Ethanol celiac plexus neurolysis (ECPN) has been shown to be effective in reducing cancer-related pain in patients with locally advanced pancreatic and periampullary adenocarcinoma (PPA). This study examined its efficacy in patients undergoing PPA resection.485 patients participated in this prospective, randomized, double blind placebo controlled trial. Patients were stratified by preoperative pain and disease resectability. They received either ECPN (50% ethanol) or 0.9% normal saline placebo control. The primary endpoint was short and long-term pain and secondary endpoints included postoperative morbidity, QOL and overall survival.Data from 467 patients were analyzed. The primary endpoint, the percentage of PPA patients experiencing a worsening of pain compared to preoperative baseline for resectable patients, was not different between the ethanol and saline groups in either the resectable/pain stratum ), or the resectable/no pain stratum ). On multivariable analysis of resected pancreatic ductal adenocarcinoma (PDA) patients, there was a significant reduction in pain in the resectable/pain group, suggesting that surgical resection of the malignancy alone (independent of ECPN) decrements pain to a significant degree.In this study, we have demonstrated a significant reduction in pain following surgical resection of PPA. However the addition of ECPN did not synergize to result in a further reduction in pain, and in fact its effect may have been masked by surgical resection. Given this, we cannot recommend the use of ECPN to mitigate cancer related pain in resectable PPA patients. Taken together, pancreatic and periampullary adenocarcinoma (PPA) presents significant clinical challenges for achieving long-term survival in afflicted patients, and therefore adjunctive and palliative therapies are extremely important in alleviating patient suffering.Pancreatic ductal adenocarcinoma (PDA) is the 412 Even in those patients who initially do not present with pain, the majority will ultimately develop this symptom during the course of their disease. 14 PPA-associated pain is typically unremitting, located in the epigastrium, and can intensify as the disease progresses. 15 Other symptoms that are associated with and known to cluster with this type of pain include fatigue, insomnia, nausea, diarrhea, weight loss, anxiety, and depression.17 These symptoms have been documented to have a significant negative impact upon patient quality of life (QOL).18 Current recommendations suggest that the most effective approach to cancer related pain treatment involves using systemic medications titrated in a progressive manner, starting with non-opioid analgesics, moving to weak opioids and then to strong opioids depending upon pain intensity.20 While opioids can effectively achieve pain relief, they are associated with many adverse side effects. Therefore, nonpharmacological adjuncts, such as ethanol celiac plexus neurolysis (ECPN) have been employed in order to offer effective pain relief while minimizing drug-related side effects.Abdominal and back pain are among the most common presenting symptoms in patients with PPA, estimated to affect 30-40% of patients at the time of diagnosis. 22 The most complete study evaluating this topic was published by Lillemoe et al. in 1993.23 This study investigated the efficacy of ECPN in PPA patients found to be unresectable during surgical exploration, demonstrating a significant reduction in pain and an improvement in survival in a small subset of patients with preoperative pain. Subsequent studies have also suggested an improvement in pain in patients with unresectable PPA who have undergone ECPN.31 Despite this strong evidence supporting the use of ECPN in patients with unresectable PPA, to date no studies have evaluated the role of ECPN in patients with resectable PPA. The question remains whether ECPN can be equally effective in reducing PPA- associated pain after surgical resection, and if this will result in an improvement in patient QOL. There is also the question of the theoretical anti-tumor effect of ablating nerves which are infiltrated by malignant cells, which could be hypothesized to exert an influence on cancer recurrence rates and overall survival.Despite the first description of celiac plexus neurolysis by Kappis in 1914, clear and convincing evidence supporting the routine use of ECPN in the management of PPA pain is lacking. In this trial, we sought to test the hypothesis that intraoperative ECPN would be beneficial for patients with resectable PPA. The primary objective was to evaluate whether ECPN would impact short and long-term tumor-related pain, while secondary endpoints included perioperative complications, QOL and overall survival.We performed a single center, prospective, randomized, double blind placebo controlled trial to evaluate the role of ECPN in mitigating cancer-associated pain in patients with resectable PPA. The trial was approved by both the Jefferson Clinical Cancer Research Review Committee and the Institutional Review Board and is registered with ClinicalTrials.gov (NCT00806611). From December 2008 to August 2013, patients undergoing abdominal exploration for presumed periampullary malignancy at the Thomas Jefferson University Hospital (TJUH) were offered participation in the study. All patients over 18 years requiring major abdominal surgery for PPA were eligible for enrollment with the exclusion of patients not found to have adenocarcinoma on the final pathology and those who had received a previous, preoperative celiac plexus nerve block. At the initial outpatient office visit and after education about the study, informed consent was obtained and patients filled out surveys of preoperative baseline pain (Brief Pain Inventory (BPI)) and QOL , version 4).Patients believed to harbor resectable PPA underwent exploratory laparotomy with confirmation of tumor resectability. If in fact the cancer was determined to be resectable (as preoperatively assessed), either pancreaticoduodenectomy or distal pancreatectomy with end-bloc splenectomy was performed depending upon the tumor's location. Patients identified at the time of exploration to have unresectable PPA underwent open biopsy (if indicated), and palliative biliary or gastrointestinal bypass as were deemed appropriate. Once the determination of resectability was made, patients were randomized to receive either the study drug or placebo control. They were stratified by tumor resectability (resectable/unresectable) and the presence or absence of preoperative pain (pain/no pain). ECPN was performed as a 20 ml injection of 50% ethanol in saline, delivered with a 20 gauge spinal needle on each side of the aorta at the level of the celiac axis . The control (placebo) arm received the same volume injection of normal saline (0.9%).  Both theThe primary study endpoint of short and long-term pain was evaluated by the change in pain scores over time compared to the patients' preoperative baseline. Using numeric pain scores from the BPI survey , the change in pain scores could be calculated to determine the effect of ECPN on tumor related pain. Secondary study endpoints including postoperative morbidity and mortality, QOL, and overall survival were also measured.The TJU Division of Biostatistics conducted the patient randomization using computer generated random permuted blocks with a 1:1 allocation (blocks of six), with surgeons and staff blinded to the process. Patients were stratified by tumor resectability and the presence or absence of preoperative pain. For the purposes of baseline pain assessment, patients were considered to be in the pain stratum if they answered yes to the binary pain question, or if they noted a pain score of 3 or greater on the (0-10) Likert pain scale that is part of the BPI. The randomization and stratification resulted in four groups for comparison: resectable with pain (R/P), resectable with no pain (R/NP), unresectable with pain (UR/P), and unresectable with no pain (UR/NP). Following stratification, a central telephone number was called within the Department of Surgery where an administrator would open in sequence an envelope containing the assignment for celiac block injection. The assignment was then passed on to the Investigational Pharmacy to deliver the ethanol or saline injection to the operating room and the assignment sheet was delivered to the Division of Biostatistics to monitor the randomization process. A copy of the treatment assignment was maintained by the study coordinator and the Division of Biostatistics for monitoring and accrual tracking.23 Among those patients with preoperative pain, the expected proportion of patients in the control group with increased pain at 12 months was set at 50%. Among those patients without preoperative pain, the expected proportion of patients with increased pain at 12 months was set at 40%. To have 90% power to detect a common odds ratio of 0.25 using a two-sided Mantel-Haenszel adjusted chi-square test it was estimated that 58 subjects were required per treatment arm. An odds ratio of 0.25 is equivalent to a reduction in increased pain from 50% to 20% in those with preoperative pain and from 40% to 14% in those without preoperative pain.The number of subjects needed for this study was based on the following assumptions for subjects with resectable tumors: Based on data reported in Lillemoe et al (1993), the proportion of patients experiencing pre-operative pain was estimated at 30%.Slightly different assumptions were made for subjects with unresectable tumors. The proportion of patients experiencing pre-operative pain was again estimated at 30%. Among those patients with preoperative pain, the expected proportion of patients in the control group with increased pain at 3 months was set at 90%. Among those patients without preoperative pain, the expected proportion of patients with increased pain at 3 months was set at 50%. To have 90% power to detect a common odds ratio of 0.25 using a two-sided Mantel-Haenszel adjusted chi-square test it was estimated that 57 subjects were required per treatment arm. An odds ratio of 0.25 is equivalent to a reduction in increased pain from 90% to 69% in those with preoperative pain and from 50% to 20% in those without preoperative pain.To achieve 116 evaluable patients for the primary end point, we made the assumption that we would have a 60% survey return rate. As the study progressed, we found that our initial return rate was much lower than expected (20%), as was the number of unresectable patients that were being enrolled. Given these developments, with permission from our IRB, we increased the sample size to 170 patients with resectable tumors per arm and 72 patients with unresectable tumors per arm, for a total sample size of 485.Continuous variables were summarized by stratum and randomization assignment using medians and inter-quartile ranges. Categorical variables were summarized using frequencies and percentages. Analyses were performed separately for resectable and unresectable patients. The primary outcome analyzed was a worsening of pain compared to preoperative baseline at 12 months in resectable patients or at 3 months in unresectable patients. In resectable patients, if the 12 month pain survey was not available, data were imputed from the 9 month survey response. If neither the 12-month or 9-month data were available then the 15 month survey was used. The relative risk of increased pain was calculated, adjusting for pre-operative pain strata using Mantel-Haenszel methods, and significance was assessed using the stratified-adjusted Mantel-Haenszel chi-square test. A secondary analysis of pain data in the subset of patients with resected PDA was performed, using mixed effects linear regression to model the longitudinal change in question 3 from the BPI (worst pain in the last 24 hours) during the first 12 months post-surgery. The survey month, treatment group and the interaction between these two terms were the main predictors included in both the multivariable and univariable models. Additionally the multivariable model controlled for diabetes, smoking history, tumor location (head or body/tail), age and baseline CA 19-9 levels. Models were fit separately based on whether a patient experienced pre-operative pain. Change in QOL was evaluated with a similar mixed effects model. Overall survival was summarized using Kaplan-Meier curves and groups were compared using log-rank tests. Treatment differences in incidence of complications were evaluated using Mantel-Haenszel chi-square tests. Differences in the number of complications were assessed using Poisson regression adjusted for stratum. The statistical software used was SAS v9.4 . Significance was accepted at the p <0.05 level.From December 2008 to August 2013, 485 patients preoperatively suspected of having resectable PPA were explored, stratified, and randomized by preoperative pain status and tumor resectability for participation in this study . Of thes32Data on postoperative pain and QOL during the study period were collected and analyzed from the questionnaires mailed to study subjects. The overall perioperative complication rate among only those patients undergoing resection was comparable between the ethanol and saline groups  . The ethThe primary outcome of the percentage of PPA patients experiencing a worsening of pain compared to their preoperative baseline was assessed at 12 months post-surgery for resectable patients. There was no difference seen in the primary outcome variable between the ethanol and the saline groups at the 12 month time point in either the R/P stratum ), or the R/NP stratum ), respectively . When anIn the unresectable PPA groups (data not shown), there was no difference between ethanol and saline in the percentage of patients who experienced a worsening of pain compared to preoperative baseline at the pre-defined 3 month post-surgery time point: UR/P stratum , and UR/NP stratum , although the numbers of respondents in each cell became quite small. As a function of time, the UR/NP stratum had a significant reduction in pain in the ethanol group at 3 months compared to the baseline measurement , however this seemed to rebound to increased pain levels in the ethanol group by 6 months (50% vs 38%). Again, the numbers were quite small at each of these time point measurements.QOL outcomes, as measured by FACT-Hep (version 4), demonstrated that patients with preoperative pain had a worse QOL compared to those without preoperative pain. When examining only the subset of patients with resected PDA, the overall median survival between the groups was nearly identical at 18.3 months in the ethanol group, and 17.6 months in the saline group . There wWe have carried out a single center, prospective, randomized, double blind placebo controlled trial to assess the efficacy of ECPN in reducing pain in patients with resected PPA. Our data show a statistically significant reduction in pain among patients who presented with preoperative pain (R/P) following surgical resection of their malignancy, which was durable to 9 months post-surgery. However, the addition of ECPN to resection did not contribute to a synergistic effect and appeared to offer no benefit. The secondary endpoints of perioperative complications, QOL, and overall survival were equivalent between groups. Overall, these results suggest that ECPN does not offer a benefit for PPA patients who are undergoing surgical resection of their malignancy.33 The source of PPA-associated pain is not well understood, though it is theorized to result in part from a variety of processes, such as neuropathy secondary to direct cancer cell invasion of the celiac plexus, infiltration of the intrapancreatic nerves, chronic pancreatic ductal obstruction, invasion of neighboring organs and also may be a byproduct of cancer therapies such as surgery or radiation. 34 By the time PPA progresses to stage 4 advanced metastatic disease, up to 90 percent of patients will experience pain as one of their symptoms.13 Currently, the most commonly used approach to pain management relies on the titration of systemic medications to appropriate doses in an algorithm described by the World Health Organization (WHO) analgesic ladder.35 By using sequentially stronger classes of analgesics, it is estimated that pharmacotherapy can successfully manage pain in nearly 80% of patients.35PPA related pain often presents as severe, unremitting epigastric abdominal pain, though a number of different pain syndromes are common. It frequently results from direct tumor involvement of the adjacent celiac nerve plexus, which is comprised of the celiac ganglia and a dense network of nerve fibers. The celiac nerve plexus transmits visceral afferents from much of the upper abdomen, including the region encompassing and surrounding the pancreas.35 In addition, as opiate dosages increase, they often produce multiple adverse side effects, most commonly constipation, nausea and vomiting, anorexia, sedation, delirium, and urinary retention.19 Given this side effect profile, other methods of pain relief, such as nerve blocks, are utilized in many patients with and without cancer. Neurolytic blocks produce analgesia by destroying nerve structures responsible for pain transmission. Disruption of these peripheral neural pathways can be achieved in a variety of ways including surgery, cryotherapy, or the injection of damaging chemicals such as ethanol, phenol, and glycerin.37 The ethanol nerve block causes nerve damage by extracting lipid compounds and precipitating cell membrane proteins, inducing a chemical neurolysis which leads to nerve fiber demyelination and subsequent axonal degeneration. This nerve fiber destruction leads to an inhibition of the transmission of afferent pain signals to the central nervous system.40While pharmacological therapy alone is often successful, opioid medications still provide inadequate pain relief in an estimated 20% of cancer patients.A number of studies have evaluated the use of ECPN in patients with unresectable PPA, with varied results. In the study by Lillemoe et al, patients with unresectable PPA received intraoperative ECPN while undergoing exploratory laparotomy and palliative bypass. One hundred thirty seven patients were randomized to receive either ECPN via an intraoperative injection of 50% ethanol or 0.9% saline placebo, and were followed for 24 weeks to determine the effect of ECPN on long-term pain relief. In patients that received ECPN, pain relief was significantly improved at 2, 4, and 6 months of follow-up (p<0.05). Patients in the ECPN group had reduced opioid consumption, suggesting improved pain management and, in those without pain at diagnosis, the time until the new onset of pain was delayed. Additionally, in a small subset of patients with preoperative pain, survival also improved significantly (p<0.0001).In the second largest study of ECPN to date, Wong et al examined the use of endoscopic ultrasound guided (EUS-guided) ECPN in 100 patients with unresectable tumors that experienced pain. Patients were stratified based on cancer stage and then randomized in a double blind fashion to receive an alcohol nerve block or systemic analgesic therapy (SAT) alone with a sham injection at the same site. After the first week, both groups experienced a reduction in pain scores, however the 53% reduction from baseline in the ECPN group was significantly larger than the 27% reduction observed in the SAT group (p=0.005). Pain intensity continued to decrease gradually and remained significantly lower in the ECPN group through 24 weeks of follow-up (p=0.01). In addition, significantly fewer patients receiving ECPN reported moderate to severe pain over the first 6 weeks of follow-up, demonstrating an improvement in those patients with the greatest amount of pain . However, other measures including quality of life, opioid consumption, physical and functional well-being, and survival did not differ between the groups.31 If shown to be beneficial, ECPN would represent a good alternative to systemic pain therapy alone, while adding minimal risk to the patient.Based upon the success of these prior studies in patients with unresectable PPA, we hypothesized that ECPN may be beneficial in patients with resectable PPA. The procedure is relatively fast, inexpensive, and is associated with few side effects, most commonly transient hypotension and rarely diarrhea.45In contrast to previous findings in unresectable patients, our data did not demonstrate a significant improvement in pain scores in patients with resectable PPA, suggesting limited to no benefit from the ECPN procedure in this cohort of patients. On multivariable analysis of a subgroup of PDA patients, we did note a reduction in pain through the first 9 months following surgery in the R/P group. This finding of reduced pain was attributable to surgical resection of the malignant tumor, without any added benefit from the addition of ECPN. In fact, surgical resection may have inadvertently masked the effect of ECPN on PPA associated pain. Interestingly, despite this improvement in pain after surgical resection, there were no corresponding appreciable improvements in QOL. In general, patients with preoperative pain experienced a reduced QOL compared to those without pain, however, there were no differences in QOL with the addition of ECPN over saline placebo. In the literature, surgical resection has been shown to result in an initial reduction in patients' QOL; this generally recovers within 6 months to preoperative levels. In the long term, most patients undergoing PPA resection eventually experience an equivalent QOL when compared to both healthy controls and other patients undergoing abdominal surgery. Resected patients have been observed to experience a better QOL than their unresected counterparts. 26Overall, we were unable to show that the benefits of ECPN previously described in unresectable patients could be translated to patients undergoing tumor resection. Survival was equivalent between the ethanol and saline groups, in the cohorts of patients with both resectable and unresectable disease. The theoretical advantage of ablating the celiac nerve plexus and the associated PPA tumor cells that had presumable invaded the plexus along with them, did not translate to any improvement in survival among ECPN patients, compared to those who received saline. This finding would generally coincide with that of the literature, where improvements in overall survival with the addition of ECPN have been rare.In addition to examining the potential therapeutic effects of ECPN in patients with resectable PPA, we also attempted to validate the prior success of ECPN with unresectable disease. However, as this was not the primary focus of our study, we did not have adequate power in the unresectable arm and therefore many of the findings do not reach statistical significance. The small number of unresectable patients combined with the low survey response rate led to a lack of meaningful findings for this subgroup.46 Second, there was incomplete information obtained from the study subjects on the use of narcotic analgesics, therefore reductions in opioid usage, which may indicate some degree of pain relief, were not documented. Third, we did not have complete and accurate information on the administration of adjuvant therapies, such as chemotherapy and radiotherapy. These have been shown to impact patients' pain experience and effect narcotic consumption when used alongside ECPN.6 Fourth, the prolonged follow-up period of 2 years was perhaps too lengthy as most prior studies have shown a benefit of ECPN extending to only 3-6 months. 48 Fifth, patients were not stratified according to tumor location as determined by final pathologic analysis, which besides impacting potential surgical techniques , has been shown to correlate with staging and symptoms at diagnosis.4 However, tumor location was incorporated into the multivariable regression model. Finally, because the study was powered to determine the effects of ECPN in patients with resectable disease, it was not possible to demonstrate an improvement in pain control in the unresectable arms as has been suggested in prior studies.It is important to note that there are a number of significant limitations to this study. First, it was a single center trial and although the study size was large there was a disappointingly low questionnaire return rate which was used to assess the primary outcome of postoperative pain. We acknowledge this most important study limitation. This is a not an uncommon problem in QOL studies in this patient population, where study surveys can represent a significant additional burden on patients who are in many cases dealing with issues of increasing disability, cancer recurrence, and death over the length of the study period. In this study, the world's largest randomized controlled trial evaluating ECPN in patients with operable PPA, we have demonstrated no benefit to patients in terms of postoperative pain and quality of life, and no effect on overall survival. Therefore, we cannot recommend the use of ECPN to mitigate cancer related pain in resectable PPA patients. However, further well designed studies in the unresectable cohort, with a high rate of complete follow-up, survey return, and meaningful QOL assessment may be warranted.


Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD.2 or need of renal replacement therapy (RRT). Minor  and major  vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL.In 96 patients  with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 mTen patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components , while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL.Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.The online version of this article (doi:10.1186/1471-2369-15-188) contains supplementary material, which is available to authorized users. Fabry disease (FD) is a rare, X-linked lysosomal storage disorder, which results from deficient activity of the enzyme α-galactosidase  and progressive lysosomal deposition of globotriaosylceramide GL-3) in several tissues and cells throughout the body . In clas in severManagement of the disease was primarily symptomatic until enzyme replacement therapy (ERT) became available for clinical use. Several clinical trials demonstrated the efficacy of ERT to prevent or slow serious organ dysfunction , 6. HoweHealth Related Quality of Life (HRQoL) is a multidimensional construct referring to patients’ perceptions of the impact of disease and treatment on their physical, psychological and social function and well being. HRQoL questions about perceived physical and mental health and function have become an important component of health surveillance and are generally considered valid indicators of service needs and intervention outcomes. In Fabry disease, patients suffer not only from the debilitating physical symptoms, but also from a compromised HRQoL, which is reported for both, males and females , 9 PossiThe purpose of the current study was to characterize HRQoL as assessed by the SF-36® questionnaire in a large cohort of patients with Fabry disease. We aimed to identify factors associated with the various dimensions of physical and mental functioning, with a focus on kidney function.Since June 2001, an increasing number of patients with genetically proven Fabry disease from all over the country are overseen at our hospital. In regular visits, physical examination and detailed evaluation of medical history and medications are performed by a trained nurse and a physician. Furthermore, patients are enrolled in an international observational cohort study if they provided written informed consent . The locHRQoL was assessed by the Medical Outcomes Study SF-36 questionnaire  at basel2, eGFR < 60 ml/min/1.73 m2 and renal replacement therapy (RRT), i.e., dialysis or kidney transplantation (KTx). History of arrhythmia, angina pectoris, significant cardiac procedure without coronary stent implantation, or transient ischemic attack (TIA) was considered as minor vascular event, whereas history of myocardial infarction, coronary stent implantation, coronary artery bypass, stroke or implantable cardioverter-defibrillator (ICD) were described as major vascular event. Pain was assessed by using the visual analog scale (VAS), ranging from no pain (score 0) to maximal pain (score 10). Patient’s pain therapy  was not altered.Glomerular filtration rate (eGFR) was estimated according to the simplified Modification of Diet in Renal Disease formula . Stages 2- test, and Fisher’s exact test, as appropriate. Factors associated with the various dimensions of HRQoL were examined using linear regression analysis. To assure a linear relationship with the dependent variable, the logarithmic form was used for “time since Fabry diagnosis”. In multivariate analyses, the following variables were included in the model; age, gender, kidney function, vascular event, pain and pain-therapy. We investigated the relationship between pain and HRQoL according to their interaction with pain-therapy. Notably, the variable “enzyme replacement therapy, initiated within three months following the first visit” was not considered as a risk factor for HRQoL since impaired physical and mental status of the patient represents the cause of initiating ERT; i.e., the variable can be seen as a measure of “sickness” and does not describe the effect of ERT.Analyses were performed using SAS 9.1 . Characteristics of study participants and the different scales of HRQoL were compared across CKD stages using ANOVA, Kruskal-Wallis test, χThe robustness of the results was further evaluated by (1) including only four variables in the multivariate model, to minimize the risk of observing potential associations by chance due to a large number of candidate variables (“overfitting”). Thus, the least significant variable was ignored; (2) including patients in whom data of the SF-36 was available within nine months prior or following the first visit ; (3) considering kidney transplant recipients (n = 2) not in the category of RRT, but according to eGFR within the respective CKD category; (4) not differentiating between minor and major CV events, but including CV events as a single category.Ninety-six patients older than 16 years of fifty-two families were treated at our center between June 2001 and August 2009. The mean age of the cohort was 40 yrs, 47% were male, and the diagnosis of Fabry disease was made a median time of nine months prior to the first visit. All patients were naïve to ERT. Characteristics of study participants stratified by kidney function are displayed in Table Data on HRQoL were missing in six patients, and in three additional patients the SF-36 was not completed within three months following the first visit, thus leaving eighty-six patients for further analyses Table . Of noteSimilar to the described findings, impaired kidney function, particularly the need of RRT, was associated with markedly reduced HRQoL across all scales in univariate linear regression analysis Tables a and b. We tested the robustness of our results in a first step by including only four explanatory variables in the multivariate linear regression model. Excluding vascular event, which represented the least significant variable, did not result in significant changes of our findings, neither on the magnitude of the direction, nor on the significance levels or the respective variables. Similarly, by including three additional patients in whom the SF-36 was completed within nine months prior or following the study visit, no significant changes in the estimates of the variables in the multivariate model were found; however, the 95% CI became narrower, resulting in pain-therapy being significant on the p < 0.05 level in the physical functioning scale. Moreover, when we analyzed the two KTx-patients in the respective eGFR category, i.e., excluding them from the RRT category, we did not detect major differences in the findings, except in the variable describing kidney function. Generally, the associations of RRT with the respective scales strengthened including narrower 95% CI in physical aspects, such as physical functioning, role physical and emotional, and the PCS. No changes were observed in mental parameters. Details are shown in Additional file Chronic kidney disease was generally associated with reduced HRQoL, especially mental health, as represented by social functioning, role emotional, and the MCS. In contrast, physical aspects, such as physical functioning, role physical, bodily pain, and the PCS, were affected even in patients with moderately impaired kidney function. Impaired kidney function, particularly the need of RRT, was associated with markedly reduced HRQoL across all scales in univariate linear regression analysis.A number of studies investigated Quality of life in patients with Fabry disease. Most studies constrain to comparisons with healthy controls which indicate major impairments in affected patients , 16, 17 We found that chronic kidney disease, although impaired kidney function and its progression is deemed to be apparently asymptomatic, was an important determinant of the patients’ wellbeing which is a crucial factor for reduced HRQoL in physical and mental and social aspects of life. Among the SF-36, reduced kidney function was connected to reduced values in all eight items, mainly affecting physical role ) and social functioning ) which is considered as clinically meaningful [.7) whichMajor therapeutic components of Fabry disease patients focus on pain medication and mental coping, including modifications of daily life activities and behavior. Suffering from pain naturally can be seen as causal for reductionsin social and physical functioning. In our analyses it was interesting that being on specific-medication, but still suffering from pain was related to even lower scores on the role physical-scale, while this finding approached significance in bodily pain, role emotional and the PCS.This might either be caused by a higher level of pain which is pledged to analgetics to reach a bearable level but is still affecting quality of life, or might be connected to the additional negative effect of destitution by ineffective pain medication.It has been suggested by various studies , 9 that In contrast, in a large analysis of Fabry patients in Canada , patientOur findings indicate that kidney disease in FD should be consideredwhen aiming for improvements of HRQoL. Aside from enzyme replacement therapy, optimal treatment of kidney disease aiming to slow the progression of CKD and an effective pain therapy may help to improve HRQoL in Fabry patients.We are aware of several limitations of our findings. As in any observational study, no relationship can be determined sufficiently, i.e., the direction of an association in cross-sectional analyses cannot be explored. It would also be desirable to investigate the changes in HRQoL in FD patients and how these may be associated with changes in renal function, optimized pain therapy, the occurrence of vascular events, but also with the potential effects of ERT. Moreover, the differentiation of pain severity according to receiving or not receiving therapy for neurogenic pain is diffuse, because it may depend on differences in perception of pain but also on differences in patient care. Besides that, an influence of pain peaks, which are not detected by the use of the VAS at one single point of time, on HRQoL is not excluded.Cardiovascular events and neuropathic pain have been considered as solely being responsible for reduced quality of life, depression as well as reduced social functioning. Our study highlights chronic kidney disease, in particular after initiation of RRT, but even early in disease progression, as a strong determinant of reduced HRQoL in Fabry’s disease.Supplementary materials. Description S1) HRQoL data of patients with a history of major CV-events. S2) Sensitivity analysis: KTx patients considered in the respective CKD category, according to eGFR; determinants of HRQoL, displayed are β- coefficients (95% CI). S3) Sensitivity analysis: CV-events treated as a single category; determinants of HRQoL, displayed are β-coefficients (95% CI). (DOCX 32 KB)Additional file 1:


Disability due to acute low back pain (ALBP) runs parallel with distress and physical inactivity. If low back pain persists, this may lead to long-term sick leave and chronic back pain. This prospective randomized study evaluated the effect on physical activity and on the course of ALBP of two different treatment advices provided in routine care.Ninety-nine patients with acute severe LBP examined within 48 h after pain onset were randomized to the treatment advices “Stay active in spite of pain” (stay active group) or “Adjust activity to the pain” (adjust activity group). Pedometer step count and pain intensity  were followed daily during seven days. Linear mixed modeling were employed for statistical analyses.p = 0.76). Although there were no statistical differences between the two groups in the parameters describing the change trajectory for step count, the increase in step count was larger in the stay active group. At day 7 the step count was 9865 in the stay active group compared to 6609 in the adjust activity group (p = 0.008). The pain intensity (NRS) trajectory was similar in the two groups. Between day 1 and day 7 it decreased linearly from 5.0 to 2.8 in the stay active group (p < 0.001), and from 4.8 to 2.3 in the adjust activity group (p < 0.001).The step count change trajectory showed a curvilinear shape with a steep initial increase reaching a plateau after day 3 in both groups, followed by an additional increase to day 7 in the stay active group only. At day 1, the step count was 4560 in the stay active group compared to 4317 in adjust activity group .ClinicalTrials.gov ( The prevalence of low back pain (LBP) is around 10 % and it causes more disability than any other condition , is commThere is substantial evidence that physical activity has beneficial effects on most musculoskeletal conditions, including LBP . For thaCompliance to the stay active advice could be an important factor influencing the magnitude of the effect on ALBP, but little has been reported. Malmivaara et al. found less hours of bed rest and more hours doing back exercises as measures of compliance in patients with ALBP receiving a stay active advice compared to patients advised to rest in bed. In the referred study, compliance was assessed by means of a questionnaire , thus, tMoreover, fear avoidance beliefs have been shown to influence the prognosis of ALBP –23. AccoThe stay active advice may not only be a treatment to improve recovery from ALBP, but also an opportunity to promote physical activity for other health benefits, such as improved cardio-metabolic function, blood pressure, and reduced body fatness , 28. An In the present study, the two treatment advices “Stay as active as possible in spite of the back pain” or “Adjust activity to pain” were implemented early after onset of acute severe LBP. The aims were to evaluate their effect on objectively measured physical activity and on the course of ALBP.A prospective randomized study was conducted at the Department of Orthopaedics, Sahlgrenska University Hospital Gothenburg, Sweden, to evaluate the effect on physical activity and on the course of acute severe LBP of two different treatment advices provided in routine care. All patients were followed for seven days from maximum 48 h after the onset of the ALBP. The Regional Ethical Review Board at the University of Gothenburg approved the study protocol. Trial registration: ClinicalTrials.gov (NCT02517762).Participants in the study were recruited consecutively among employees from a large local manufacturing company representing several different factories. All employees had been informed to immediately contact the company physiotherapist or the nurse coordinating the study in case of acute severe pain in the lower back. Eligible participants were subjects between 18 and 65 years of age, with acute severe LPB, with duration from onset less than or equal to 48 h, with or without radiating leg pain, with or without neurological signs, and the pain had to exceed 50 mm on the Visual Analog Scale (VAS). Patients were requested to fill out and return a seven-day diary and those who did so were included. Excluded were those who had been on sick leave because of LBP in the last month or because of pain in the spine. Employees determined eligible were enrolled in the study after giving informed consent, and were immediately referred to an academic orthopedic department for further examinations. Enrolment took place from March 2005 until December 2008.At the hospital the patients underwent an X-ray examination of the lumbar spine  followed by a magnetic resonance imaging (MRI) examination including T1 and T2 weighted and short time inversion recovery (STIR) sequences. They also underwent an extensive physical examination performed in a standardized way by one of three orthopedic spine specialists. The physician explained for the patient the imaging findings as well as the results of the physical examination. The patients were also asked to complete a battery of questionnaires  coveringThereafter, each patient was randomly allocated to one of the two treatment advices, using a random table. A sealed envelope with the treatment assignment was distributed to the physician, who instructed the patient about the content and practical aspects of the actual treatment advice according to protocol see  below. TThe patients were advised either to stay as physically active as possible in spite of the LBP , or to adjust the activity according to the pain . Patients with the AA advice were instructed to avoid activities, movements, or positions that caused or worsened the pain. Of the 109 randomized patients, 52 patients (47.5 %) were allocated the SA advice and 57 patients (52.5 %) to the AA advice.All the patients who wanted help with pain relief were prescribed either paracetamol and/or NSAID. The number of prescriptions in the two groups was similar but the use of the drugs was not checked.After the clinical examinations and the allocation to the treatment, each patient received a diary to record daily step count (pedometer), pain intensity (NRS), pain location and pain-related disability (DRI) during the following 7 days. In addition, they described in the diary all kind of physical activities performed under the 7-day follow-up period.Step count was used both as a measure of daily physical activity, and as an indicator of compliance to treatment advice over the 7-day follow-up. Each patient received a digital pedometer  and was instructed to wear it during all waken hours and to record the daily step count in the diary. This type of pedometer has been validated in previous studies for estimating the total daily number of steps , 33. TheThe Numerical Graphic Rating Scale  is a box scale consisting of 11 numbers from 0 (no pain) to 10 (pain as bad as it could be). The patients were asked to place an “X” at the number that represented their pain. The NRS is easy to administer and there is good evidence for its construct validity . The VASInformation regarding work absenteeism and sick leave due to the current back problems was collected from the company records up to one month after the onset of the ALBP episode.Due to the lack of previous information on step count from patients with ALBP, a power calculation was performed as follows. Based on an estimated mean difference in daily step count between the 2 groups of 1000 steps (SD = 2000/day) reported by healthy subjects , to achit-test (age and days of absenteeism). Linear mixed models (LMM) were used to estimate the shape of the step count and pain intensity (NRS) change trajectories over seven repeated measures , as they provide greater flexibility to repeated measures designs and their specific variance structures [p < 0.05. All statistical analyses were performed using SPSS 22 .Group comparisons at baseline were performed using the Chi-squared test , the Mann–Whitney test , and the ructures . A thirdructures . A seconp > 0.05). In addition, there were no differences between the groups regarding the reported cause of ALBP, occupation or initial pain intensity (VAS).One hundred-and-nine participants with acute (≤48 h) severe LBP (VAS > 50 mm) were enrolled in the study. The mean age for all the participants was 42.1 years (range 20–63). Seventy-two percent were men and 57 % percent were white-collar. Thirty-five percent of the patients claimed that their ALBP arose while working and 32 % reported that their back problems arose without any obvious external exertion. The diagnoses (ICD10 coding) were acute lumbago in 88 % (M545), acute lumbago with sciatica in 10 % (M544), and lumbar spinal stenosis in 2 % (M480). The majority of the patients (76 %) returned directly to work after the clinical examination, whereas 17 % were absent from work less than 5 days, and 7 % were absent from work between 6 to 8 days. The return to work rate was the same in the two treatment groups. There were no differences between the two groups for age, gender or sick leave due to the ALBP (p > 0.05). There were no statistically significant differences between the responders and non-responders regarding gender or ethnicity (p > 0.05). Differences in the initial scores on DRI were found between the groups, where the responders scored higher (p < 0.05). For the responders included in the statistical analyses, 47 patients were assigned to the stay active group (SA) and 52 to the adjust activity group (AA)  completed and returned the diary with the information regarding step count, pain intensity (NRS) and pain-related disability (DRI). The average age was 37.3 years (range 27–53) for those not returning the diary, and 42.5 years (range 20–63) for those returning the completed diary ( % complep < 0.001) that leveled off and reached a plateau after day 3 . From day 6 there was an additional increase in step count . However, the change trajectory in step count was not similar in the two treatment groups. At the first follow-up day there was only a small difference of 243 steps between the groups . Although there was no statistically significant effect of treatment advice on any of the three change trajectory terms , the increase in step count was larger in the SA group compared to the AA group. At the plateau at day 3 the difference between the groups was 1133 steps (p = 0.09). Thereafter, the step count increased only in the SA group with statistically significant difference between groups reached at day 6 . At the first day of the follow-up, 2 % in the SA group and 8 % in the AA group reached the recommended 10000 steps. At the last day, the corresponding proportions were 39 % in the SA group compared to 8 % in the AA group.Figure p < 0.001). The SA group showed somewhat higher pain intensity and a somewhat slower decrease in pain intensity compared to the AA group, however, there was no statistically significant effect of treatment advice on the pain intensity change trajectory . The estimated pain intensity decreased between day 1 and day 7 from 5.0 to 2.8 (p < 0.001) in the SA group, and from 4.8 to 2.3 (p < 0.001) in the AA group.Figure The present study contributed with the follow-up of the effect of two treatment advices on objectively measured physical activity and on the course of ALBP from early after its onset. The patients advised to stay active (SA) in spite of LBP increased their activity more than the patients advised to adjust activity (AA) to the pain, which confirmed compliance with the advices. Due to this compliance and the early inclusion after the pain onset, it can be stated that the SA advice did not alter the course of ALBP. However, the SA advice promoted a pronounced increase in daily activity among these patients who reached the recommended level of 10000 steps for additional health benefits , 36, 39,In a supportive clinical environment where general practitioners have a positive attitude to active rehabilitation in combination with early assessment and treatment, the fear of motion or avoidance of pain among patients advised to be physically active might be less pronounced –20. AmonPrevious research often involved ALBP patients from primary care settings recruited after three or more days of LBP duration , 40, 41.One could argue that a patient whose back problem decays within a week is a minor clinical problem. However, even with the very short duration in the majority of patients with ALBP, there is a considerable risk for future recurrence and/or development into chronic LBP, as previously stated –7. The cOne strength in the herein study is the use of objective measure of physical activity, which has not been used in prior research to confirm compliance with the stay active advice in patients with acute severe LBP. Subjective methods tend to exaggerate intervention effects related to physical activity . The useTreatment advice given in acute severe LBP is complied with. Patients advised to stay active showed a more active behavior compared to patients advised to adjust their activity to the pain. A large proportion in the SA group reached recommended level of 10000 steps per day defined for a population without pain. Thus, the stay active advice is appropriate for the early treatment of acute severe LBP and to promote additional physical activity for more health benefits among workers in risk for suffer from LBP.The present study demonstrates the opportunity within the health care setting to support return to habitual levels of physical activity and early return to work after onset of acute severe LBP, using inexpensive methods in form of the stay active advice and pedometers. It also demonstrates that even higher levels of physical activity can be promoted with these methods to prevent recurrence/chronicity of pain and for additional health benefits.


Chronic pain after cesarean section (CS) is a serious concern, as it can result in functional disability. We evaluated the prevalence of chronic pain after CS prospectively at a single institution in Japan. We also analyzed perioperative risk factors associated with chronic pain using logistic regression analyses with a backward-stepwise procedure.Patients who underwent elective or emergency CS between May 2012 and May 2014 were recruited. Maternal demographics as well as details of surgery and anesthesia were recorded. An anesthesiologist visited the patients on postoperative day (POD) 1 and 2, and assessed their pain with the Prince Henry Pain Scale. To evaluate the prevalence of chronic pain, we contacted patients by sending a questionnaire 3 months post-CS.Among 225 patients who questionnaires, 69 (30.7%) of patients complained of persistent pain, although no patient required pain medication. Multivariate analyses identified lighter weight (p = 0.011) and non-intrathecal administration of morphine (p = 0.023) as determinant factors associated with persistent pain at 3 months. The adjusted odds ratio of intrathecal administration of morphine to reduce persistent pain was 0.424, suggesting that intrathecal administration of morphine could decrease chronic pain by 50%. In addition, 51.6% of patients had abnormal wound sensation, suggesting the development of neuropathic pain. Also, 6% of patients with abnormal wound sensation required medication, yet no patients with persistent pain required medication.Although no effect on acute pain was observed, intrathecal administration of morphine significantly decreased chronic pain after CS. Severe m period . Chronicm period . Due to m period , relieviStudies have elucidated the risk factors associated with the development of chronic pain after cesarean delivery: poorly controlled acute pain , 5, typeWe wished to investigate prospectively the incidence of chronic pain after cesarean section in a single institution in Tokyo, Japan. We also analyzed the type of perioperative risk factors associated with chronic pain.This prospective observational study was conducted at Kyorin University Hospital . The study protocol was approved by our Institutional Review Board on Human Research . Written informed consent was obtained from all patients. The study period was between May 2012 and May 2014. Patients who were scheduled for elective cesarean section during the study period were recruited into the study. Maternal demographics  were collected.via the intrathecal route received a continuous infusion of epidural ropivacaine or subcutaneous fentanyl as postoperative analgesia. Details of surgery and anesthesia, such as the type of anesthesia , procedure type (elective or emergency), duration of surgery and type of incision  were also recorded.Spinal, combined spinal–epidural or general anesthesia were chosen at the discretion of the attending anesthesiologist. For spinal anesthesia, a local anesthetic (12mg bupivacaine) with 10 μg fentanyl was injected into the subarachnoid space with or without 0.1 mg of morphine. An intravenous sedative (diazepam or midazolam) and/or an opioid (fentanyl), and/or epidural local anesthetic were given during surgery at the discretion of the attending anesthesiologist. Patients who did not have morphine 2) and pulse rate as determined by a pulse oximeter. These parameters were recorded by nurses until 9 am the next morning. Nurses were educated about respiratory depression with morphine (i.t.) and instructed to call an anesthesiologist if the respiratory rate reached ≤10 breaths/min, or if SpO2 reached ≤95%. Prevalence of maternal adverse reactions  and use of supplemental analgesics and medication for adverse reactions were gathered from nursing records. An anesthesiologist visited patients on postoperative day (POD) 1 and 2, and assessed pain with the Prince Henry Pain Scale (PHPS) [Postoperatively, patients received pentazocine (30 mg i.v.), flurbiprofen , loxoprofen , or acetaminophen  if they complained of pain. We routinely monitored hourly respiratory rate, consciousness, continuous oxygen saturation (SpOe (PHPS) .To evaluate the prevalence of chronic pain, we contacted patients by sending a questionnaire 3 months after cesarean section. In the questionnaire, we asked if they were experiencing pain and, if so, to detail its frequency, intensity and type . The quet-tests and Wilcoxon rank sum tests were used for normally and non-normally distributed continuous data, respectively.Data are the mean ± standard deviation (SD) and median ± interquartile range (IQR) for normally and non-normally distributed continuous data, respectively. Unpaired For multivariate analyses of factors associated with persistent pain at 3 months, logistic regression analyses with a backward-stepwise procedure were used. Covariates were selected based on clinical knowledge and previous studies, and were kept to multivariate analyses if p<0.1 was observed by univariate analyses, as with the study by McCabe et al . During All statistical analyses were done with EZR , which is a graphical user interface for R  . Levels We recruited 280 patients during the study period, and 225 letters (80.4%) were returned. Maternal demographics as well as details of their surgery and anesthesia are shown in Pain severity on POD1 and 2 is shown in Patients with abnormal wound sensations comprised more than half of all patients, so the sensations after delivery seemed to be as serious as persistent pain. via the intrathecal route (p<0.001).We excluded patients with general anesthesia, and analyzed whether there were significant differences in persistent pain 3 months after delivery between patients with and without intrathecal morphine. We found that intrathecal injection of morphine significantly decreased the NRS of persistent pain (p = 0.0276).We calculated the ratio of persistent pain at 3 months following delivery among patients who underwent spinal anesthesia only. As shown in We investigated the prevalence of chronic pain after cesarean section prospectively in a single institution in Japan. Among 225 patients who returned our questionnaires, 69 30.7%) of patients complained of persistent pain 3 months after surgery, but no patient required medication. This prevalence was significantly high compared with that noted in studies evaluating chronic pain [0.7% of ppost partum was 10.9%. In our study, 8.3% of patients complained of pain at rest on POD1. Although the prevalence of severe acute pain was comparable, its prevalence at <24 h was not associated with persistent pain.Severe acute postoperative pain has been highlighted as a factor that increases the risk of chronic pain . With reChronic pain after cesarean delivery was 30.1%, which was higher than that of studies in other countries: it also has wide variations, mainly because ethnicities and sampling methods are different . In 2004One factor that might have influenced the high prevalence of chronic pain in our study was the high mean age (35.4) of mothers, obviously meaning advanced reproductive age with increased pregnancy complications and chronic pain. According to the Japanese Ministry of Health, Labor and Welfare, the average age of first-time mothers has been increasing; it was 29.7% in 2009 and 30.6% in 2015, while the average age is relatively higher in Tokyo compared to other cities. The most frequent age group of first-time mothers is 30 to 34 in Japan. Because our institution is a university hospital in Tokyo, and 50.7% of patients had repeated cesarean delivery, the mean age tended to be over 35. Andreea et al reported that 27.4% of all women who died of pregnancy complications during 2006 to 2010 in the Unites States were aged 35 years or older . In a stvia the intrathecal route, possibly due to the time involved in preparing a small dose of morphine. Patients who had general anesthesia usually did not receive spinal anesthesia and morphine via the intrathecal route. . After excluding confounding factors, neither procedure type nor type of anesthesia had an effect, but instead intrathecal administration of morphine was the defining factor for chronic pain.Known risk factors associated with the development of chronic pain after cesarean delivery include poorly controlled acute pain ,5, type It may reflect Japanese women's cultural perspectives, i.e., that although 30.7% of patients complained of persistent pain and 4.4% patients complained of pain that limited daily function, no patient required medication. Doering et al reported that most women manage labor pain without pharmacological interventions in Japan, and that Japanese women's cultural perspectives and passive attitudes were found to influence the decision-making process concerning pain relief . Accordivia the intrathecal route, which is the “gold standard” for pain management with cesarean section [via the intrathecal route was 0.1 mg, and respiratory depression was not reported. We now routinely use intrathecal administration of morphine for cesarean section.The present study showed a novel finding: absence of intrathecal administration of morphine increases chronic pain after cesarean section. This result reflected the fact that anesthetic management for cesarean section in our institution is not standardized, and that some patients did not receive morphine  section . Known a section . Use of hiatus might have reflected poor observation of patients, and might have resulted in poor management of their pain. However, the median score of the PHPS as assessed by anesthesiologists was 2, suggesting that acute pain was managed to some degree.This prospective study had several limitations. First, collecting information on maternal adverse reactions  on POD1 and 2 was suboptimal. These data were obtained from nursing records, so this via the intrathecal route in the study period, and this type of administration was limited to anesthesiologists who favored it. This factor may have been because patients given morphine via the intrathecal route tend to be cared for by specific anesthesiologists.Second, we did not standardize use of morphine given We found that 30.7% of patients complained of persistent pain after cesarean section. Although no effect on acute pain was observed, intrathecal administration of morphine significantly decreased the prevalence of chronic pain.


Central neuropathic pain has a prevalence of 40 % in patients with spinal cord injury. Electroencephalography (EEG) studies showed that this type of pain has identifiable signatures, that could potentially be targeted by a neuromodulation therapy. The aim of the study was to investigate the putative mechanism of neurofeedback training on central neuropathic pain and its underlying brain signatures in patients with chronic paraplegia.Patients’ EEG activity was modulated from the sensory-motor cortex, electrode location C3/Cz/C4/P4 in up to 40 training sessions Results. Six out of seven patients reported immediate reduction of pain during neurofeedback training. Best results were achieved with suppressing Ɵ and higher β (20–30 Hz) power and reinforcing α power at C4. Four patients reported clinically significant long-term reduction of pain (>30 %) which lasted at least a month beyond the therapy. EEG during neurofeedback revealed a wide spread modulation of power in all three frequency bands accompanied with changes in the coherence most notable in the beta band. The standardized low resolution electromagnetic tomography analysis of EEG before and after neurofeedback therapy showed the statistically significant reduction of power in beta frequency band in all tested patients. Areas with reduced power included the Dorsolateral Prefrontal Cortex, the Anterior Cingulate Cortex and the Insular Cortex.Neurofeedback training produces both immediate and longer term reduction of central neuropathic pain that is accompanied with a measurable short and long term modulation of cortical activity. Controlled trials are required to confirm the efficacy of this neurofeedback protocol on treatment of pain. The study is a registered UKCRN clinical trial Nr 9824. Central neuropathic pain (CNP) is caused by an injury to the somato-sensory system with a high prevalence in amputation , spinal Neuroimagining studies have confirmed that neuromodulation techniques such as hypnosis and meditation, can globally influence pain matrix , 10. NeuNeurofeedback is a type of biofeeback in which patients are provided information about their brain activity in a visual or auditory form. It is believed that neurofeedback facilitates global brain connectivity and leads to neuroplasticity .Neurofeedback has been used for treatment of chronic pain, such as complex regional pain syndrome , fibromyDuring neurofeedback for treatment of chronic pain, EEG is typically measured at the training site only, providing no evidences of global modulation of EEG during training. Likewise, there is also the lack of evidence whether prolonged neurofeedback treatment produced long-term changes in cortical activity.Previous research studies have shown that CNP affects resting state EEG causing increase in theta power and the shift of dominant alpha frequency towards the lower range , 18. SevIn a recent study of our group  we showe(I)Testing the immediate and longer term effect of neurofeedback training on CNP,(II)Understanding the putative mechanism through which neurofeedback induces wide-spread changes of EEG activity during neurofeedback training,(III)Assessing the long term effect of training on all cortical structures involved in processing of pain.We therefore hypothesize that similar to rTMS and tDCS, neurofeedback can target the motor cortex, resulting in normalization of evoked responses and reduction of CNP. We propose neurofeedback training for treatment of CNP in chronic paraplegic patients setting three objectives:Seven chronic patients with paraplegia  having CNP under the level of injury were recruited for the study from a cohort of 10 patients recruited for our previous study . The neuAt the beginning and at the end of the study patients filled out the Brief Pain Inventory . Prior tDuring neurofeedback training patient’s EEG was recorded using 16 channel Usbamp, . Sampling frequency was 256 Hz and electrode impedances were below 5 kΩ. The neurofeedback treatment was provided from one electrode at the time but up to 16 electrodes  were recorded simultaneously. The ground electrode was placed on the mastoid on the training side and the reference electrode was placed on the opposite side.2, Neuroscan, USA) with electrodes placed according to standard 10/10 locations [Multichannel EEG recording for off-line analysis was performed before the first training day and after the last training day, from 61 channels  in Simulink, Matlab . A graphical user interface was developed in LabView .th order IIR Butterworth) in the selected bands and was then squared and smoothed/averaged over a half second sliding window, updated after each sample, to obtain the bandpower features.To calculate EEG power in selected frequency bands, EEG of each channel was bandpass filtered  with patients having their eyes closed, for relaxation purposes. Training parameters were calculated in the lower α band (7–10 Hz) at Oz to account for lower peak frequency in patients with CNP , 18, 22.Following the audio training patients were provided with a visual neurofeedback as a therapy to reduce pain. EEG power was calculated in θ (4–8 Hz), α (9–12 Hz), lower β (12–15 Hz) and higher β (20–30) Hz bands. The higher β will be referred as β further in the text and 12–15 Hz will be called the Sensory Motor Rhythm (SMR). Relative power was calculated with respect to 2–30 Hz band.Contingencies were set such that increases in the α or SMR and decreases in the Ɵ and β were reinforced. Increased Ɵ band power was found positively related to the presence of CNP , 22, 27 During training patients sat in front of a computer screen that showed three bars, the size of which corresponded to the relative EEG power in three chosen frequency bands Fig. . The barProtocol 1 rewarded SMR and inhibited Ɵ and β at Cz,. Protocol 2 rewarded α and inhibited Ɵ and β at P4; Protocol 3 rewarded α and inhibited Ɵ and β at C3. Protocol 4 rewarded α and inhibited Ɵ and β at C4.We tested four protocols: To test for the placebo effect a) patients were shown data from a pre-recorded neurofeedback session, b) they were provided with a visual neurofeedback training to reinforce the α activity at Oz with eyes open; Oz is located at the occipital area, normally not associated with pain.Resting state EEG was recorded with 61 channels under the open eyes and closed eyes condition in a quiet room. The resting state EEG was recorded for 2 min for each condition repeated 3 times, alternating between the conditions. Assessment sessions were performed twice, up to a week before the first neurofeedback session and up to a week after the last neurofeedback sessions but never on a day of neurofeedback training. Post neurofeedback assessment was performed for patients who had 20 or more neurofeedback sessions.10PSD for normalization purposes. For each frequency, the unpaired t-test was performed to compare between two conditions and Holms-Bonferroni correction was applied to reduce the Type I error due to multiple comparisons.EEG recorded during neurofeedback training was visually inspected and sections containing blinking, muscle activity or amplitude over 100 μV were removed, leaving a minimum of 3 min recording. A power spectral density (PSD) was calculated using Hamming windows over 4 s long recording overlapped for 2 s. Logarithmic PSD was calculated as 10∙logTo calculate changes in connectivity during a training session compared to the baseline, coherence was calculated for each channel pair for 4 s long EEG epochs. The average coherence value was calculated for a chosen frequency band. The same statistical analysis was used as for PSD.Y = K1 + K2 ⋅ X was performed to find the best fit curve between the pain intensity and the number of training sessions using the parametric Pearson test.Linear regression analysis For 61 channel off-line EEG analysis, data were re-referenced to the average reference. Noise was removed as described above. The current source density was calculated for 4 s long epochs in the Ɵ, α and β band. Localisation of the cortical three-dimensional distribution of the current density of EEG was performed using the Standardised Low Resolution Electromagnetic Tomography sLORETA . The sLOFor a group level comparison, data of each patient were normalised prior to averaging. A paired t-test was applied to find a statistically significant difference between EEG before and after the therapy. A 5000 voxel randomization of statistical non-parametric mapping  implemenFive out of seven patients with pain (P1-5) completed the study. Two patients withdrew after 3 sessions, one because of problems with transportation, although experiencing reduction of pain (P 6) and the other because of the lack of response (P7). Four patients received 40 treatment sessions and the fifth patient, who stayed at the hospital for the purpose of the study, received 20 sessions. Patients who travelled from their homes received 1–3 sessions per week while the patient who stayed at the hospital received five sessions per week.None of patients reported reduction of pain during training with Protocol 1. Patients P2 and P4 reported the moderate reduction of pain as a result of training with Protocol 2. Both Protocols 3 and 4 resulted in a substantial reduction of pain, going down to 0–2 on the visual numerical scale during training. However, patients P3-5 reported strong spasm during training with Protocol 3, which manifested as uncontrollable movements of their paralyzed legs while sitting in front of the computer screen practicing neurofeedback. Patients were trained with Protocol 4 on most of training days as it provided best relief from pain with minimum side effects. Fig. th and 20th training day. The effect of mental rehearsal of neurofeedback was tested within the last 5 training days.The effect of placebo training was tested on two days, between 10nd or 3rd daily treatment. Initially however that reduction was short-term, during neurofeedback. All five patients who received 20 or more treatment sessions achieved a statistically significant reduction of pain, being clinically significant  in four patients .Six out of seven patients reported the immediate reduction of pain already during 2Two patients who before treatment suffered from spasticity/clonus (P3) and spasm/tightness (P4) reported the reduction of this symptoms on the days of training. All patients who experienced the reduction of pain, including patients with the complete loss of sensation, reported the pleasant sensation of warmth in their legs which preceded pain relief and lasted for several hours.Patients P2-5 were able to self-regulate their brain activity between treatment sessions (documented by EEG recordings) which helped reducing their pain. An example for P3 is shown in Fig Figure Figure Figure Figure In the α range, training resulted in the increase of power over the central cortex, on both contra and ipsilateral site in P1,2,4 5 while in P3 training resulted in the shift of a maximum α power from the occipital to the central region. In general, the α rhythm characterizes the idle state, and simply focusing attention on object on a computer screen should therefore result in decrease of α power. A wide-spread increase of α power during neurofeedback training could therefore be attributed to the voluntary modulation of brain activity rather than to the general increase of attention. A wide spread increase in the α power can be partially explained by the volume conduction effect, spreading the α activity from the training site at C4. However in P1 and P2 the α power increased more on the contra than on the ipsilateral site of training and in P3 the maximum of α activity shifted from the occipital to the central area.In four patients (P2-P5) the suppression of the frontal β (20–30 Hz) can be noticed during training, being stronger than suppression at the training site.Figure Figure A multichannel EEG (61 channles) in a relaxed state was analyzed in the Ɵ, α and β frequency ranges. Statistically significant changes on a group level were noticed in the β band only where reduced activity was noticed in several pain related areas Table . StrongeOn the individual level, P1 had a significantly reduced activation in the Ɵ band at the primary sensory and motor cortices and the posterior parietal cortex and P2, P4 and P5 had significantly increased α activity over the primary sensory and motor cortices and over all cortical structures reported in table This paper presents the effect of neurofeedback training on reduction of CNP and on related neurological measures. Using a visual feedback, patients learned how to modulate their brain activity in a desired directions which resulted in reduction of pain.Six out of seven tested patients achieved short-term immediate reduction of pain during neurofeedback training. To achieve longer lasting reduction of pain repeated neurofeedback sessions were required. Four out of five patients who received a long term training achieved a clinically relevant reduction of pain (>30 %) lasting at least a month following the treatment. A negative correlation between the intensity of pain and the number of training sessions indicate that the long-term reduction of pain was gradual and required long training. All patients experienced the reduction of pain while receiving a neurofeedback training from electrodes located above the primary motor cortex (C3/C4), which was also a preferred stimulation site for rTMS and tDCS , 34. In Volunteers from our study that achieved the clinically significant reduction of pain reinforced the α power and to some extent suppressed the β power during training. Although the Ɵ band power is believed to be the signature of CNP , the onlAlthough neurofeedback was dominantly practiced from the right side of the central cortex at C4, patients reported reduction of pain in their legs, confirming observations from rTMS studies that the exact somatotopical location of stimuli is less relevant .Because patients were occasionally trained with different protocols, one cannot claim that training specifically at C4 produced long-term changes. However all protocols involved sensory-motor area and were based on decreasing theta and higher beta band and increasing alpha or lower beta band. In addition, training at one electrode caused wide spread changes so one can assume that all training protocols globally affected sensory-motor cortex, though they caused to some extend different physical responses. In this study, a multichannel EEG was recorded only during training from C4 (Protocol 4). In the future, it would be interesting to compare global effect of training from the electrode locations included in the training protocols (P1-P3).It is believed that chronic pain disrupts ‘a default mode network’ . NeurofeThis study tested neurofeedback protocols from the primary motor cortex which is not the part of the standard pain matrix . It is pA perceived sensation of pleasant warmth reported by all patients, including these with a complete loss of sensation, might be an indicator of indirect activation of corresponding thalamic nuclei, being in a close proximity to pain nuclei . AlternaThe ability to ‘self-administer’ therapy i.e. to modulate their brain activity at will without a visual feedback was achieved by 4 out of 5 patients; this ability was previously reported by patients practicing mindfulness and hypnosis , 44. ThiAlthough some patients reported spasm during training, in two patients this resulted in reduced tightness and clonic activity following neurofeedback. It is believed that sensory-motor cortex is one of the sites from which it is possible to modulate monosynaptic reflexes  that migThe results of the study show that prolonged neurofeedback training may have a potential to reduce CNP. Neurofeedback training affects deeper cortical structures involved in processing of chronic pain. We tested neurofeedback treatment on patients who had long-standing CNP. The effect of neurofeedback might be better on patients who suffered from CNP for a shorter period of time, as prolonged pain might cause long lasting changes in brain connectivity


In Tanzania, a country of 42 million, access to oral morphine is rare.To demonstrate the effectiveness of palliative care teams in reducing patients’ pain and in increasing other positive life qualities in the absence of morphine; and to document the psychological burden experienced by their clinical providers, trained in morphine delivery, as they observed their patients suffering and in extreme pain.One hundred and forty-five cancer patients were included from 13 rural hospitals spread across Tanzania.A mixed method study beginning with a retrospective quantitative analysis of cancer patients who were administered the APCA African POS tool four times. Bivariate analyses of the scores at time one and four were compared across the domains. The qualitative arm included an analysis of interviews with six nurses, each with more than five years’ palliative care experience and no access to strong opioids.Patients and their family caregivers identified statistically significant (p < 0.001) improvements in all of the domains. Thematic analysis of nurse interviews described the patient and family benefits from palliative care but also their great distress when ‘bad cases’ arose who would likely benefit only from oral morphine.People living with chronic cancer-related pain who receive palliative care experience profound physical, spiritual and emotional benefits even without oral morphine. These results demonstrate the need for continued advocacy to increase the availability of oral morphine in these settings in addition to palliative care services. Efforts to provide palliative care without access to oral morphine have lacked credibility. Anne Merriman, a pioneer in African palliative care, observed that ‘palliative care without morphine is only supportive care… and lack of access to morphine is torture.’9The World Health Organization (WHO) defines palliative care as being a holistic approach for patients and their families who are living with life-threatening diseases, particularly emphasising the treatment of pain.10 Due to the vast distances involved, the immobility of the very sick and limited training of clinical staff, very few patients will have access to a palliative care service.In 2010, the WHO estimated that over 14 000 of Tanzania's population of over 40 million will die of cancer each year.11 presumably because of low availability  and limited prescription, even when available.Tanzania's Pharmaceutical Board requires individual hospitals to apply for a licence to administer morphine; few hospitals currently have this licence and even when such a service is available the supply of oral morphine may be limited as a result of stringent reporting and access regulations. Overall consumption of morphine at the national level remains very low,12 What is the experience of the few palliative care patients and their providers in settings with no morphine? There is little available in the literature to document the value and limitations of palliative care in these settings. Through a retrospective study of data gathered from 2009 to 2010, we aim to address this gap.Palliative care is relatively new to Tanzania. Initial efforts began in the early 1990s at the Ocean Road Cancer Institute in Dar es Salaam, but it was not until this century that other organisations began concerted efforts with regard to provision of palliative care. By 2002 there were three further sites: PASADA , Muheza Hospice (Tanga Region) and Selian Hospice (Arusha Region).16 in 13 of the ELCT hospitals, which varied in size from 60 to 400 beds and served catchment areas of between 100 000 and 400 000 people.In 2004, the Evangelical Lutheran Church in Tanzania (ELCT) began a programme in palliative care, emulating the growth of Selian's service. Using a hospital-based approach, trained palliative care teams were developed through 18 rural ELCT hospitals, scattered widely throughout the country . In 2007CHAT ran from 2007 to 2010 and comprised a supervising palliative care team and mobile hospital-based teams with vehicle transport that provided home-based care (HBC) and monitored pain and the quality of care systematically with a validated assessment tool, the APCA African Palliative Outcome Scale (POS). CHAT funders allowed all patients with terminal illness, including cancer, admission to the programme.17 within the limits of the drugs they had at their disposal. At the time of the study oral morphine was not accessible in most of rural Tanzania, including the 13 sites that were part of CHAT. As a result, the practice of pain management faced significant challenges requiring each palliative care team clinician and nurse to become proficient in the systematic use of the available analgesics, of which tramadol was the most potent.The palliative care teams had been trained to treat moderate to severe pain using the WHO Analgesic Ladder18 but there is little information about such care for cancer patients where oral morphine is lacking. While it might be intuitive that the general well-being of any patient would be enhanced by attention from a palliative care team, is the team's efficacy compromised by the absence of morphine? Although tramadol has been studied in the treatment of cancer pain, it has been in the context of more potent options.22 The teams administered tramadol to a maximum dose of 400 mg/d to all patients with moderate to severe pain and combined it according to patient response and tolerance with ibuprofen, paracetamol and/or amitriptyline.Studies have very clearly shown the benefit of HBC programmes for people living with HIV,The aim of this paper is twofold. First is to document, using the POS indicators, the value of palliative care for patients living with cancer but without access to morphine. Second is to document the psychological burden experienced by their clinical providers, who are trained in morphine delivery but have no access to the drug, as they observe their patients suffer in pain.The study was conducted from January 2009 to December 2010, employing a combination of quantitative and qualitative methods. The quantitative component comprised a retrospective cohort analysis of 145 cancer patients across the 13 hospital sites that did not have access to oral morphine. The qualitative arm involved face-to-face interviews with nurses from the hospital sites.24 For our study a Swahili version of the POS – Swahili is the official language of Tanzania – was used by the attending nurse with translation into the local dialect or language where necessary. The POS contains seven questions for the patient and three questions for family caregivers. Patients identify physical symptoms, including pain and psychological status, on a scale of zero to five. . Prior to data analysis, low-scoring positive scores, such as a ‘2’ for minimal worry were reversed numerically so that all negative scores were skewed toward the higher numbers and could be compared with ease. To assess statistical significance over time, scores from the first and last visits were compared for each question. The Shapiro-Wilk test indicated that the key outcome variables, pain and other domains as measured by the POS were not distributed normally, thus the non-parametric Wilcoxon-signed rank test was applied. The statistical level of significance was set at 25 specifically, years of experience and palliative care training. Three of the nurses held diplomas in palliative care whilst the other three each had at least seven years of experience working in palliative care. All six nurses had received training from APCA, Nairobi Hospice or Hospice Uganda, each being a well-established programme in East Africa.In order to assess clinical providers’ perspectives on quality of pain management for cancer patients in settings without morphine, the first author conducted face-to-face interviews with six nurses from six of the CHAT hospitals. We selected nurses using criterion sampling,We used a semi-structured interview guide to conduct each interview and tape-recorded all sessions. The core questions asked the nurse to (1) describe in detail the case of a patient with cancer who, whilst under their team's care, had poor pain control; (2) describe the case of a patient with cancer with very good pain control; and (3) reflect on the value of palliative care in the setting of no access to oral morphine for chronic pain control.The first author conducted all the interviews; five in Swahili and one in English. The same author transcribed all of the interviews and translated the Swahili interviews into English prior to data analysis. Two authors (K.H. and M.D.) conducted a thematic analysis of the interview transcripts with particular attention to the nurses’ perspectives on their patients’ pain control and quality of life and their own experience in coping as professionals with no access to morphine. The two analysts used an iterative process of independently identifying themes and quotes within the interviews and then comparing results. The final set of themes emerged after discussion and further iterative analysis of the transcripts.The University of Cape Town (UCT) and the National Institute of Medical Research (NIMR) of Tanzania gave ethical approval for the study . Each nurse provided written voluntary consent to be interviewed.Of the 153 satisfactorily-completed POS records, eight patients had died before the third visit, leaving 145 records for inclusion in the study. Women made up 87 (60%) of the patients and had an average age of 57 compared with men at 56. Given the limited diagnostic procedures and treatments available in rural areas precise diagnoses, including co-morbidities, are rarely available so we did not attempt to collect such data.p < 0.001). The worst problem at each visit was pain, with the average first visit pain score being 3.8 (slightly higher for men), which compared with the next worst score of 3.4 for patient anxiety. By the last visit the average pain score for both men and women was 2.3, similar to that of several other symptoms At a funeral for a patient attended by the palliative care team, families shared their appreciation:‘Many are so happy to be visited and listened to, because we really try hard to address all of their problems, and comfort them even when they are in pain.’Nurse 1 added:Although pain reduction is a primary service, the emotional and psychological support provided to patients and their families can be seen in these quotes as well as the POS scores.‘With our African setup you cannot simply say that now I managed the physical pain and everything is OK. There are other aspects of pain like the social pain, the spiritual pain and so on. They contribute a lot to pain and so if you are able to manage these other pains like the social pain and the spiritual pain and psychosocial pain then you will find that to some extent a lot of these pains are associated with the physical. For example, there might be family conflicts, or poverty, the child is not going to school, the breadwinner is unable to work; so you find some of these elements are adding pain into the physical pain.’ (Nurse 3)The value of the holistic nature of a palliative care approach in a context of limited resources was best summarised by this quote:All six nurses however, felt that their pain management would be improved by having access to oral morphine. Four of the six nurses trained to use morphine for severe, chronic pain expressed concern over not having access to potent pain relievers. Each nurse could easily tell the story of one or more patients who had suffered considerable unrelieved pain before death. ‘My thoughts and advice is that the relevant ministries and government leaders should make the process of getting pain medications to be fair and easy. After all it is a basic human right for patients to get that service.’ (Nurse 5)The nurses’ collective frustration with the limited access to oral morphine also proved to be an incentive for advocacy. Each of them spoke of lobbying within their own hospital with doctors and pharmacists. In addition, they spoke of the need to reduce government bureaucracy so that more hospitals could provide morphine. Nurse 5 spoke passionately:27 For example, in South Africa average APCA African POS scores went from 4 to 1 over six visits with morphine compared with our results of 4 to 2 with no morphine.27 This suggests the value of holistic palliative care to patients without access to morphine. However, without a breakdown by disease process it is difficult to assess how comparable the two populations are. The nurses, despite their frustration at not having access to oral morphine, nonetheless affirm the value of palliative care in the absence of morphine. In this rural Tanzanian setting palliative care is valuable and offers a significant degree of pain control in the absence of oral morphine, but not to the degree that could be achieved if morphine was available. Given that much of the world currently lacks access to a strong opioid for treating cancer pain,28 this finding has significance. Recent availability of the APCA African POS as a validated tool makes such assessment feasible. There are few examples of results in the peer-reviewed literature using the APCA African POS.27 This study contributes to a nascent body of literature on this tool in different African settings.Our results indicate that even in the absence of morphine there is a benefit in providing palliative care to cancer patients. Overall pain scores improved from an average of 3.8 out of 5 (moderately severe pain) to 2.3 out of 5 (moderate pain) and non-pain symptoms and other indicators – psychological, spiritual and family issues – improved significantly as well. Both women and men experienced similar decreases in pain and positive changes in the other domains over the period of the four visits. However, the average last visit POS score still indicates a moderate degree of pain and is higher than that reported by facilities using morphine.From the nurse interviews there is, as a result of their training, a clear belief that pain control would be even better with oral morphine. All recalled difficult pain cases which might have been better managed had they only been able to access morphine. There is a burden to the team in having knowledge of optimal treatment without being able to deliver it. The psychological hardship for palliative and other community teams in resource-constrained environments is an area that has been under-researched.There are a number of limitations to this study. We did not have access to a comparison hospital site with access to morphine and using POS – such direct comparison would have been very useful. Having only one investigator doing interviews and translations raises the possibility of bias and error. For the language of the POS, whilst Swahili is the dominant language in Tanzania there are more than 120 distinct languages in the country, some of which are in use amongst the 13 rural sites of this study. Translations from Swahili into the local language were occasionally done on the spot by the health professional administering the POS, or through a family interpreter.29 shows the positive impact of palliative care for HIV clients and the nurse interviews in this study point out that clients have a great appreciation and sense of improvement when receiving palliative care. In South Africa, with access to oral morphine and where the POS is used regularly, average pain scores improved from 4 to 1 over time.27 Detailed data comparison from South Africa and APCA would be an area for further study, with the hypothesis that pain control is improved significantly with the availability of oral morphine.Nonetheless, our results are in line with data from other palliative care providers in Africa. Loy et al.'s work32Pursuit of oral morphine is an ongoing challenge for many palliative care advocates around the world. The mention of advocacy by several of the nurses suggests that there appears to be little danger of palliative care teams abandoning their pursuit of oral morphine access. This study, and indeed the CHAT project with its associated emphasis on quality measurement, is an important advocacy tool for accessing oral morphine and for palliative care in general. The availability of client-centred data is valuable in care provision, particularly in areas such as rural Tanzania where information is limited. In this regard the POS is an invaluable tool.33 and as was written up in the FHSSA newsletter,34 it is as a result of this very emphasis on quality and advocacy that 12 out of 13 CHAT sites  had, as of February 2011, been granted approval for oral morphine usage by the Tanzania Food and Drug Authority. A year later (January 2012), continued advocacy and training brought morphine access to a total of 19 ELCT facilities, including all of the CHAT sites. With other programmes such as Muheza in Tanga Region and Tearfund in the Lake Zone35 having gained access to oral morphine, the prospects for pain management in rural Tanzania are much improved. By the end of 2012, there were 50 facilities – a mix of public and private – which had gained approval for oral morphine use through the Tanzania Food and Drug Authority . Although no funding is available at this time, future research in these same hospitals with similar patient populations to this study would be desirable in order to observe if there are differences in POS results now that morphine is more widely available.The information in this and similar studies can be used to lobby government decisions regarding health policy. As Mmbando described in the APCA newsletter of April 2011,This study shows that palliative care without morphine is beneficial to cancer patients, but comparison with other studies suggests that pain control would be even better with access to oral morphine. A degree of pain relief for most cancer patients can be accomplished without strong opioids in the context of palliative care. A trained palliative care team, equipped with education and medications, can be a powerful advocate for people at the end of life, whether the disease be cancer, HIV, or any other. Effectiveness of the care, whether for pain or other domains of palliative care, can be measured and shown to be of value for clients and their families, but there is a psychological burden for nurses trained in palliative care and the use of morphine when they are asked to deliver palliative care without access to the world's most available strong analgesic.Whilst palliative care team leaders can become excellent advocates for accessing oral morphine, more research is warranted in the area of supporting such teams that often operate without the full range of tools necessary to meet all of their patients’ needs.