswered questions regarding clinical practice . It is uAlthough evidence exists suggesting that some diseases causing neuropathic pain respond differently to the same medications , we can Taking all these findings and considerations into account we developed a treatment algorithm for pain management in patients (adults as well as children) with FD at our hospital . In line with the expert panel report , the incStudies on the effect of ERT on neuropathic pain have shown conflicting results. Agalsidase alfa reduced the severity of neuropathic pain in a randomized controlled trial (RCT), but an imbalance in baseline pain scores hampers the interpretation of the results . A RCT oThe predominance of case-reports in this review has to be considered as a source of bias and therefore caution is needed in interpreting the data. Meaningful comparison of effectiveness with other interventions is not possible. In addition, this review suffers greatly from the lack of details provided in the case reports and case series.Perhaps the most important conclusion of this review is the need to perform large, high quality, long duration studies using robust endpoints that actually measure effectiveness of different analgesic drugs in FD neuropathic pain. It would be of particular interest to compare first generation  with second generation antiepileptics . Such a study would require a uniform group , and an easily interpretable clinical endpoint  for an extended period of time. As soon as such study results are published we will be able to update the currently presented treatment algorithm.All authors declare that the article has not been submitted for publication elsewhere. All authors thoroughly inspected the manuscript and contributed equally. Every author agreed to submit the article in BMC Neurology.


This study aimed to examine the efficacy and safety of cryoablation, combined with zoledronic acid or alone, in the treatment of bone metastatic pain. A total of 84 patients were randomly divided into three groups: group A (cryoablation plus zoledronic acid), group B (cryoablation) and group C (zoledronic acid). In group A, the overall response [OR = complete response (CR) + partial response (PR)] was 85.7% (24/28), the CR was 35.7% (10/28) and the PR was 50.0% (14/28). In group B, the OR was 50.0% (14/28), the CR was 14.3% (4/28) and the PR was 35.7% (10/28). In group C, the OR was 67.9% (19/28), the CR was 21.4% (6/28) and the PR was 46.4% (13/28). The differences in OR, CR and PR among the three groups were statistically significant (P<0.05). The mean onset time of pain relief for the cryoablation combined with zoledronic acid treatment group was 1.96±2.26 days, for cryoablation treatment alone was 1.43±1.79 days and for zoledronic acid alone was 11.67±3.14 days; there were statistically significant differences among the three groups (P<0.05). The response duration was 146.68±1.89 days in group A, 71.60±2.94 days in group B and 112.99±1.37 days in group C; the differences among the three groups were statistically significant (P<0.01). In conclusion, cryoablation combined with zoledronic acid is an effective and safe therapeutic strategy for the treatment of bone metastatic pain. Bone metastasis is one of the most common complications in late stage malignancies, including in lung, breast, prostate and renal cancer. Approximately 20~70% patients with malignancy have bone metastases in the later stages and bone metastatic pain is a highly discomforting condition for patients . EffectiRadiotherapy and surgery had been used for the relief of bone metastatic pain. However, there are limitations to these approaches, particularly the injury of normal tissue surrounding the diseased lesions. Percutaneous ablation offers an effective minimally invasive alternative therapy to treat patients with limited bone metastases. Ablation may also be considered as an alternative to, or used in conjunction with, systemic therapies. Cryoablation with accurate ablation extent monitoring is an excellent form of ablation for eliminating the lesions of bone metastases ,13.Bisphosphonates are analogs of pyrophosphates that are able to improve bone metabolism and inhibit several components of the bone resorptive process. Bisphosphonates currently have an important role in the treatment of skeletal complications associated with metastatic bone disease. Zoledronic acid is a later-generation bisphosphonate that has been identified as having the most potent inhibitory activity as an antiresorptive drug. To the best of our knowledge, there are no other studies concerning the use of cryoablation in combination with zoledronic acid treatment in bone metastatic pain –16.The purpose of this prospective case-controlled study was to determine the safety and efficacy of percutaneous cryoablation combined with zoledronic acid for the reduction of bone metastatic pain, with the aim of improving the quality of life for patients with painful metastatic tumors involving bone.A total of 84 cases of malignant tumor bone metastases with pain between June 2008 and October 2012 were recruited into the study. Patients were randomly divided into three groups. Group A patients were subject to targeted argon-helium cryoablation once and were monthly administered an injection of zoledronic acid (4 mg) dissolved in 0.9% sodium chloride injection (100 ml), by intravenous drip for >15 min, for a total of >6 times. Group B patients were subject to targeted argon-helium cryoablation of metastatic lesions once. Group C patients were monthly administered an injection of zoledronic acid (4 mg) dissolved in 0.9% sodium chloride injection (100 ml), by intravenous drip for >5 min, for a total of >6 times.2+ levels were >2.00 mmol/l; iv) the functions of heart, liver, kidney and other vital organs were mostly normal; v) physical Karnofsky performance status (KPS) was >60. 0%; vi) patients enrolled signed an informed consent form; and vii) subjects were able to tolerate preoperative and postoperative plain and enhanced CT scanning.The inclusion criteria of this prospective study were: i) a metastatic bone tumor confirmed by histological or cytological examination and/or imaging, including systemic computed tomography (CT) and magnetic resonance imaging (MRI), and bone emission computed tomography, with moderate to severe pain; ii) a life expectancy of >6 months; iii) blood routine examination was normal and serum CaThe exclusion criteria of this prospective study were: i) patients diagnosed with primary bone cancer by pathology; ii) patients with impending fractures; iii) unwilling to accept cryoablation and/or zoledronic acid therapy; iv) intolerant of targeted argon-helium cryoablation due to severe dysfunction of vital organs, including heart, liver and kidney; v) blood coagulation disorders; and vi) serious hypocalcemia.2 test. The present study was conducted in accordance with the Declaration of Helsinki, and with approval from the Ethics Committee of the First Hospital of Lanzhou University . Written informed consent was obtained from all participants. The detailed demographic data are summarized in A total of 84 cases of malignant tumor bone metastatic pain in patients aged between 37 and 72 years were enrolled. Among them, there were 44 male cases and 40 female cases. The patients suffered from lung cancer in 30 cases, breast cancer in 23 cases, digestive system cancer in 7 cases, kidney cancer in 9 cases, nasopharyngeal carcinoma (NPC) in 4 cases and other tumor types in 11 cases. Patients were randomly divided into three groups: group A (28 cases) argon-helium cryoablation combined with zoledronic acid), group B  and group C . There were no statistically differences in gender, age, pain intensity and activity ability among the three groups, as determined by a Student’s t-test and χA minimally invasive, targeted argon-helium cryoablation operating system was used, which comprised an argon-helium cryoablation system, and cryoprobes with diameters 1.7, 2.4 and 3.8 mm  and a 16- or 64-slice CT instrument .All patients were informed of the relevant precautions and operational risk and provided informed consent. Preoperative plain CT scanning was obtained to confirm tumor range and select the freezing levels, and to identify the feeding angle and direction. Metal markers were used as guides to determine the puncture point. The group A patients were provided targeted argon-helium cryoablation to metastatic lesions once and were monthly administered an injection of zoledronic acid (4 mg) dissolved in 0.9% sodium chloride injection (100 ml) by intravenous drip for >15 min, for a total of >6 times. Group B patients were subject to targeted argon-helium cryoablation to metastatic lesions once. Group C patients were monthly administered an injection of zoledronic acid (4 mg), as described for group A.Prior to therapy with cryoablation, the effect of focal painful bone metastasis was assessed by use of the verbal rating scale (VRS), and the KPS was used for assessment of the patient’s quality of life. Analgesic medicine use was also recorded. Each patient was instructed to specifically respond to the VRS questions with respect to the focal painful metastasis that was to be treated. Patients were physically examined by an interventionalist prior to treatment to determine whether the site or sites of focal pain correlated with the available imaging, including CT, MRI and ultrasound imaging, which was obtained immediately following entrance into the study. A complete blood count and prothrombin time were obtained within one week of the ablation procedure. Each patient’s history of previous chemotherapy and radiation therapy was recorded. Complications were recorded throughout the follow-up period and classified via Common Terminology Criteria for Adverse Events  .Following routine sterile preparation, 0.2% chloroprocaine was used to anesthetize the puncture point. The 1.7, 2.4 or 3.8 mm cryoprobes were placed into a 6, 9 or 11F sheath tube and inserted into the metastatic lesions; the feeding direction and depth were under the guidance of plain CT scanning. A single cryoprobe was placed for lesions ≤3 cm in diameter. For larger lesions, two to five additional cryoprobes were systematically placed with CT guidance. Cryoablation treatments were focused on the margin of the lesion involving bone to treat the soft-tissue-bone interface . Plain C2+ is 2.0–2.6 mmol/l.The pain improvement was continuously observed for 180 days following the treatments. One day prior to treatment and 7, 14 and 21 days following treatment, the general condition, blood calcium, blood routine, liver function, renal function, blood biochemistry, urine routine and electrocardiogram of patients were measured. The normal range of blood CaThe VRS was presented to the patient as a series of descriptions, ranked and numbered as follows: no pain, 0; mild pain, 1; moderate pain, 2; intense pain, 3; extremely intense pain, 4. The primary endpoints were complete response (CR) defined as the absence of pain without the need for increasing analgesic relief, and partial response (PR) defined as an improvement ≥2 on the ordinal scale with no requirement for increasing analgesic relief. The patients with the same or worse pain level at three weeks were considered to have no response (NR). The responses were assessed by follow-up or with telephone interviews. The responses were examined at 3 and 24 weeks. The response durations were calculated from the first date evaluated at 3 weeks to the date of relapse, or in absence of relapse to the date of last assessment or mortality ,19.Potential adverse reactions of the therapies include active bleeding, frostbite, fever, muscle pain, nausea and vomiting, skin rash, hypocalcemia and dysfunction of the kidneys and liver.2 test was used to assess the differences in gender, malignant hypercalcemia, pain medication and primary tumor location and type. P<0.05 was considered to indicate a statistically significant difference.Student’s t-test was used to assess the differences in age, KPS score and VRS score of each group. χFollowing 180 days of treatment, according to the efficacy assessment criteria, the CR, PR and OR were counted in each group. In group A, the OR was 85.7% (24/28), the CR was 35.7% (10/28) and the PR was 50.0% (14/28). In group B, the OR was 50.0% (14/28), the CR was 14.3% (4/28) and the PR was 35.7% (10/28). In group C, the OR was 67.9% (19/28), the CR was 21.4% (6/28) and the PR was 46.4% (13/28). Next, the therapeutic effects were compared between each of the groups. The statistical results demonstrated that the analgesic effect in group A was the highest, compared with that in groups B and C (P<0.05). No distinct difference in analgesic effect was observed between groups B and C .The results revealed that in group A the onset time of pain relief was 1–4 days, averaging at 1.96±2.26 days, with the fastest onset time in a patient noted as 1 day. In group B, the onset time was 1–3 days, averaging at 1.43±1.79 days. In group C, the onset time was 6–14 days, with an average of 11.67±3.14 days. The onset time was significantly different among the three groups (P<0.05). The fastest onset times in group A and B were markedly shorter than that in group C . The resThe incidence of adverse effects and complications was 85.7% in group A, 82.1% in group B and 14.3% in group C. The adverse effects and complications were considered to arise mainly due to the argon-helium cryoablation; therefore, they were significantly higher in groups A and B compared with those in group C . The majority of the adverse effects and complications were relatively mild and the majority were alleviated following short-term treatment .Bone metastasis is one of the common complications in late malignant tumors. Approximately 50% of patients who develop bone metastases will develop poorly controlled pain during the course of their disease –22.The present study reported significant evaluation of analgesia and improvement in quality of life for patients with focal painful bone metastases following percutaneous cryoablation combined with zoledronic acid treatment. Profound analgesic relief was reported in the three groups of patients, with rates of 85.7% in group A (24/28), 50.0% in group B (14/28) and 67.9% in group C(19/28). All of these strategies relieved the pain associated with bone metastases, but cryoablation combined with zoledronic acid appeared to have more efficacy than that observed for either treatment alone. The response duration for the patients was 146.68±1.89 days in group A, 71.60±2.94 days in group B and 112.99±1.37 days in group C. The analgesic relief provided by percutaneous cryoablation combined with zoledronic acid lasted longer than that in the other two groups.Bone metastasis itself is not fatal in the short term. However, it may develop into pathological fracture and spinal cord compression resulting in severe complications, including paraplegia, if it is not effectively treated and well controlled.Zoledronic acid has been reported to be the most effective of all bisphosphonate drugs. The mechanisms of zoledronic acid in the treatment of malignant tumor bone metastases include: i) inhibiting the maturation of osteoclasts; ii) restraining the gathering and functioning of osteoclasts; iii) reducing the production of cytokines (such as IL-6); iv) direct antitumor activity  inhibiting tumor cell adhesion and infiltration in the bone matrix; and vi) antiangiogenic effects –25.Previous studies have reported that zoledronic acid has a strong effect on bone metastatic pain, prolonged analgesic activity and mild adverse reactions; therefore, it has become one of the main analgesics used to relieve the pain of bone metastases. Zoledronic acid is the first bisphosphonate that has demonstrated effectiveness in all types of malignant tumor bone metastases. In the present study, groups A and C were administered zoledronic acid to treat metastatic bone pain, and the duration of the effect was longer than that observed in group B  without zoledronic acid. By contrast, the onset time of zoledronic acid alone was slower than that of cryoablation, and its effect was poorer than that for its combination with cryoablation. Argon-helium cryoablation has a number of unique advantages in treating cancer-associated pain, particularly bone metastatic pain ,27.There are numerous causes of pain in cancer patients; the primary causes are invasion and oppression of the neighboring bone, nerves, skin, viscera and pleura by tumors, which often cause continuous and or severely irritant pain. As argon-helium cryoablation has been confirmed to be effective in destroying tumor lesions locally by freezing, it may relieve or reduce the invasion and oppression of neighboring tissues and organs by the tumor. Therefore, cryoablation possesses potential analgesic and pain-relieving properties. Cancer pain due to tumor development and invasion is the main diagnostic indicator for the initiation of cryoablation therapy. The effective treatment of cancer-associated pain by argon-helium cryoablation is based on its ability to directly destroy tumors. Compared with other therapies, cryoablation may not only relieve pain but also control and regulate the pathological effects of the tumor. Furthermore, it has a confirmed effect, causes only mild injury, has fewer complications and has no toxic adverse effects, amongst other advantages ,29. In tIn the present study, argon-helium cryoablation was applied to treat bone metastatic pain. A CR was achieved in 85.7, 50.0 and 67.9% of patients in the groups treated with cryoablation combined with zoledronic acid, cryoablation alone and zoledronic acid alone, respectively. There were statistically significant differences among the three groups (P<0.05). The results demonstrated that cryoablation combined with zoledronic acid exerted significantly fast responses and durable effects on bone metastatic pain, which was superior to that of cryoablation or zoledronic acid alone as this combination remedies the demerits of both therapies. Additionally, no severe adverse effects and complications were observed for this combination, suggesting that this combined treatment is an acceptable therapeutic option for patients with bone metastatic pain. However, further large-scale studies are required to confirm these results and determine their clinical utility in the treatment of bone metastatic pain.


Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease-specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by chronic abdominal pain and/or discomfort, and accompanied by altered bowel patterns , 2. AlthIBS is considered a ‘functional disorder’ given that alterations in bowel function and associated symptoms manifest in absence of any apparent structural or biochemical disease process. Despite the fact that IBS diagnosis has evolved from one entirely based on exclusion to a symptom-based approach currently embodied by Rome III criteria , 11, diaTo date, the pathophysiology of IBS is not well understood. The etiology of this syndrome is considered multifactorial, with central sensitization a likely contributing factor –15. A nuThe primary aim of this study was to identify concurrent structural and functional brain changes in adolescents with a clinical diagnosis of IBS relative to healthy controls using MRI. A secondary aim was to examine whether alterations in brain morphology were related to abdominal pain severity, health-related quality of life (HRQOL) as it pertains to GI-specific symptoms, and clinical measures of disease duration and pain intensity (over the past week). Specifically, we asked the following questions: (1) Are there significant structural and functional changes in the brains of pediatric patients with IBS compared to healthy cohorts? (2) If so, do these brain changes in adolescents with IBS parallel those reported in adults? and lastly, (3) To what extent are these changes associated with the severity of current abdominal pain, impact of GI-related symptoms on health and well-being, and clinical variables such as disease duration and retrospective pain intensity ratings?Nineteen adolescents  diagnosed with IBS  were prospectively enrolled in this study. All patients were frequency matched to healthy controls on the basis of age and gender . All study-related procedures and materials were approved by the Boston Children’s Hospital (BCH) Institutional Review Board  and conducted in accordance with the Declaration of Helsinki.Pediatric patients with IBS were recruited from the Motility and Functional Gastrointestinal Disorders Center and the General GI Clinics at BCH. Diagnoses were made by a gastroenterologist (S.N.) using pediatric Rome III criteria , 21. AllAll patients fulfilled diagnostic criteria for IBS using The Questionnaire on Pediatric Gastrointestinal Symptoms—Rome III Version . In addiThe API was used to provide an overall measure of abdominal pain severity and consisted of five items assessing the frequency, duration, and intensity of abdominal pain in the past two weeks. The PedsQL is a 23-item questionnaire, using a 5-point Likert scale , that measures the core dimensions of health and well-being in terms of physical (8-items), emotional (5-items), social (5-items) and school functioning (5-items). This measure yields a PedsQL total score with lower scores representing greater GI related symptoms and decreased health-related quality of life. The PedsQL GI Symptoms Module contains 74-items from 14 different scales describing both GI and non-GI related symptoms. All items on this measure, like the core PedsQL, use the same 5-point Likert response scale. The PedsQL GI Symptoms Total Score (58-items) was calculated by reverse scoring and averaging responses from the ten GI-specific symptom scales . This yielded a measure of the impact of IBS-related symptoms on overall health and well-being across the last month, with lower scores reflecting greater impairments in quality of life. In addition, impairments in physical functioning and limitations due to symptoms were assessed using the FDI, a 15-item measure that asks participants’ to rate the level of difficulty associated with performing routine daily activities on a 5-point Likert scale ranging from 0 (“no trouble”) to 4 (“impossible”), with higher scores reflecting greater functional disability. The presence of mood disorders, including depression and anxiety was evaluated using the RCADS. The RCADS is a 47-item, self-report questionnaire with subscales that include separation anxiety disorder, social phobia, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and major depressive disorder. It also yields a Total Anxiety Score . Items are rated on a 4-point Likert-scale from 0 (“never”) to 3 . Lastly, the PCS-C is a 13-item questionnaire used to examine how catastrophic thinking is related to the experience of pain in children. The pain catastrophizing construct is comprised of three dimensions: rumination, magnification, and helplessness. Patients are asked to rate how strongly the thought or feeling prevails when experiencing pain. Items are rated from 0  to 4 .In addition, clinical outcome measures including disease duration (duration of IBS symptoms in yrs.) and pain intensity (over the past week) in relation to IBS symptoms were evaluated by a gastroenterologist at the time of the clinical visit, with the latter assessed verbally using a 0 to 10 numerical rating scale .Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution, T1-weighted magnetization-prepared rapid gradient-echo sequence was acquired for each participant . The anatomical scan was followed by a functional T2-weighted echo-planar imaging scan during ‘resting-state’ wherein participant was instructed to relax with eyes open . Diffusion tensor imaging and pseudo-continuous arterial spin labeling scans were also acquired following the resting-state functional MRI (fMRI) scan (data to be presented in a separate report). Total scan time was approximately 50 min.http://surfer.nmr.mgh.harvard.edu), a semi-automated toolbox for reconstruction and visualization of the cortical surface  or eTIV . Furthermore, the Chi-square test showed no difference in the proportion of males to females between groups .Out of the 19 adolescent patients enrolled in the study, two were excluded from all statistical analyses; one patient was omitted due to being asymptomatic (no longer presenting with IBS symptoms) at the time of scanning, while another patient’s structural data was deemed unusable due to excessive motion artifacts. Thus, the final study sample consisted of 17 adolescents with IBS  that were age and gender matched to 17 healthy cohorts . The demographic distribution for ethnicity of the entire sample was 88.24% Caucasian (30/34), 8.82% Asian (3/34), and 2.94% African American (1/34) . One-way ANOVAs reveled no significant group differences between age  and therefore will not be discussed further.Surface-based analysis revealed significant associations between cortical thickness and abdominal pain severity as assessed by the API . In patiPediatric patients with greater HRQOL and reduced GI-specific symptoms , exhibited significant cortical thinning in the right PCC and left anterior insula (aINS) . NegativResults from the cortical thickness linear regression analysis with clinical variables are presented in a priori hypotheses, we limit the presentation of these findings to the results section; however, supplementary information including a table , buried deep within the ventral bank of the posterior cingulate sulcus. The PCC is putatively involved in a number of processes : (1) it In addition to increased cortical thickness in the dPCC, significant cortical thinning was also observed in pediatric IBS patients, relative to controls, in fronto-parietal areas such as the DMPFC, DLPFC, and PPC. The latter two areas comprise nodes of the cognitive control network (CCN)  and haveIn a study conducted by Seminowicz et al. (2010) gray matter volume (GMV) decreases were also observed in the PPC and rostral areas of the DLPFC (BA 46) in adult IBS patients compared to controls, whereas increases in the caudal portion of the DLPFC (BA 9) were found . Thus, oAnother important finding to emerge from this study was that pediatric IBS patients reporting greater abdominal pain severity, assessed using the API, showed significant bilateral cortical thickening in the inferolateral areas of SI, corresponding to the intra-abdominal or ‘viscerotopic’ homunculus and extending into the intraoral area. Histochemical tract-tracing and extracellular recording studies performed in monkeys and cats have shown that the intra-abdominal area of SI receives viscero-viscero and viscero-somatic inputs from third-order neurons arising predominantly via the spinothalamic tract, however, dorsal-column medial lemniscal , 88 invo2; NVtxs = 12), but this was in the opposite direction. Furthermore, Davis et al. did not examine cortical thickness in relation to behavioral indices, making direct comparisons between studies untenable. Jiang et al. (2013) did examine disease severity and other psychometric measures in adult patients versus controls in relation to cortical thickness, however they report no significant correlations between cortical thickness in the aINS and their disease severity measures. Others have reported aINS thickening that was associated with longer disease durations [We also identified cortical thinning in the left aINS and right dPCC that was associated with greater HRQOL and a lessening of GI-specific symptoms in pediatric patients. These findings are intriguing given the role that the insula and PCC plays in pain processing and interoceptive awareness and in context of previous neuroimaging studies demonstrating abnormal functioning of these areas in patients with IBS and other chronic pain conditions , 100–106urations  in adultAdditionally, our finding of cortical thickness changes in the superior temporal sulcus (STS)  in relation to improved HRQOL and a lessening of GI-specific symptoms is also of interest. While little is known about the role of this  region of the temporal lobe in relation to chronic pain, previous reports indicate that there may be a consistent contribution to pain processing. Alterations in functional responses to noxious heat  in an ovDisease duration was correlated with cortical thickening in the bilateral DLPFC, an area which has been implicated in higher-order functions including cognitive control processes such as decision making, attention and descending pain modulation. It is noteworthy that cortical thickening in the supramarginal gyrus and cortical thinning in the lingual gyrus were also significantly related to duration of IBS symptoms. We have previously reported increased functional changes in the supramarginal gyrus in response to noxious heat in migraine patients and suggested a putative role for this region in pain may relate to cognitive interpretive processes . This rea priori using 3dClustSim . Nevertheless, the discrepancy in findings between our study conducted in adolescents and previous studies conducted in adults may relate to a number of factors, including differences in age, severity of IBS symptoms, and duration of disease. Clearly, the pediatric brain is not mature and therefore highly mutable in comparison to the adult brain. Although age was specified as regressor of no interest in the present study and therefore controlled for in the analysis, these differences in findings could be due to the developing nature of the pediatric brain relative to the more mature, adult brain. Moreover, as one might expect our adolescent IBS patients had much shorter disease durations (1–10 yrs.) compared to adult IBS patients (2–20 yrs.) sampled in the study by Blankstein et al. (2010) and this difference may underlie the observed differences in aINS cortical thickness since longer disease durations may produce more profound structural and functional brain changes that are not readily observed in the early stages of this syndrome. The notion that early brain changes may produce secondary effects with time has not been evaluated in adult or pediatric patients , but should be an area of future study.In contrast to previous findings reported by Blankstein et al. (2010) demonstrating cortical thinning in the aINS associated with longer disease durations in adult patients with IBS, we found no significant relationship between cortical thickness and disease duration for this brain region . However3 receptor antagonist that was predicted by attenuated activity in the bilateral OFC and left medial temporal gyrus in response to rectal distention prior to drug treatment [We also report an association between pain intensity scores and structural changes in the OFC. Specifically, patients reporting greater pain intensity associated with their IBS symptoms also showed significant cortical thickening localized to the bilateral OFC. The OFC is highly interconnected to limbic structures including areas involved in autonomic and stress-related physiological and behavioral responses . This rereatment . Additioreatment . Using VHere we used resting-state fMRI and the regions noted above, that exhibited significant group differences in cortical thickness presumably due to underlying pathophysiology of IBS, as seeds in our RS-FC analysis . We also examined seeds in areas that showed structural changes that correlated with measures of abdominal pain severity and GI-specific symptoms in relation to HRQOL in the right intra-abdominal area of SI and the left anterior insula. In this way insights into how structural changes may be linked to reorganization of functional brain networks can be ascertained, although causal inferences still cannot be made.Our seed-based analysis revealed altered RS-FC within key nodes of the DMN and CCN networks in adolescent patients with IBS. Specifically, we identified significant differences in RS-FC between the right PCC seed and the left DLPFC in patients relative to healthy cohorts of similar age. Inspection of the data revealed that this difference in RS-FC was not simply due to greater increases in RS-FC between the PCC-DLPFC in patients versus controls, but rather resulted from a diminution in anti-correlated connectivity patterns in the former group relative to the latter. Previous reports of alterations in canonical nodes of intrinsic connectivity networks such as the DMN have been described in clinical pain conditions , 125–128Several limitations should be mentioned in context of the present study findings. First, our sample of adolescents with IBS diagnosis was heterogeneous with respect to bowel habit subtype, with the majority of patients classified as constipation predominant, therefore limiting the generalizability of our results. A second major limitation was that medications with psychotropic effects were not controlled for in the patient group and this could have negatively influenced our results. However, it should be noted that inclusion of patients on psychotropic medications was restricted to those patients on low to moderate, stable doses. Third, a lack of psychometric measures for the healthy control group limits our ability to determine whether depression or anxiety influenced our results since we had little to no data with regard to these metrics between groups and therefore could not control for these variables in our analyses. Lastly, our study design was cross-sectional and therefore prevents us from making causal inferences. Future studies utilizing a longitudinal design in pediatric IBS patients are needed in order to determine whether the observed alterations in brain architecture and intrinsic network functioning are a consequence of IBS symptoms over time, or represent an antecedent, premorbid brain state that renders the brain vulnerable to the development of gut-brain signaling abnormalities, which in turn may lead to IBS.In the present study, we evaluated concurrent structural and functional brain changes in adolescents with a diagnosis of IBS relative to a healthy cohort. We report both increases and decreases in cortical thickness in areas involved in cognitive inhibitory control, pain-related processes, viscerosensory motor and interoceptive functions, that were correlated with measures of abdominal pain severity, HRQOL in relation to GI-specific symptoms and disease severity measures such as duration of IBS symptoms and pain intensity. In addition, we also found atypical intrinsic RS-FC patterns between DMN and cognitive control network nodes, a finding which may reflect a shifting of attentional resources towards viscerosensory and interoceptive processes related to ongoing, abdominal pain. Whether these structural and functional brain changes are disease-driven or antecedent to the onset of childhood IBS remains to be determined. These brain changes  may have long-term consequences on future behavior , health and well-being, of individuals affected by IBS during their childhood years.S1 Fig(TIF)Click here for additional data file.S1 TableAbbreviations: NVtxs = number of vertices; R = right; L = left; PPC = posterior Parietal Cortex; PCC = posterior cingulate cortex; SI = primary somatosensory cortex; MNI = Montreal Neurological Institute.(DOCX)Click here for additional data file.S2 TableAbbreviations: PedsQL = Pediatric Quality of Life Inventory; PedsQL GI Module = Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module; API = Abdominal Pain Index; FDI = Functional Disability Inventory PCS-C = Pain Catastrophizing Scale−Child version.(DOCX)Click here for additional data file.S3 TableAbbreviations: NVtxs = number of vertices; R = right; L = left; MNI = Montreal Neurological Institute; FDI = Functional Disability Inventory; SI = primary somatosensory cortex; PCC = posterior cingulate cortex; PPC = posterior parietal cortex; PCS-C = Pain Catastrophizing Scale−Child version; DLPFC = dorsolateral prefrontal cortex.(DOCX)Click here for additional data file.


Cancer-related fatigue greatly influences quality of life in cancer patients; however, no specific treatments have been established for cancer-related fatigue, and at present, no medication has been approved in Japan. Systematic research using patient-reported outcome to examine symptoms, particularly fatigue, has not been conducted in palliative care settings in Japan. The objective was to evaluate fatigue, pain, and quality of life in cancer patients at the point of intervention by palliative care teams.Patients who were referred to palliative care teams at three institutions and met the inclusion criteria were invited to complete the Brief Fatigue Inventory, Brief Pain Inventory, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative.Of 183 patients recruited, the majority (85.8%) were diagnosed with recurrence or metastasis. The largest group (42.6%) comprised lung cancer patients, of whom 67.2% had an Eastern Cooperative Oncology Group Performance Status of 0–1. The mean value for global health status/quality of life was 41.4, and the highest mean European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative symptom item score was for pain (51.0). The mean global fatigue score was 4.1, and 9.8%, 30.6%, 38.7%, and 20.8% of patients’ fatigue severity was classified as none (score 0), mild (1–3), moderate (4–6), and severe (7–10), respectively.Cancer-related fatigue, considered to occur more frequently in cancer patients, was successfully assessed using patient-reported outcomes with the Brief Fatigue Inventory for the first time in Japan. Results suggested that fatigue is potentially as problematic as pain, which is the main reason for palliative care. Cancer-related fatigue (CRF) is defined as “a physical, emotional, and/or perceived fatigue or tiredness, with a persistent and subjective sense related to cancer or cancer treatments that is disproportionate to recent activities and interferes with usual functioning.” The prevThere is evidence that 4 mg dexamethasone is effective for cancer-related fatigue . TherefoIn Japan, Morita et al. researched various symptoms experienced by patients, which were estimated by a palliative care team (PCT) and a palliative care unit, using the Japanese version of the Support Team Assessment Schedule (STAS), in which symptom levels are rated using a scale ranging from 0 to 4 . The preMinton et al. recommend the use of the Fundamental Assessment of Cancer Therapy: Fatigue questionnaire and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess CRF . In addiThis study investigated relationships between fatigue, pain, and QOL by focusing on fatigue in PROs. We selected the BFI, Brief Pain Inventory (BPI), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative (EORTC QLQ-C15-PAL) as assessment tools and included the Pain Management Index (PMI) to evaluate the correlation between inadequate analgesia and QOL. Our expectation was that fatigue assessed via an appropriate tool would be as prevalent as pain and exert an impact on QOL. The objective of the study was to evaluate patients’ QOL and the prevalence of fatigue and pain at the point of PCT intervention, in order to elucidate relationships between fatigue, pain, and QOL.The protocol for this observational study was prepared according to the Helsinki Declaration and the Ethical Guidelines for Epidemiology Research . EthicalThe following inclusion criteria were applied: 1) aged between 20 and 80 years, 2) a performance status (PS) of 0–3 on the Eastern Cooperative Oncology Group (ECOG) scale, 3) a diagnosis of any type of cancer, and 4) ability to complete the questionnaire unaided. The exclusion criteria were as follows: 1) presence of dementia, agitation, or delirium; 2) presence of a mental disorder; and 3) an investigator’s decision that a request for survey participation would be inappropriate .Of the patients referred to PCTs at three institutions between May 2012 and August 2013, 185  met the inclusion criteria and were invited to complete self-rated questionnaires to determine QOL and fatigue and pain levels.The BFI is a questionnaire, originally developed in English, for which validity and reliability have been verified. It is designed to assess fatigue in cancer patients . OkuyamaThe EORTC QLQ-C15-PAL was developed by reducing the EORTC QLQ-C30, which is a comprehensive evaluation tool for cancer patients receiving palliative care . The EORThe BPI is a comprehensive assessment tool for pain, developed by the Pain Research Group of the World Health Organization Collaborating Centre for Symptom Evaluation in Cancer Care . The valThe PMI is a measure of the appropriateness of pharmacological strategies and compares the potency of prescribed analgesic medications using patient-reported pain levels. Analgesics were classified into four levels: 0: no analgesic; 1: nonopioid; 2: weak opioid; 3: strong opioid. Pain levels were scored as follows: 1–3: mild; 4–7: moderate; and 8–10: severe. PMI scores are calculated by subtracting patient-reported pain levels from analgesic levels, which produces a score range of -3 to 3. Negative scores (<0) indicate inadequate analgesia, and positive scores (≥0) indicate adequate analgesia .The mean scores for each of the 9 BFI items were calculated to produce GFSs, for which mean values were obtained. The proportions of patients in the mild, moderate, and severe fatigue groups were also calculated. Summary statistics were produced for QOL (EORTC PAL-15) and pain (BPI and PMI) upon PCT referral, and the relationship between these scores and fatigue was discussed. Spearman’s correlation coefficients were estimated to determine associations between measured items. JMP-Pro 11 (SAS Institute Inc.) was used in the analysis.Of the 185 registered patients included in the study, data from two, who did not complete the BFI questionnaire, were excluded. The mean (SD) GFS value was 4.1 (2.5), and the mean score (SD) for the worst fatigue experienced (BFI-3) was 4.3 (2.8). Regarding the influence of pain on daily life, the lowest and highest mean scores were found for “relationships with other people” (3.6) and “normal work” (4.8), respectively.Moderate to severe fatigue and pain were reported by 59.5% and 64.1% of patients, respectively.The mean BPI-3 (the worst pain) score was 4.9 (SD 3.0). The supporting information file (S1) summarizes the correlations between all measured items. GFS was strongly positively correlated with all BFI items (0.80–0.89). BFI-6  and nausea and vomiting (0.10) were weakly positively correlated, as were BFI-5 (mood) and dyspnea (0.15)This study evaluated fatigue, pain, and QOL in cancer patients referred to PCTs in three acute care hospitals. Approximately 60% of the patients demonstrated worse than moderate fatigue (according to GFSs), indicating that such patients experience moderate to severe fatigue.Although the proportion of patients experiencing CRF has been reported within a wide range (14–95%), to our knowledge, no Japanese studies have used PROs to assess global fatigue –22. Our GFS results showed that moderate or severe CRF, was found in a high proportion of patients (59.5%). This indicated that the majority of patients referred to PCTs at acute care hospitals experience moderate to severe fatigue.The BFI subscales, BFI-4 to BFI-9, and BFI-8 (relationships with other people) displayed the lowest score (mean: 3.6). This finding may have resulted from only observing inpatients. The hospital environment is presumed to limit relationships with others, which may have been reflected in the scores.In our study, moderate to severe fatigue and pain were reported by approximately 60% and 64% of patients . This inA previous study, reported by PCTs and conducted at one of the hospitals involved in the current study , used a proxy the Support Team Assessment Schedule (STAS) . ModeratLee et al.  reportedIn this study, PMI results  showed tWith respect to symptom scores, average pain and fatigue scores were high at 51.0 and 50.6 respectively, and the emotional functioning score was the highest at 64.5. Pain and fatigue were strongly positively correlated, with a correlation coefficient of 0.4, and emotional functioning and pain and fatigue were strongly negatively correlated, with correlation coefficients of -0.4 and -0.5 respectively. In previous studies, pain, fatigue, and depression have been reported to form symptom clusters –31. In oProportions of patients experiencing moderate and severe fatigue in GFSs and pain on the BPI (classified according to the PMI) were high at 59.5% and 64.1%, respectively. This suggests that fatigue is as problematic as pain for cancer patients hospitalized in acute care hospitals. As approximately 20% of patients experience severe fatigue, it is considered an important symptom that should not be ignored in PCT interventions.Bone metastasis was observed in 35.5% of participants and is commonly assumed to be a cause of pain. All participating study sites were acute care hospitals, and a high proportion of patients, 42.1%, were treated with chemotherapy upon admission to the hospital. Therefore, PCTs in acute care hospitals have the greatest likelihood of observing adverse events. Regarding the timing of PCT intervention, the high proportion of patients with metastasis, at 77.6%, and the median value of 4 months since diagnosis indicated that early stage interventions had not yet been effective.A radical treatment for fatigue is to eliminate the causes. However, in most cancer patients, causes can be specified but cannot be eliminated; therefore, drug treatment is chosen. Medications, such as psychostimulants, phytotherapeutic agents, growth factors, and corticosteroids, show evidence of positive effects , but no Finally, the data should be interpreted cautiously, with consideration of the possible omission of patients with poor PS. Further, patients without pain may not be referred to a PCT. Anemia, considered to exert a strong influence on fatigue, was not assessed in terminally ill cancer patients to avoid unnecessary blood collection. In this study, patients referred to the team were all registered; therefore, the influence of primary doctors’ intentions on the results is undeniable.In conclusion, CRF, considered to occur more frequently in cancer patients, was successfully assessed using PROs with the BFI for the first time in Japan. When patients are referred to PCTs, many complain of fatigue. This suggests that fatigue is potentially as problematic as pain, which is the main reason for palliative care. As treatment choices for CRF are extremely limited in Japan, the research and development of treatments to reduce fatigue is urgently required.S1 Database(XLSX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.