To examine the effects of low-amplitude, low frequency electromagnetic field therapy (EMF) therapy in patients with persistent chronic lower back pain associated with degenerative disc disease.Double-blind, randomized and placebo controlled.EMF using a medical device resonator; control group underwent same procedures, except the device was turned off.Pain reduction and mobility.Improvements in overall physical health, social functioning and reduction in bodily pain were observed in the EMF group. The pain relief rating scale showed a higher level of pain relief at the target area in the EMF group. An increase in left lateral mobility was seen only in the EMF group.EMF treatment may be of benefit to patients with chronic nonresponsive lower back pain associated with degenerative disc disease. Lay abstract: In this preliminary study, we examined the possible value of using a medical device that generates low energy electromagnetic fields for reducing pain and increasing movement in individuals with persistent lower back pain associated with degeneration of the discs of the spine. After five treatment sessions (each lasting 1 h) over a 2-week period, it was found that as compared with those individuals that were not exposed, low energy electromagnetic fields at the pain area may not only improve physical functioning, but also may reduce pain. It has been estimated that up to 84% of adults have low back pain at some point during their lives ,2. InterPresently, there is a paucity of information available in the literature that describes the clinical utility of very low EMF in the treatment of chronic LBP associated with degenerative disc disease. Accordingly, in this pilot study, a placebo-controlled, randomized, double-blind study design was employed to assess the efficacy and safety of low-amplitude/low-frequency EMF in the management of nonresponsive chronic LBP and functional capacity in patients with some degenerative disc disease. In addition, quality of life scores as well as mobility measurements were collected to further assess effectiveness of EMF in this cohort of subjects.Twenty one subjects were referred to participate in the study through family physicians, physical medicine and rehabilitation, sports medicine, orthopedics and rheumatology departments from the Health Sciences Centre, Winnipeg, Manitoba. The protocol was approved by the institutional review committee. Subjects were male and female, over 25 years of age who had documented chronic LBP persisting more than 6 months, which was not responsive to conservative therapy, MRI radiographic confirmation of diagnosis  and no herniation. In these subjects, the disc degeneration resulted in discogenic low back pain  or EMF treatment (n = 14) arm. Randomization was carried out by the subject drawing an envelope containing a preassigned number. The envelope was handed unopened to the operator of the device. The operator of the device opened the envelope in the control room where no other persons involved in the study were present. Inserts of envelopes containing even numbers were assigned to the treatment arm, whereas inserts of envelopes containing odd numbers were assigned to the control arm. Since the device operates in total silence and there are no other indicators of when the device is on or off, the study was blinded for the patient, and the clinical assistant doing the positioning of the patient. Subsequent visits to the center remained blind as only the operator of the device had the record of what the previously assigned subject number was and which arm of the study the subject was in.The magnetic fields to be used in this pilot study were generated by a medical device resonator. This resonator is a noninvasive device that does not utilize ionizing radiation and produces a uniform low-amplitude/low-frequency EMF through a Helmholtz coil  operatedt-test. Differences in scores on the Roland Disability Questionnaire and SF-36 Health Survey between baseline and end point for each group were analyzed by the Wilcoxon matched pairs test based on ranks. The level of statistical significance was set at p < 0.05. Scores on the Pain Relief Scale and McGill Visual Analogue Scale for visits 2–8 were graphed in order to represent the pattern across time and between groups, as there were insufficient numbers of subjects and not enough statistical power to allow for a more formal statistical analysis such as two-way repeated measures ANOVA. Scores on the McGill Present Pain Intensity Index and forward, left and right lateral mobility were graphed at baseline and end point for the two groups. Differences in scores between groups and across time presented in the graphs are linearly scaled. The data were analyzed by SPSS .Demographic and medical variables at baseline were compared for differences between the two groups using the independent group Demographic and medical variable comparison of EMF and control groups is shown in The EMF group reported a higher level of ‘pain relief at the target area’ following treatment as compared with the control group on six of the seven visits . AlthougSeveral recent commentaries have suggested that EMF treatment may provide moderate benefit in terms of pain relief and/or physical functioning in different pathophysiological conditions , but no The present study also provided suggestive evidence that left lateral mobility increased following EMF treatment compared with the controls. Importantly, in the present study, there were no adverse events or side effects related to the device, treatment or protocol reported. An unexpected finding in our study was that despite a significant reduction in bodily pain, physical functioning was reported to be worse in the EMF group when comparing baseline to end point values. This could be explained on the basis that our study was conducted with a small number of subjects and bias in the questionnaire responses may have occurred, thus impacting on the statistical analysis of the data on physical functioning. Furthermore, it is conceivable that questions asked, with regards to certain daily activities, could have been indicated as difficult to perform even with less back pain. Therefore, a larger study is warranted in order to further validate the findings of the present pilot study and control for accidental biases.-8 G to 3.43 × 10-7 G) and low-frequency (0.92–7.7 Hz) EMF. The selection of the applied signal was based on other studies that have used similar low-amplitude, low-frequency magnetic fields [Although EMF in the 150 Gauss (G) range has been used for treatment of chronic low pack pain disorders  we, emplc fields . Howeverc fields . We beliA limitation of our study is that there were more male subjects in the control group and more female subjects in the EMF group. This imbalance of gender in the groups was a reflection of the randomization process that was undertaken in assigning subjects to the two different groups. While we cannot exclude the possibility that the beneficial effects of EMF in our study may be related to sex, future studies are needed to prove this assumption right or wrong. While the results obtained in the present pilot study are positive in the short term, it is, however; a small study and thus some caution must be exercised in the interpretation of the data obtained. Therefore, a study with a larger patient sample and a long-term (at least 6 months) follow-up period is warranted.The pilot data suggest that the EMF treatment protocol used in the present study may have clinical relevance and may emerge as a safe and effective adjuvant option in the approach for management of pain in patients with degenerative disc disease.A double-blind, randomized, placebo-controlled pilot study was conducted to assess the efficacy of electromagnetic field therapy (EMF) for the management of chronic lower back pain associated with some degenerative disc disease.A larger reduction in the total score was observed in the EMF group.Overall physical health, social functioning and reduction in bodily pain were observed in the EMF group.A higher level of pain relief at the target area was observed in the EMF group.Although a decrease in pain intensity was observed in the EMF group, an increase occurred in the control group.Left lateral mobility was increased only in the EMF treated group.EMF treatment may be of benefit to patients with some degenerative disc disease with chronic nonresponsive lower back pain.


Objectives. To elucidate the differences in perception between patients and physicians concerning NSAID plasters. Subjects. We conducted two surveys about NSAID plasters on patients and physicians. 600 patients currently using plasters and 200 physicians currently prescribing NSAID plasters were studied. Methods. Questionnaire included items concerning usage, efficacy and side effects, site and intensity of their pain, pain management strategies, characteristics they desired from NSAID plasters, and their satisfaction with them. Results. The characteristic most frequently reported as desirable by patients was analgesic efficacy, followed by avoiding skin irritation and low medication cost. The characteristics most frequently reported as desirable by physicians were analgesic efficacy, alignment with patient preference, safety to skin, and comfort when applied. Our survey revealed that both patients and physicians prioritized analgesic efficacy of NSAID plasters. However, approximately half of the patients and physicians were unsatisfied with the analgesic efficacy of plasters. Conclusions. Physicians may improve patient satisfaction by discussing analgesic efficacy, skin complications, and price with patients before prescription.In Japan, adhesive skin plasters containing nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat pain of musculoskeletal origin. There are many reports on their efficacy but few on patients' impressions of usability or levels of satisfaction.  Topical plasters containing nonsteroidal anti-inflammatory drugs (NSAIDs) are designed to relieve pain of musculoskeletal origin and are indicated for a wide variety of diseases. They are frequently used as a route of administration of analgesics in Japan. Causing gastrointestinal complications less frequently than oral analgesics, NSAID plasters are safer for elderly patients , 2 and wAiming to examine factors that could potentially raise patient satisfaction with NSAID plasters, we conducted two online surveys that enquired with patients and physicians about their treatment expectations of, and satisfaction with, such medications and compared their responses.Our patient survey was an online survey run for six days , administered using an existing mailing list of people in the general population. Of the 12,083 respondents, those who were not currently using NSAID plasters were excluded. The eligible respondents were stratified by age  and sex. The first 100 were included in each respective age group of both sexes for a total of 600 (average age = 53.2 y). After 100 respondents were included for each category, further responses were excluded. Questionnaire items asked patients about the department or clinic that prescribed their NSAID plasters, the site and intensity of their pain, their pain management strategy, expectations and satisfaction of treatment with NSAID plasters, and their mental associations with the expression “comfort” when applied .Our physician survey was an online survey run for three days , administered using an existing mailing list of physicians. Of the 995 respondents, those who prescribed NSAID plasters to more than 50 patients in the past month were included. The respondents were sorted by specialty and practice type . 50 respondents who specialized in orthopedics and general practice  for each practice type were chosen in chronological order for a total of 200 physicians. After 50 respondents were included for each category, further responses were excluded. Questionnaire items asked physicians about their affiliated clinical department, their concerns and priorities when prescribing NSAID plasters, their satisfaction with existing drugs, their estimations of patient satisfaction, and specific factors that they associate with the expression “comfort” when applied.The types and available formulations of the plasters included in this survey are shown in This study was approved by the Hirosaki University Graduate School of Medicine Ethics Committee.223 (37.2%) patients used NSAID plasters in combination with oral analgesics. The prescribing entity was most commonly a physician from an orthopedic surgery department (67%), followed by general internal medicine department (17%), general surgery department (3%), and other departments (1% each). In terms of frequency of use, 31% of patients used NSAID plasters almost every day, while 35% used them 1–3 times per week.Patients most frequently reported pain in their lower back (68.3%), followed by the shoulder (58.0%), the knee (38.2%), and the neck (37.8%). 74.7% of patients complained of pain at multiple sites . Women hItems related to analgesic efficacy were highly ranked among patients' desired characteristics of NSAID plasters, including strong pain relief (73.0%), length of action (57.8%), and early onset of action (57.2%). The next most desired characteristics were avoiding skin irritation (56.3%) and low price (38.3%) . Young aPatients' perceptions of NSAID plasters' analgesic effects differed by the affected site. Although 20–33% responded that they did not feel any noticeable improvement, the majority of patients reported improvement of symptoms . With reIn the second survey, 34.5% of physicians reported analgesic effects to be the single most important characteristic desired of NSAID plasters. The next most frequent response was whether the NSAID plaster matched their patient's preference (26.5%), followed by safety to skin (12.0%) and comfort when applied (12.0%) . 57.5% rBoth patients and physicians were asked about specific factors that they associate with the expression “comfort” when applied. The responses most frequently seen were “not irritating to skin” , “not itchy” , “no discomfort” , and “easy to apply”  . Physicians also associated the term “comfort” with adhesiveness, but fewer patients felt the same  .Respondents to our patient survey reported lower-back pain most frequently, followed by pain in the shoulder, knee, and neck, while 74.7% complained of pain at multiple sites. In addition, large differences were observed in rates of visitation to medical institutions depending on the pain site, from a maximum of 82.9% of all patients with lower-back pain to a minimum of 54.1% of all patients with hip-joint pain. This suggests that patients may have different expectations of medical care depending on the site of their pain and may in some cases choose other treatments such as alternative therapies. Patients using NSAID plasters who visited medical institutions comprised a higher proportion of our patient population than in past studies. This is likely because we specifically administered our survey to patients who were prescribed NSAID plasters at a medical institution.The development and spread of transdermal NSAID plasters have followed a unique path in Japan. They are a frequently prescribed mode of administration for NSAIDs in Japan today, owing to a lower incidence of systemic adverse effects and superior safety of topical administration , 3. The Our survey revealed that both patients and physicians prioritized analgesic efficacy highest among the desirable characteristics of NSAID plasters. Moving forward, we believe that a detailed examination of the efficacy of NSAID plasters according to specific diseases and disease severity, in combination with the continued development of topical agents with even stronger analgesic efficacy, will help to further improve patient satisfaction.Both patients and physicians viewed safety to skin as an important characteristic for NSAID plasters. This may reflect the fact that 39.3% of patients have experienced some form of skin complication due to the use of NSAID plaster medications . After aPatient–physician differences in satisfaction were also observed for other items. A mere 43.0% of patients were satisfied with NSAID plasters' analgesic efficacy, compared with the estimated satisfaction rate of 57.5% in physicians, suggesting patients may be less satisfied with the treatment than physicians perceive. Failure to meet patients' treatment expectations and functional status have been raised as factors that reduce patient satisfaction in general practice . Skin plFewer than half of patients and physicians were satisfied with NSAID plasters in terms of their safety to skin, suggesting there is room for improvement in the design of transdermal plasters. Also, 40% of patients responded that they do not report side effects and preferences to their physician. When considered with the low utilization of medical facilities, side effects and dissatisfaction with plasters are likely to be underrepresented and underrecognized. In light of this, there may be a role for the pharmacist who can educate the patient concerning proper usage and side effects. Pharmacies are more easily accessible and usually have information of medications for multiple medical facilities, making them ideal for identifying and differentiating adverse effects and drug interactions.Only 20% of physicians considered extradermal side effects, and 1.5% responded that they were the most desired characteristics. Although NSAID plasters are systemically absorbed, systemic side effects are rare. Evans reported that topical NSAIDs did not increase the risk of upper gastrointestinal bleeding in a case-control study . The ris50.0% of patients were satisfied with the comfort of NSAID plasters. There was a high degree of agreement between patients' and physicians' perception of “comfort” when applied, which may have contributed to a higher satisfaction rate. A factor that was not taken into account was the relationship between adhesiveness and climate. Japan has a very diverse climate, so the temperature and humidity may vary greatly between geographic locations at any given time. Clothing and perspiration may also affect the adhesiveness of plasters and influence satisfaction. This study was not designed to assess differences between locations, but from the available data, there was no difference in responses concerning satisfaction in comfort and the perception of adhesiveness between regions. This may be due to the availability of various sizes, thicknesses, and adhesiveness, which patients may choose for their specific needs. Indeed, 101 (16.8%) of respondents used multiple types of plasters.Musculoskeletal pain is extremely common: according to the 2013 National Livelihood Survey, respective reported incidences for men and women were 9.22% and 11.82% for lower-back pain, 6.02% and 12.50% for stiff shoulders, and 4.18% and 7.03% for limb-joint pain, respectively. However, a mere 4.22% of men and 5.85% of women visit medical facilities because of lower-back pain.One study found that only 19% of people visit a medical facility to treat chronic musculoskeletal pain, while 20% use alternative therapies  and 55% do not consult with a physician at all . The finOur investigation had several limitations: as it was an Internet survey, we did not directly examine patients and could not confirm the diagnosis of the underlying diseases. In addition, while 37.3% of patients were taking oral medication in combination with an NSAID plaster, we did not examine the details of their oral medication regimen. Also, as we did not have a control group, we could not compare the satisfaction between different treatment modalities .The most desirable characteristics of NSAID plasters according to both patients and physicians were strong analgesic efficacy and avoidance of skin complications. Patients and physicians had relatively high satisfaction with “comfort” of plasters, and their conceptions of the term had much in common. We conclude that when prescribing transdermal NSAID plasters, physicians should be knowledgeable about their analgesic effects, potential skin complications, and prices. Sufficiently explaining these aspects to patients, along with prescribing in consideration of underlying diseases, should accordingly lead to increased satisfaction. “High-absorption” transdermal plasters have been recently developed, which allow for high absorption of NSAIDs into the skin , 16: the


We examined the effectiveness and tolerability of transdermal buprenorphine (TDB) treatment in real-world setting in Asian patients with musculoskeletal pain.This was an open-label study conducted in Hong Kong, Korea, and the Philippines between June 2013 and April 2015. Eligible patients fulfilled the following criteria: 18 to 80 years of age; clinical diagnosis of osteoarthritis, rheumatoid arthritis, low back pain, or joint/muscle pain; chronic non-malignant pain of moderate to severe intensity , not adequately controlled with non-opioid analgesics and requiring an opioid for adequate analgesia; and no prior history of opioid treatment. Patients started with a 5 μg/h buprenorphine patch and were titrated as necessary to a maximum of 40 μg/h over a 6-week period to achieve optimal pain control. Patients continued treatment with the titrated dose for 11 weeks. The primary efficacy endpoint was the change in BS-11 pain scores. Other endpoints included patients’ sleep quality and quality of life as assessed by the 8-item Global Sleep Quality Assessment Scale (GSQA) questionnaire and the EuroQol Group 5-Dimension Self-Report Questionnaire-3 Level version (EQ-5D-3 L), respectively. Tolerability was assessed by collecting adverse events.p < 0.0001 for both). The proportion of patients who rated sleep quality as ‘good’ increased from 14.0% at baseline to 26.9% at visit 6. By visit 6, the mean EQ VAS score increased by 7.7 units (SD 17.9). There were also significant improvements in patients’ levels of functioning for all EQ-5D-3 L dimensions from baseline at visit 6 . Seventy-eight percent of patients reported TEAEs and 22.8% of patients discontinued due to TEAEs. TEAEs were generally mild to moderate in intensity (96.5%).A total of 114 eligible patients were included in the analysis. The mean BS-11 score at baseline was 6.2 (SD 1.6). Following initiation of TDB, there was a statistically significant improvement in BS-11 score from baseline to visit 3 (least squares [LS] mean change: -2.27 [95% CI -2.66 to −1.87]), which was maintained till the end of the study (visit 7) (LS mean change: −2.64 [95% -3.05 to −2.23]) .ClinicalTrials.gov  Musculoskeletal disorders are among the most common causes of chronic non-malignant pain in adults. Unrelieved pain has significant physiological and psychological impact on patients, affecting their daily quality of life as well as increasing their financial burden . A comprSystematic reviews examining evidence on the use of opioid analgesics for the treatment of chronic non-malignant pain suggested these are efficacious in treating pain of various etiologies , 4. HoweTransdermal buprenorphine (TDB) patches , in three dose strengths: 5 μg/h, 10 μg/h, or 20 μg/h, have been developed . It is lTDB has demonstrated good efficacy and an acceptable tolerability profile in patients with chronic non-malignant pain in randomized controlled trials –25. PainThis was a prospective, multicenter, open-label, single-arm study conducted in 16 hospital sites across three countries or territories in Asia  between June 2013 and April 2015. The study comprised a screening and baseline visit (visit 1) to assess patient eligibility and collect baseline data, followed by a titration period of up to six weeks, during which patients received the study medication and their dose was adjusted as necessary to achieve optimal pain control. Patients then entered an 11-week treatment period and attended a follow-up visit two weeks after completion of treatment. The study consisted of at least seven scheduled visits at specified intervals  18–80 years of age; (ii) clinical diagnosis of osteoarthritis, rheumatoid arthritis, low back pain, or joint/muscle pain; and (iii) chronic moderate to severe pain [defined as a score of ≥4 on the Box Scale-11 (BS-11) pain scale], not adequately controlled with non-opioid analgesics and requiring an opioid for adequate analgesia. Exclusion criteria included the following: (i) pregnant or lactating females; (ii) females of childbearing potential who were not willing to use appropriate contraception during the study; (iii) current diagnosis or history of cancer ; (iv) previous surgery or required surgery; (v) history of alcohol or drug abuse, or behaviors suggestive of addiction or substance abuse; (vi) presence of any contraindication to the study medication; (vii) other chronic conditions that required frequent analgesic therapy; (viii) history of allergy to analgesic agents; (ix) history of prior treatment with study medication; (x) history of opioid treatment; (xi) current or history of steroid treatment; and (xii) deemed unsuitable for participation by the study physician.7-day TDB patches, available in three dose strengths: 5 μg/h, 10 μg/h, and 20 μg/h, were used in this study. Patients started with a 5 μg/h buprenorphine patch at the baseline visit and were titrated as necessary to a maximum of 40 μg/h over a 6-week period to achieve optimal pain relief. Dose titration and patch application were carried out according to the instructions stated in the local summary of product characteristics or patient information leaflet –15. PatiPatients’ demographics and disease characteristics were collected at visit 1. Information relating to concomitant illness was collected throughout the study. Concomitant illness was defined as any medical condition, other than the primary condition, that occurred within the last five years prior to study entry or during the course of the study.The primary efficacy assessment was the BS-11 pain score. Before the start of treatment (visit 1) and at each subsequent visit, patients rated their pain level on the BS-11 scale, ranging from a scale of 0 (no pain) to 10 (unbearable pain) .Global Sleep Quality Assessment Scale (GSQA)Before treatment (visit1) and at the end of treatment (visit 6) and the follow-up visit (visit 7), patients evaluated their overall sleep quality, degree of sleep disturbance, and sleep duration using the 8-item GSQA scale questionnaire. The GSQA scale ranges from 0 to 10, with higher scores indicating a higher degree of sleep disturbance.EuroQol Group 5-Dimension Self-Report Questionnaire-3 Level Version Survey (EQ-5D-3 L questionnaire)Patients assessed their quality of life using the EQ-5D-3 L questionnaire at visits 1, 6, and 7. The questionnaire includes the EQ-5D visual analogue scale (EQ VAS) where patients rated their overall health state on a scale ranging from 0  to 100 . It also includes the descriptive system comprising the following five dimensions: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression where patients indicated their levels of functioning at one of the three levels: no problems, some problems, and extreme problems .Global Impression of Change AssessmentBoth patients and physicians evaluated the change in overall pain condition since the initiation of treatment. They completed the Patient Global Impression of Change questionnaire  and the Concomitant rescue medication usePatients recorded their rescue medication intake in the patient diary throughout the study.The secondary efficacy assessments were as follows:Local language version of all questionnaires was used in each country or territory.The physicians recorded all adverse events (AEs) that occurred during the study. Vital signs measurements and physical examination were performed at visits, 1, 6, and 7.The sample size was estimated based on the results of previous studies –25. AssuThe primary efficacy endpoint was the change in BS-11 pain scores between baseline and each visit. A linear mixed model-repeated measures analysis was performed to estimate the least squares (LS) mean change in scores from baseline and 95% confidence intervals (CIs). Baseline score, visit, and country or territory were included as covariates in the model.Secondary endpoints evaluated included: (i) GSQA overall sleep quality rating, sleep disturbance scores, and sleep duration; (ii) EQ VAS score and ratings for individual EQ-5D-3 L dimensions; (iii) patients’ and physicians’ Global Impression of Change scores; and (iv) prescribed concomitant rescue medications. The Bowker-McNemar test was used to compare patients’ ratings for their overall sleep quality and individual ED-5D-3 L dimensions between visits. Parametric tests were performed where assumptions of normality were met. Otherwise, nonparametric tests were used. The Wilcoxon signed-rank test was used to compare patients’ GSQA sleep disturbance scores and sleep duration between visits, and to compare patients’ and physicians’ Global Impression of Change scores. The paired t-test was used to compare EQ VAS scores between visits. Rescue medication use was summarized using descriptive statistics.p-value of less than 0.05 was considered as statistically significant.The intent-to-treat (ITT) population was the primary population for efficacy analysis. The efficacy data were analyzed using the per-protocol (PP) population to provide confirmation. The ITT population included eligible patients who received at least one dose of study medication and had pre- and at least one post-intervention assessment of efficacy variables. The PP population was defined as a subset of the ITT population who had completed all the visits without major protocol deviation or violation. All analyses were conducted using available data; no imputation was performed for missing data. A Key safety endpoints evaluated included the incidence of treatment-emergent adverse events (TEAEs) and incidence of TEAEs leading to discontinuation, as well as changes in vital signs and physical examination parameters from baseline to visits 6 and 7. A TEAE was defined as any AE with an onset date on or after the first dose of TDB. Medications prescribed for prevention or for treatment of AEs associated with the study medication were also evaluated. Safety results were descriptively summarized for the safety population. The safety population included eligible patients who received at least one dose of study medication and had at least one safety follow up. All statistical analyses were performed using SAS software, version 9.3 .The flow of patients through the study is shown in Fig. Patients’ demographics and characteristics at study entry are summarized in Table n = 100) and was titrated to 10.0 (range 5.0 to 40.0) μg/h among those who required additional titration (n = 67). It decreased to 5.0 (range 5.0 to 40.0) μg/h at visit 3 and was maintained at the same dose for the rest of the treatment period  weeks, at a median dose of 5.0 (5.0 to 40.0) μg/h over the study period. All patients were initiated on TDB at a median dose of 5.0 μg/h. The dose during titration was 5.0 (range 5.0 to 10.0) μg/h at visit 2 . The corresponding LS mean change in score from baseline was −2.27 (95% CI -2.66 to −1.87) at visit 3 and −2.64 (95% -3.05 to −2.23) at visit 7.Figure p = 0.054) in overall sleep quality assessment was observed at visit 6. The proportion of patients rating sleep quality as ‘good’ increased from 14.0% at baseline to 26.9% at visit 6. Patients reported a median sleep duration of 6.0 (range 2.0 to 9.0) hours per night over the seven days prior to the start of treatment. There was no clear improvement in sleep duration from baseline at visit 6. Patients reported minimal or low degree of sleep disturbance for all six variables at baseline (Table p < 0.0001 for both). There were no clear improvements in scores for the other sleep variables at visit 6  after treatment. By visit 6, the mean EQ VAS score had increased by 7.7 units (SD 17.9). There were also significant improvements in patients’ levels of functioning for all EQ-5D-3 L dimensions from baseline at visit 6  . Patients’ overall health state improved significantly from baseline (ll) Fig. . The proll) Fig. .Fig. 4Cop = 0.248). The median Global Impression of Change score was 3.0 (range 1.0 to 5.0) for both patients and physicians, indicating perceived improvement in overall pain condition at the end of TDB treatment.There was no significant difference between patients’ and physicians’ Global Impression of Change scores at visit 6 , followed by diclofenac (23.6%). Other medications were less frequently used (0.8–7.3%).Overall, eighty-nine patients (78.1%) reported TEAEs, most of which were mild to moderate in intensity (96.5%). The most common TEAEs reported during the study were nausea (39.5%) and constipation (31.6%), followed by dizziness (27.2%), somnolence (19.3%), vomiting (16.7%), headache (8.8%), pruritus (7.9%), and -application site reactions (6.1%). Sixty-eight percent of patients had TEAEs that were assessed to be related to the study medication by the physician. One serious TEAE was reported during the course of the study. A patient experienced a hypertensive crisis; the event was moderate in severity but was not considered related to the study medication. The incidence of TEAEs leading to discontinuation was 22.8%, most of the events were mild-moderate in intensity (92.9%). TEAEs that frequently led to discontinuation of the study medication included nausea (11.4%), dizziness (7.9%), and vomiting (5.3%).Table There were no clinically significant changes in vital signs or physical examination results between baseline and the end of the study.This is the first multinational study of TDB treatment in Asian patients who were suffering from moderate to severe pain due to a range of musculoskeletal conditions. This study, reflecting real-world clinical practice, demonstrates that TDB provides effective pain relief and improves daily functioning and quality of life in Asian patients with chronic musculoskeletal pain after 11 weeks of treatment. Additionally, TDB demonstrates an acceptable tolerability profile in our Asian cohort over the treatment period, consistent with that observed in Caucasians.In the present study, patients entered the study with an average BS-11 pain score of 6.2. After initiation of TDB, the mean BS-11 score decreased by 2.3 unit one week after the end of the titration period and the reduction was maintained till the end of the treatment period (LS mean change: −2.5 at visit 6). A reduction of approximately 2 units from baseline on the 11-point numeric rating scale has been demonstrated to correspond to a clinically meaningful improvement . The impSignificant differences in the metabolism and response to medicines have been documented among racial groups . The preThe goal of chronic pain management encompasses not only the relief of pain, but also maintaining or improving the daily functioning and quality of life of patients . In the Consistent with the decrease in pain scores in the present study, both physicians and patients rated TDB treatment as associated with improvement in the overall pain condition. Previous studies of TDB have also reported favorable physician and patient ratings for TDB treatment , 26. In No unexpected safety or tolerability concerns were raised in the present study. Although the incidence of AEs and the incidence of discontinuations due to AEs were high, these were not unexpected as the incidence rates were consistent with those reported in previous studies of TDB conducted in Caucasian patients (incidence of AEs: 86 to 91% and incidence of discontinuations: 15 to 35%) –26. As wClinical guidelines from the American Pain Society-American Academy of Pain Medicine and the European Association for Palliative Care (EAPC) recommend physicians to employ preemptive intervention or symptomatic management of AEs to minimize the common side effects of opioid therapy , 35. In In the present study, the incidence of AEs and the incidence of discontinuations varied across the countries or territories. The incidence rates appeared consistent with the practice pattern in side effect management of TDB treatment in each country or territory. Lower incidence rates were observed in Korea where medications for management of common AEs were prescribed both prophylactically and after TDB treatment. In contrast, higher incidence rates were observed in Hong Kong and the Philippines where physicians tended to prescribe medications to treat AE rather than to prevent their occurrence. These findings highlight the importance of preemptive and active management of side effects of TDB treatment in supporting treatment adherence. While practice pattern in side effect management influence the incidence rates, it is possible that ethnic differences in the development of AEs may exist. More studies are needed to confirm if the varying AE profile across the countries or territories is due to ethnic differences. This will provide valuable information for physicians to properly manage the use of TDB for pain management in different ethnic groups.Our findings need to be interpreted within the limitations of the study. First, the treatment duration of 11 weeks is relatively short, and whether the observed treatment effect continues in the longer term would require further research to confirm. Next, the GSQA questionnaire has not been formally validated. Nevertheless the use of a structured questionnaire to assess sleep disturbance and sleep quality ensured consistency in data collection before and after TDB treatment and minimized bias to some extent. Another limitation is that the study population comprised a heterogeneous mix of musculoskeletal conditions with distinct pathophysiological mechanisms. It is probable that some conditions responded better than others to the treatment. However, the sample size is too small to allow parsing of the results by musculoskeletal condition. Future studies in additional populations of patients are needed to evaluate the effect of TDB in different conditions. In addition, there is potential for bias due to the open-label study design and the lack of active control in this study which preclude evaluation of the extent to which the observed effect is caused by the treatment. Nonetheless, the present study closely reflects the real-life clinical setting and the results are more likely to translate effectively into real-world clinical practice.Our study provides real-world clinical evidence on the effectiveness and tolerability of TDB in Asian patients with moderate to severe chronic pain. Treatment with TDB resulted in effective and sustained pain relief over the 11-week treatment period, accompanied by improvements in daily functioning and quality of life. The tolerability profile was as expected as previous studies of TDB. Our results indicate that TDB can be considered a suitable alternative treatment option to control non-malignant musculoskeletal pain. Studies on the long-term efficacy and safety of TDB treatment are required to further confirm these findings.


SWOG S0421 was a large randomized trial comparing docetaxel/prednisone plus placebo (DPP) to docetaxel/prednisone plus atrasentan over 12 cycles for patients with metastatic castration-resistant prostate cancer (mCRPC). The current report presents the PRO results for this trial, an important secondary endpoint.The trial specified two primary PRO endpoints. Palliation of worst pain was based on the Brief Pain Inventory (BPI), where a 2 point difference is defined as clinically meaningful. Improvement of functional status was based on the Functional Assessment of Cancer Therapy – Prostate Cancer Trial Outcome Index (FACT-P TOI); a 5-point difference has been defined as clinically meaningful. We compared rates by arm using chi-square tests. Longitudinal analyses using linear mixed models addressed changes by arm over time.p = .70) or functional status . Longitudinal comparisons indicated no differences over time by arm for BPI Worst Pain scores . Patients on the DPA arm had improved functional status of 1.78 points on average, a statistically significant (p = .02) but not clinically meaningful difference.Four-hundred eighty-nine patients on each arm were evaluable for PRO endpoint data. There were no differences by arm in clinically meaningful pain palliation  contains supplementary material, which is available to authorized users. Patients with metastatic castration-resistant prostate cancer (mCRPC) are no longer sensitive to a continued regimen of androgen deprivation treatment (ADT). This condition is defined based on confirmed objective progression and/or increases in prostate specific antigen (PSA) in the presence of castrate ranges of testosterone; bone metastases are often present. Bone is the most common site for metastasis in prostate cancer disease and is associated with significant morbidity, the most common of which is pain . There aThe inclusion of Patient-Reported Outcomes (PROs) in studies of prostate cancer are vital for informing trial interpretations, as they provide key insights into patients’ symptoms and treatment response . Men witThis report describes the PROs for SWOG S0421, a study designed to examine whether the addition of atrasentan to docetaxel would increase progression-free survival and overall survival compared to docetaxel and a matching placebo for atrasentan. SWOG S0421 clinical outcomes were previously reported . SWOG S02 every 21 days, intravenously) with atrasentanSWOG S0421 was activated in August, 2006 and closed in May, 2010. In total, 1038 patients with mCRPC were randomized to docetaxel  (DPA) or placebo (DPP) for up to 12 cycles administered every 3 weeks of 36 weeks . ContinuMajor secondary objectives of the SWOG S0421 trial included PRO measures to monitor palliation of bone pain and improvement in functional status. Multiple PRO measurements were administered: a Symptom Questionnaire (comprised of the Brief Pain Inventory (BPI) , and theThe PRO outcome measures to assess pain, functional status, and vitality are consistent with the currently recommended measures suggested for studies of treatment for prostate cancer described by the various working groups. A National Cancer Institute (NCI) Symptom Management and Health-related Quality of Life Steering Committee Working Group on the inclusion of PRO measures in prostate cancer clinical trials recommended assessing four domains in prostate cancer clinical trials  . The EurPain was measured with the BPI Short Form, the psychometric properties of which have been previously documented . Among iFunctional status was assessed by the FACT-P. This questionnaire addresses four general PRO domains  as well as symptom concerns associated with prostate cancer and its treatment , 14. HigThe total score for the four-item Medical Outcomes Study Short Form-36 (SF-36) Energy/Vitality Scale ranges from “0” to “100”, with higher scores reflecting more vitality . The SF-Two items from the EORTC QLQ-C30 were also included to address global or overall health and quality of life during the past week .Patient analgesic use was monitored using Pain Medication Logs. The Pain Medication Log was developed for use in SWOG S0421 and modified for ease of data entry . Clinic n = 156 patients with QOL assessments at week 52 (16%)).The Symptom Questionnaire was administered at baseline and at the end of each of the 12 cycles. The FACT-P was administered every three cycles , and after the end of treatment [beginning of week 37]. Additional follow-up was collected through week 52 but these data are not reported due to extensive missingness after 37 weeks  or to drop out, resulting in 540 patients available for examinations of PRO endpoints. Data from Tannock et al. which included the control arm in this study (DPP), indicated that 35% of the patients in this arm achieved pain palliation . Based oTo account for measurement error present in a single pain measure, the BPI Worst Pain baseline measure was defined as the average of the PreStudy and week 4 assessments for pain. SuccessLongitudinal measures over time were described for the primary endpoint measures (BPI Worst Pain and FACT-P TOI), as well as secondary PRO measures including BPI pain interference, SF-36 energy/vitality, the EORTC global QOL score, the FACT-P Total Score, and the FACT-G emotional and social well-being subscales. For the primary endpoints, we examined longitudinal PRO measurements using linear mixed models using SAS PROC Mixed , 28. We S0421 was activated in August of 2006, with accrual closed in May of 2010. A total of 1038 patients were enrolled (518 on DPP and 520 on DPA), of whom 489 patients on each arm were evaluable for the QOL companion study . In total, 521 patients  had sufficient data to examine pain palliation. Successful palliation of baseline pain was achieved for 41.7% (110/264) of patients on the DPP arm and 44.0% (113/257) on the DPA arm. This difference by arm of 2.3% did not achieve our pre-specified target of 15% and was not statistically significant (p = .66). Determining the “true” number of patients meeting clinically significant change in worst pain is difficult due to the multifaceted definition of change in pain and the missing data in these various components . However, including criteria for clinically significant change is critical for more accurate interpretation of these results.The baseline/4 week average worst pain score was < 2 for 170 patients on the DPP arm and 183 patients on the DPA arm. Baseline or 4 week data were missing for an additional 55 patients on DPP and 49 patients on DPA. Total missing data for the pain palliation endpoint did not differ by arm (p = 0.13) and did not meet our 6-point hypothesized treatment arm difference for functional status.Many fewer patients had missing data for the examination of clinically meaningful change in functional status since all patients had adequate baseline scores to potentially achieve a clinically meaningful difference in functional status, and only a single baseline and follow-up assessment were required. The proportion of patients experiencing a clinically meaningful change in functional status between baseline and follow-up was 24.2% (118/487) on the DPP arm and 28.7% (139/484) on the DPA arm; this difference was not statistically significant , although the magnitude of this difference was small (1.78 points on average), suggesting a statistically significant but not clinically meaningful difference.Patterns of BPI worst pain and the FACT-P TOI score by arm over time are illustrated in Fig. p = .19) and the FACT-P TOI score (p = .01).Cohort plots suggested strong evidence that patients who dropped out earlier reported both more pain and worse function status  population. Such a limitation is common among network groups trials given limited resources available to sites. Further, missing data for PROs has been recognized as a problem in trials involving patients with advanced stage disease . Even thThe PRO measures included in SWOG S0421 did not identify substantial treatment arm differences for pain and functional status. However, with any new study, we do not know the extent to which patients will report improved or deteriorated status. Therefore, we encourage researchers to include as comprehensive a PRO assessment as resources will allow. The PRO data can be of use to a wider group of “consumers” of the clinical trial’s results. In our case, the treatment arms had similar average effects on patient HRQL.Additional file 1:Table S1. Identifying Best Fit Model for Longitudinal Analyses of BPI Worst Pain and FACT-P TOI Scores, Figure S1. Cohort plot of average BPI worst pain scores by missing data patterns and arm, Figure S2. Cohort plot of average FACT-P TOI scores by missing data patterns and arm. (DOCX 115 kb)


We used resting-state fMRI to investigate regional homogeneity (ReHo) changes in patients with TN before and after PRT procedure, and to speculate about its possible mechanisms.Thirty-one TN patients underwent the PRT procedure had MRI scans just before and 6 months after surgery. The anatomical and resting-state functional images were all acquired. Patients’ visual analog scales (VAS) scores, facial numbness, and disease duration were also recorded. Voxel-wise ReHo analysis was performed to detect the altered regional clusters after surgery. The correlations between the mean ReHo values of each significant cluster and clinical variables were examined.Compared with presurgical condition, patients after the PRT procedure showed a significant ReHo value increases in the right fusiform gyrus (FG) and bilateral anterior cingulate cortex (ACC), but decreases in the left inferior parietal lobule (IPL), right calcarine, right middle temporal gyrus (MTG), left postcentral gyrus (PoCG), and left insula. We demonstrated a positive correlation between ReHo in the left PoCG and VAS scores, a negative correlation between pre-surgical ReHo in the right MTG and VAS changes (ΔVAS).Alterations of ReHo post-surgical were found in several regions, which are related to sensory, affective, and emotional processes. The MTG may be a specific area that is associated with analgesic efficiency of PRT procedure. Despite advances in the therapy of trigeminal neuralgia (TN), such as microvascular decompression (MVD) Gamma Knife radiosurgery (GKRS) and percutaneous radiofrequency thermocoagulation (PRT), some 5% to 10% of patients may not achieve immediate pain relief after initial surgeries, and recurrence rates rise up to 50% at 10 years, leading to significant personal, social, and economic burden. However, it has been evidenced that the compressed nerve may represent a risk factor for the development of TN, but other reasons may also involved in the elicitation of TN.,5 Jannetta described 12% of his investigated TN patients had no nerve vessel conflict, whereas as Kakizawa et al indicated that up to 49% of people without TN show a nerve vessel contact on magnetic resonance imaging (MRI). Moreover, numerous MRI studies indicate that both structural and functional alterations of central nervous system exist in patients with TN.,8–10According to current opinion, TN is caused by a proximal nuerovascular compression at the trigeminal nerve root entry zone in the prepontine cistern leading to secondary demyelination of trigeminal nerve root. By using task functional MRI (fMRI), Moisset et al detected a mass of abnormal activation areas of the brain in TN patients when painful stimuli was applied to the trigger zone.Obermann, using voxel-based morphometry, found that gray matter (GM) volume reduction in TN patients compared to healthy controls in multiple cortical and subcortical areas of the brain and the reduction within anterior cingulate cortex (ACC), parahippocampus, and temporal lobe are correlated with increasing disease duration. reported that the ReHo was decreased in amygdala, parahippocampal gyrus, and cerebellum and increased in the inferior parietal lobule (IPL), inferior temporal gyrus (ITG), postcentral gyrus (PoCG), and thalamus. ReHo measures the local synchronization of spontaneous fMRI signals by calculating similarity of dynamic fluctuations of voxels within a given cluster, which has been recognized as a highly sensitive, reproducible, and reliable neuroimaging marker in diagnosis and assessment of numerous nervous system diseases.,13 However, little is known about the alteration of ReHo in TN patients after effective neurosurgical treatment.In resting-state fMRI (rs-fMRI) studies, altered patterns of ReHo were detected in patients with TN. Wang et alOur objective was to detect the whole brain resting-state ReHo changes in patients with TN before and after the PRT procedure in order to identify specific spontaneous activity patterns that may be associated with the development and persistence of this debilitating facial pain condition. We also performed correlation analysis between ReHo and clinical variables so as to speculate about the possible brain areas that mediate the surgical impact on pain relief or facial numbness severity.22.1In this study, 38 patients who underwent the PRT procedure for classical TN were recruited from the Department of Pain Management at XuanWu Hospital between June 2015 and January 2016. The patients were all right-handed. All of them had right-sided pain affecting the maxillary and/or mandibular division of the trigeminal nerve, and met the criteria for classical TN as outlined by the International Classification of Headache Disorders-II (2004). They are all characterized by little or no pain at rest, with intermittent paroxysms of shooting pain. The exclusion criteria were (1) patients with chronic pain other than TN, (2) patients with neural diseases, diabetes, or brain surgery history, and (3) patients unable to undergo MRI scanning because of claustrophobia or other psychological disorders, or metal implantation.There were 2 scheduled scanning sessions; 1 was in 1 week before the PRT procedure, and the other one was 6 months after the surgery. Patients on carbamazepine or other pain medications were asked to discontinue use of their medication for 1 week before their MRI scans. To make sure that patients maintained pain-free state during scanning session, they could halt the experiment by activating a safety mechanism held in one hand, if they suffered a facial pain paroxysm. If any patient got pain recurrence or did not receive pain relief during the following 6 months after the PRT procedure, the VAS would also be recorded. The Research Ethics Committee of Xuanwu Hospital approved this study and written informed consent was obtained from each participant.The duration of pain, frequency of pain paroxysms, and visual analog scales (VAS) for pain intensity were obtained before the first MRI scanning. Facial numbness classification (grade I to IV) was recorded before the second MRI scanning.2.2,14 The puncture of gasserian ganglion was according to the Hartel anterior route. The best puncture approach to the oval foreman and the corresponding skin insertion point was determined by CT scanning. Motor  and sensory  were performed to confirm or readjust the needle tip position to confirm the accuracy. The gasserian ganglion was thermally coagulated with radiofrequency at 75 °C for 120 s.The PRT procedure was performed according to our previously reported.2.3 All patients were instructed to lie with their eyes open, think of nothing in particular, and not fall asleep. High-resolution T1-weighted anatomical images were obtained by using rapid gradient echo sequence with the following parameters: repetition time (TR) = 1900 ms, echo time (TE) = 2.19 ms, flip angle (FA) = 9°, field of view (FOV) = 256 mm, sections = 176, voxel size = 1 × 1 × 1 mm3. Resting-state functional datasets were recorded using a T2∗-weighted echo-planar imaging (EPI) sequence with the following parameters: TR = 2000 ms, TE = 30 ms, FA = 90°, FOV = 240 mm, sections = 33, thickness = 4 mm.MRI examinations were acquired using a Siemens Tim Trio 3 T MRI system . Foam padding and headphones were used to limit head motion and reduce scanner noise.2.4http://www.fil.ion.ucl.ac.uk/spm) and Data Processing & Analysis for Resting-state Brain Imaging . The first 10 volumes of each functional time series were discarded because of instability of initial magnetic resonance imaging signal and adaptation of participants to the circumstance. The remaining 230 volumes were corrected for the acquisition time delay between the different slices and were also corrected for geometrical displacements according to the estimated head movement and were realigned to the first volume. Patients whose head motion translation values were >2.0 mm in any direction of x, y, z, rotation values >2° of any angle, or the mean frame-wise displacement (meanFD) >0.4 mm were excluded.,18 After motion correction, the mean structural image was co-registered to the mean realigned functional image and then spatially normalized by using DARTEL . A multiple linear regression analysis was performed to remove several nuisance signals, including 6 head motion parameters, the white matter signal, and the cerebrospinal fluid signal. The linear trend of the time series was removed and band-pass filtering (0.01 Hz < f < 0.1 Hz) was performed to reduce the influence of physiological noise, such as the respiratory and cardiac rhythms. Besides excessive head motion, all patients with bad brain extraction, tissue segmentation and with bad surface construction were also excluded from the subsequent analysis.All preprocessing steps and ReHo analyses were carried out using statistical parametric mapping  Gaussian kernel.ReHo is computed as Kendall's coefficient of concordance (KCC) value of the ranked time series of a given voxel to its nearest neighbors. To optimize the trade-off between mitigation of partial volume effects and generation of Gaussian random fields, we chose 27 voxels to calculate the ReHo, as it is more appropriate for covering all directions in 3D space.2.6t tests. Voxels with a P value < 0.005 and cluster size > 54 were considered to show significant difference, which was equal to a corrected threshold of P < 0.05, determined by the Monte Carlo stimulation (the AlphaSim program in the DPABI toolbox).Within-subject comparisons were made to compare pre- and postsurgical voxel-wise ReHo values using paired samples z stats) of these significant clusters and clinical scales in patients were performed by Pearson's correlation analysis with a threshold of P < 0.05. The change of ReHo between the pre- and postsurgical conditions (ΔReHo) was also calculated as the correlation coefficient with clinical variables.The correlations between the ReHo values , but decreases in the left IPL, right calcarine, right middle temporal gyrus (MTG), left PoCG, and left insula  after the PRT procedure  and bilateral ACC . The presurgical ReHo in the right MTG was negatively correlated with ΔVAS scores . A significant negative correlation was shown between disease duration and postsurgical ReHo in the left IPL , accompanied by a negative correlation between duration and ΔReHo in the bilateral ACC . The significant correlation between age, numbness, and ReHo was not found  after the PRT procedure indicates that PoCG plays a highly modulated role in the sensory aspects, including the localization and discrimination of pain.The involvement of S1, located in the PoCG, in pain processing has been known for a long time. Borsook et al described an increased activation of the insula during evoked and spontaneous tics in TN patients in comparison to healthy controls. Direct stimulation of the insula in humans can produce intense shock-like pain, which is similar to the paroxysms of TN. In patients with and without allodynia, light tactile stimulation of the affecting division induced activation of the insula. However, the enhanced activation was disappearing after the PRT procedure. The increased activation in the insula may be correlated with the exaggerated expectancy of pain and attention. A recent combined structural and FC analysis of insular subdivisions supported that the anterior insular part is associated with cognitive-affective dimension of pain. According to the same insular subdivision system, we found decreased ReHo in the left anterior insular part in patients after surgery.Functional studies showed that the insula processes both in acute and chronic pain perception. The rostral ACC and insula are activated by attention to the unpleasantness of pain, and patients with chronic pain exhibit increased functional connectivity between the ACC and anterior insula at rest and during pain processing.,28 However, the effect of ACC in TN is still controversial. A large portion of the ACC was active during spontaneous tics in patients with TN. The painful stimulation at the trigger zone activated the bilateral posterior part of ACC [caudal areas of BA (Brodmann area) 24 and 32].,29 But the abnormal activity of ACC has not been detected in TN patients at resting state. Of note, we found the decreased rostral ACC (anterior area of BA 32) activation after surgery, which may correspond with its activation in patients with treated complex regional pain syndrome (CRPS) in Becerra's study. These findings suggest that different regions of ACC might play different roles in TN.Another important area for the occurrence of TN and that shares important interactions with the insula is the ACC. ACC and anterior insula are known to be important parts of salience network, which activates during salient changes in the sensory environment.,32 DMN is the most thoroughly investigated and stable resting-state network, and the posterior lateral subdivision of this network is involved in mediating the recognition and rumination of pain.,33 Moreover, this network can be affected by a chronic pain state. Greater clinical pain in chronic low back pain and fibromyalgia patients was associated with greater intrinsic DMN and DMN-insula connectivity. In comparison to healthy control, patients with migraine showed decreased connectivity in prefrontal and temporal gyrus of the DMN. Greater connectivity between the DMN and the insula is directly associated with the duration of migraine attacks. In our present work, the decreased activation of both IPL and MTG in patients after surgery was detected. However, the alternations of functional connectivity between the 2 cortices and within the DMN remain to be explored.IPL and MTG are located at the posterior lateral cortices, which is 1 of 3 major subdivisions of the default mode network (DMN). It has been known that this area is involved in both detection and identification of faces. In this study, we did not perform any visual stimulation to the patients, so we inferred that TN might impair the self-face perception of the patients. When pain was relief, the activation of FG was reinforced. This finding is in line with a voxel-based morphometry study on TN. Parise et al found the reduction of cortical thickness at FG in TN, and the thickness is correlated negatively with the carbamazepine dose.A significant ReHo increase was noticed in the right FG, an area often associated with facial recognition. Patients with low back pain displayed activation of FG, and the activation can be enhanced by visualization of painful experiences. Both structural and functional abnormalities of FG have been identified in patients with migraine. The left FG had an increased volume in patients with aura compared to patients without aura and healthy controls, whereas it was significantly atrophied in patients without aura. The fALFFs , measures that quantify the activation of brain regions, in migraine patients were significantly decreased in the right FG. However, the assignment of FG in TN in addition to facial perception has not been known at all.Other than the involvement of facial perception, FG also plays some role in chronic pain condition. Postoperative pain can activate the ipsilateral FG.,44,45 A novel finding in the present study was the lower baseline ReHo of the MTG was associated with greater pain relief (ΔVAS) after the PRT procedure. The result indicates that the pre-surgical ReHo values in this area can be used as neuroimaging markers for predicting response to the treatment. Moreover, the dynamic ReHo changes observed at PoCG, in association with the varying VAS scores observed in our study, might represent the important role that PoCG plays in monitoring pain intensities. Other findings like the negative correlation between ΔReHo in the bilateral ACC and disease duration, and the negative correlation between post-surgical ReHo in the left IPL and duration, suggested that the dysfunction in these brain regions becomes more and more serious along with TN progression.It is worth noting that ReHo is not merely a reliable metric to investigate the spontaneous neuronal activities in resting-state fMRI, but also has correlation with some clinical variables in chronic pain situations.There were several limitations that should caution in the interpretation of the current results. First, our results were limited to a small sample size, and no resistant or recurrent patient was observed. So we were not able to apply a subgroup analysis to identify specific brain regions as prognostic indicators. Second, we only examined patients with right-sided pain to avoid flipping the scans. However, it may have produced bias in identification of the predominant side of brain regions. At last, ReHo is a widely used tool for local connectivity analysis, but the remote or long-distance relationships in cerebral cortex parcellation should also be detected.5 Alterations of ReHo post-surgical were found in several regions, including PoCG (S1), insula, ACC, IPL, MTG, FG and calcarine, which are related to sensory, affective, and emotional processes. Furthermore, a negative relationship between pain relief and pre-surgical ReHo in the MTG was identified. These results may help to improve our understanding of abnormal neural activities in TN. However, further studies are needed with a large sample size, longitudinal observation, and multimodality imaging analysis.Our findings contribute to the growing body of evidence indicating that functional alterations of central nervous system exist in TN patients after receiving the PRT procedure.


Immediate laparoscopic cholecystectomy is the accepted standard for the treatment of acute cholecystitis. The aim of the present study was to evaluate the feasibility of a standardized approach with tailored care maps for pre- and postoperative care by comparing pain, nausea and patient satisfaction after elective and emergent laparoscopic cholecystectomy.vs. emergency cholecystectomies. Visual analogue scales (VAS) were used to measure pain, nausea, and satisfaction from recovery room until 96 hours postoperatively.From January 2014 until April 2015, data on pain and nausea management were prospectively recorded for all elective and emergency procedures in the department of visceral surgery. This prospective observational study compared consecutive laparoscopic elective vs.13%, p = 0.009) and less postoperative nausea and vomiting (PONV) prophylaxis (77% vs. 97% p = <0.001). Perioperative pain management was similar in terms of opioid consumption  and wound infiltration rates . Postoperative consumption of paracetamol, metamizole and opiod medications were similar between the 2 groups. VAS scores for pain (p = 0.191) and nausea (p = 0.392) were low for both groups. Patient satisfaction was equally high in both clinical settings .Final analysis included 168 (79%) elective cholecystectomies and 44 (21%) emergent procedures. Demographics  were comparable between the 2 groups. In the emergency group, patients did not receive anxiolytic medication This study was retrospectively registered by March 01, 2016 in the following trial register: The online version of this article (doi:10.1186/s12893-016-0194-6) contains supplementary material, which is available to authorized users. However, increased length of hospital stay has been described after emergent cholecystectomy, whereas discharge at the first postoperative day seemed realistic without negative impact on outcomes [Even if conversion rates are two- to three-fold higher in emergently performed cholecystectomies, a recent study showed no significant difference in morbidity or mortality, supporting early surgical management in emergency situations . These foutcomes . Median One reason for these positive results might be the use of care maps, with standardized, peri- and postoperative patient care regardless of the elective or emergent setting. The beneficial effect of standardization has been repeatedly shown within Enhanced Revovery After Surgery (ERAS) pathways , coming Several limitations of this study need to be addressed. The cohort is small, and the analysis was performed retrospectively. Confirmation of our findings by independent groups is therefore necessary.A standardised pathway allowed equally successful control of pain and nausea after elective and emergency cholecystectomy resulting in high patient satisfaction in both situations.


Accelerated diagnostic pathways (ADP) have been designed to identify low-risk chest pain patients in the emergency department. This review article discusses the Asia-Pacific Evaluation of Chest Pain Trial (ASPECT) score, the Accelerated Diagnostic Protocol for Chest Pain Trial (ADAPT) score, the Emergency Department Assessment of Chest Pain Score (EDACS), the HEARTScore and the HEART pathway. These ADPs have been validated in various studies and aid the emergency provider with identifying the low-risk chest pain patient who is appropriate for discharge home, while at the same time highlighting those patients who would benefit from further in-patient work up. These approaches should be paired with patient input and shared decision-making strategies. Chest pain is one of the most frequent complaints of patients presenting to the emergency department (ED). Approximately 10–20% of patients who present to the ED with chest pain are suffering from an acute coronary syndrome (ACS), requiring early intervention and treatment.The American College of Cardiology and American Heart Association (ACC/AHA) have developed guidelines in an attempt to standardize the approach to patients with chest pain. The 2010 and 2014 guidelines recommend the use of the Global Registry of Acute Coronary Events (GRACE) score or thrombolysis in myocardial infarction (TIMI) risk score as part of the initial evaluation for possible ACS. However, neither TIMI nor GRACE was designed for ED chest pain risk stratification. The TIMI score was designed to be applied to patients with unstable angina or non ST-elevation myocardial infection (NSTEMI) to determine their risk for 14-day mortality, new or recurrent acute myocardial infarct (AMI) or severe recurrent ischemia requiring urgent revascularization.5Accelerated diagnostic pathways (ADP) were developed to provide guidance to emergency clinicians to determine the level of risk for patients with possible ACS and support appropriate testing for each patient with chest pain. The goal of ADPs is to identify the very low-risk patients for early discharge, while at the same time identifying those patients more likely to benefit from stress testing and angiography. ADPs are starting to appear in ACC/AHA guideline updates. A more detailed description of the most commonly used ADPs is found below.The ASia-Pacific Evaluation of Chest Pain Trial (ASPECT) aimed to prospectively validate the safety of a predefined two-hour ADP to identify ACS patients. The study was conducted in 14 EDs in nine countries in the Asia-Pacific region.6Those with a TIMI risk score of 0, no new ischemic changes on the electrocardiogram (ECG) and a negative 0- and 2-hour point-of-care biomarker results were deemed low risk and eligible for early discharge. Primary endpoint was major adverse cardiac events (MACE) within 30 days. MACE was defined as death (not clearly non-cardiac), cardiac arrest, an emergency revascularization procedure, cardiogenic shock, ventricular arrhythmia needing intervention, high-degree atrioventricular block needing intervention and acute myocardial infarction. A total of 3,582 patients were enrolled, of which 352 (10%) were considered low risk. Within the low-risk group there were three (0.85%) MACE. The ASPECT ADP had a 99.3%  sensitivity with a negative predictive value of 99.1% (95% CI 98–100) for MACE.The Accelerated Diagnostic Protocol for Chest Pain (ADAPT) trial was a prospective observational study from the same investigators as the ASPECT trial.In the Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) validation study, patients were classified as low risk if they had a TIMI score of 0 or 1 , a non-ischemic ECG and normal 0- and 2-hour high sensitivity troponin measures .8 Of theThe Emergency Department Assessment of Chest Pain Score (EDACS) is the first emergency medicine-based risk score derived from clinical data and was developed as a chest pain score to identify patients safe for early discharge. The derivation cohort consisted of patients enrolled in the ADAPT study.The EDACS score was incorporated into an ADP, where low risk was identified as an EDACS score < 16, no new ischemia on ECG and a negative 0- and 2-hour troponin. In this observational cohort patients who met these criteria were identified who would have been safe for discharge home without further workup. The derivation cohort  and the validation cohort (608 patients) identified 40–50% of patients as low risk. The sensitivity was 99% (95% CI [96.9–99.7]) for MACE. EDACS has been validated in a randomized trial comparing EDACS to ADAPT.10The HEARTScore was developed to score predictors of primary end points based on clinical experience and previous medical literature.In the first retrospective validation study 122 patients presented to the ED with chest pain. Results are presented in Sixteen patients died (0.7%), 13 of whom died of a cardiac cause. One of these patients was in the low-risk HeartScore group, five were in the intermediate-risk group and seven in the high-risk HeartScore group. The C-statistics of the HeartScore when compared to TIMI and GRACE were as follows: HEART 0.83, TIMI 0.75, GRACE 0.70 (p<0.0001). This study provided additional support for use of the HeartScore as an ADP for low risk chest pain patients.th percentile upper-reference limit.While the HeartScore is predictive of MACE, many clinicians consider the 1.7% risk of MACE in a patient identified as low risk by the HeartScore to be too high. Furthermore, with the HeartScore it is possible to have a patient with a low-risk HeartScore, despite a positive troponin. The Heart pathway was designed to lower the missed MACE rate of the HeartScore below 1%, by separating the troponin results from the remaining “Hear” score and using two troponin measures (at 0 and 3 hours) instead of one. To be considered low-risk using the HeartScore pathway you must have a Hear(t) score of 0–3 and have both serial troponin measures less than the 99The first study to validate the HeartScore in the U.S. enrolled 1,070 chest pain patients in an observation unit and revealed that five patients with an NSTEMI had low-risk HeartScore.In recent years there has been growing attention to shared decision-making. Shared decision-making involves educating patients on their health risks, as well as the risks of testing, and discussing their treatment options. This is often done using a pictogram developed at the Mayo Clinic called the Chest Pain Choice.The low-risk patient with chest pain can be a high-risk scenario for the emergency physician. Accelerated decision protocols have been designed to aid the emergency physician in decision-making with regards to assessment of these patients. The use of these ADPs can reduce cost, length of stay and risk of unnecessary testing in chest pain patients. It is important for all emergency physicians to be familiar with different ADPs, and to know their benefits and limitations. All of the above-described ADPs are validated choices for risk assessment of low-risk chest pain patients in the ED. UsTe of any of these ADPs should be considered within standard of care. The choice to select a specific ADP for use in the ED can be done on an institutional level or can be the choice of the individual practitioner. Within the authors’  institution, the Heart pathway was implemented alongside a shared decision model for its high sensitivity, negative predictive value and ease of use. Shared decision-making tools may assist patients with acute chest pain and their providers to navigate difficult disposition decisions.