The majority of advanced cancer patients suffer from pain, which severely deteriorates their quality of life. Apart from analgesics, bisphosphonates, and invasive methods of analgesic treatment , radiation therapy plays an important role in pain alleviation. It is delivered to a growing primary tumour, lymph nodes, or distant metastatic sites, producing pain of various intensity. Currently, different regiments of radiation therapy methods and techniques and various radiation dose fractionations are incorporated into the clinical practice. These include palliative radiation therapy, conventional external beam radiation therapy, as well as modern techniques of intensity modulated radiation therapy, volumetrically modulated arch therapy, stereotactic radiosurgery or stereotactic body radiation therapy, and brachytherapy or radionuclide treatment . The review describes the possibilities and effectiveness of individual patient-tailored conventional and innovative radiation therapy approaches aiming at pain relief in cancer patients. The majority of cancer patients suffer from pain during course of their disease . Pain maAbout 50% of all cancer patients will develop bone metastases . The frep < 0.0001) with a slight trend favouring 10 × 3 Gy RT scheme [p = 0.03 for PYD and p = 0.04 for DPD) [The exact mechanism of radiation-induced pain relief is unknown. The analgesic effect of radiation is achieved by stimulating ossification, diminishing osteoclasts’ activity in bone microenvironment, and killing cancer cells along with reduced osteolysis, which results in decreasing tumour burden ,14. RapiT scheme . An assoT scheme . Re-irraT scheme . Signififor DPD) .Radiation therapy with external beams may be delivered using different radiation techniques, the most common of which, for the purpose of irradiation of painful bone metastases, are the following: Two-dimensional radiation therapy (2D-RT) , still uThe optimal choice of fractionation schedule for the treatment of painful bone metastases is still an unresolved issue. Most skeletal metastases are multiple in nature and only 10% are diagnosed as solitary ones .During the last three decades, many randomized and observational trials focused on the optimal choice of the dose and fractionation regimen for pain relief ,26,27,28p < 0.00001) [A meta-analysis of 25 randomized clinical trials revealed that up to 80% of patients with uncomplicated bone metastases experience analgesic response to external beam radiotherapy and 25–30% of patients achieve complete pain relief within 3–4 weeks after radiation therapy . Pain coDespite the same efficacy of a single 8 Gy fraction, compared with multiple-fraction regimens and available published guidelines ,15, to dp < 0.001) [The decision making should be based on treatment-related costs as well. In this context, some study results are of interest. A Dutch randomized controlled trial enrolling 1157 patients revealed that the cost of radiation therapy, including re-treatments and other nonmedical costs, was significantly lower for a single fraction regimen compared to a multiple fraction schedule  . Similar< 0.001) . Further< 0.001) . It has < 0.001) ,42,43. O< 0.001) , which m< 0.001) ,41,42,43The neuropathic pain component represents a special issue. It occurs in 19–39% of cancer patients ,45,46. PIn case of spine metastases, combining percutaneous vertebroplasty  with radiation therapy (exhibiting antitumor effect) provides better pain relief than radiotherapy alone  Figure .In a scenario of spinal cord or cauda equina compression caused by a metastatic mass, direct decompressive surgery followed by radiation therapy seems to be superior to radiotherapy alone . The usup = 0.04 and 83%, p-0.002, respectively).It should also be depicted that the histology of a metastatic tumour influences its radiosensitivity and the analgesic effect of radiation therapy. Arcangeli et al.  demonstrIn summary, the decision on RT fractionation should be supported by the American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline . The panIn patients with multiple painful bone metastases, hemibody irradiation using external beams may be a treatment option. The upper, middle or, lower half of the skeleton may be irradiated. Both photon beams and electron beams may be used ,55. DeliAs was mentioned earlier, since conventionally delivered radiation therapy leads to pain relief in approximately 80% of patients, but complete pain alleviation is only experienced by 25–30% of them, another concept of radiation therapy has emerged. Furthermore, the oligometastatic state in clinical practice has been defined when 1–5 distant metastases are found in a cancer patient . AdvanceMost studies report that pain control continues for 1-year after spine SBRT in as many as 84–90% of patients ,61,62,64To date, the optimal dose and fractionation schedule of SRS/SBRT is unclear. Chang et al.  reportedFractionated SBRT to spine metastases (27 Gy in 3 fractions) resulted in pain relief in 52% of renal cancer patients after one year . An 84% Palliative radiation therapy of bone metastasis for recurrent pain after previous palliative radiotherapy may be administered. It depends, however, on the location, prior radiation dose, fractionation schedule, and the time between radiation treatments . Results2, the interval between treatments is more than 6 months, and no course of radiation therapy exceeds the dose of 98 Gy2 [In the case of previously irradiated, but progressing spinal metastases, re-irradiation should be ordered with caution, since the spinal cord is a radiosensitive structure ,79. The f 98 Gy2 ,80 Sahgaf 98 Gy2  found thf 98 Gy2 . Accordif 98 Gy2 .This review is concentrated on radiation influence on pain control in cancer patients, but one has to realise that the final decision on qualification of patients to the SRS/SBRT should be taken at a multidisciplinary tumour board, assisted by the oncologic, neurologic, mechanical, and systemic framework defined by Laufer et al. , which aBrachytherapy consists in the application of radioactive sources inside the patient’s body (directly to the tumour burden or to the postoperative tumour bed) temporarily or permanently, which is meant to damage cancer cells’ DNA and destroy their ability to divide and grow. It allows for the use of a higher total dose of radiation to treat a smaller area in less time than the conventional external beam radiation therapy. Brachytherapy is a rarely used treatment option for bone metastases. Recently, a systematic review was published, which summarized the role of the treatment modality in painful spinal metastases . Seven sPain relief contributes to improved quality of life of cancer patients, which is currently one of the most important goals of the treatment. Radiation therapy is widely used for decreasing pain in the population, however, in some patients “pain flare” can occur after this treatment. It is observed in 2–40% of patients ,91 and iIn cancer patients suffering from multiple bone metastases, bone-seeking radiopharmaceuticals have proven to be an effective alternative ,96,97,98The mechanism of pain palliation resulting from beta particles or alpha particles emitted by radionuclides is not clear yet. Beta or alpha particles kill tumour cells; therefore, pain relief occurs because of mechanical pressure reduction . Pain coThere is solid data on the efficacy of Strontium-89 Chloride for bone pain relief in patients with prostate and breast cancers, with a pain relief rate of 63–88% ,109,110.Reduction of bone pain occurs in 62–78% of patients with bone metastases within 1 week of Samarium-153-EDTMP administration, with a definite dose-response relationship ,120,121,A phase III randomized double-blind placebo-controlled trial, ALSYMPCA, investigated the effectiveness of Radium-223-dichloride in 921 patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases, previous use of analgesics or radiotherapy to bones, and no visceral metastasis. There was a significant improvement in median overall survival in the Radium-223-dichloride group vs. the placebo group (14.9 vs. 11.3 months respectively) and median time to the first symptomatic skeletal event  ,126,127.Clinical studies assessing Rhenium-186-HEDP were mainly performed on patients with prostate cancer and breast cancer ,132,133.In a study by Palmedo et al. , with RhThe above-mentioned agents may produce some side effects such as gastrointestinal ulceration, enhanced bleeding, neutropenia, and disturbed renal function . In abouProgressing soft tissue tumours may also produce mild to severe pain. Primary or metastatic brain tumours, particularly those presenting with a larger mass effect or surrounding oedema, are frequently associated with pain. Surgery and radiotherapy are under consideration in the group of patients, depending on different factors . Brain radiation therapy, among others—whole brain radiation therapy—may help reduce tumour mass and volume of oedema, thus leading to pain relief. Lung cancer patients may suffer from severe pain resulting from the invasion of brachial plexus by the direct apical tumour. Meta-analysis of 14 randomized clinical trials evaluating palliative radiation therapy for lung cancer patients revealed satisfactory symptomatic relief, among others—pain reduction . VariousComplete response: A pain score of 0 at the treated site and no concomitant increase in analgesic intake, which means stable or reduced analgesics in daily oral morphine equivalent (OMED).Partial response: Pain decrease of 2 or more at the treated site on a scale of 0 to 10 without analgesic increase, or analgesic dose decrease of 25% or more from the baseline without an increase in pain intensity.Pain progression: Increase in pain score of 2 or more above the baseline at the treated site with stable OMED, or an increase of 25% or more OMED in comparison to the baseline with the pain score stable or 1 point above the baseline.Intermediate response: Any response that is not captured by those defined above .There is no uniform pain assessment in cancer patients receiving radiation therapy. Some authors report pain control as subjective physician/patient reports ,102,157.18F-Fluorodeoxyglucose—positron emission tomography) results, is another interesting concept [New and high-quality prospective data is awaited that will answer several questions and allow for definite statements regarding different combinations of radiation therapy  with surgery (kyphoplasty or vertebroplasty for spine metastases or intramedullary fixation or endoprosthetic reconstruction for long bone metastases) and/or novel molecularly targeted agents/immunotherapy. Prospective phase III randomized studies will define the optimal use (in terms of efficacy and toxicity) of SBRT for treatment of newly diagnosed or recurrent painful spinal metastases. The STEREO-OS trial, which assesses the effect of standard systemic treatment in oligometastatic (3–5 sites) prostate, breast, and/or lung cancer patients in combination with SBRT for painful bone metastases , may ser concept . Deliver concept . Further concept . Prospec concept ,165.A novel concept is a radiosurgical hypophysectomy for intractable bone metastases pain. Australian researchers will assess whether delivery of a single high dose (150 Gy) of radiation therapy to a small area of the pituitary gland and pituitary stalk in a highly precise manner may be helpful in reducing intractable pain from bone metastases .The Palliative Radiotherapy and Inflammation Study (PRAIS) aims to find predictive factors associated with inflammation for palliative RT for cancer-induced pain response . FurtherDevelopment of higher quality data will further help find the best combinations of EBRT with bisphosphonates, radiopharmaceuticals, and novel biological agents reducing formation/activity of osteoclasts and bone resorption, like monoclonal antibody directed against RANKL—Receptor Activator for Nuclear Factor κ B Ligand  ,172 or rRadiation therapy plays an important role in pain relief in cancer patients. As the radiation oncology field evolved, a number of challenges appeared. Important issues exist which have to be resolved, such as the following: Inconsistent endpoints of trials, difficulty in measuring the response, reluctance to practice evidence-based medicine , differences in physicians’ and patients’ perspectives, as well as incorporating systemic treatment in combination with radiation therapy .Evidence-based treatment guidelines should be established and followed. Collaboration in multidisciplinary tumour boards provides the best, personalized, holistic care, which leads to, among others, pain reduction and an improved quality of patients’ life.


Symptom drawings are widely used as a qualitative and quantitative method of assessing pain symptoms for both clinical and research purposes. As electronic drawings offer many advantages over classical pen-and-paper drawings, the last years have seen a shift toward tablet-based acquisition of symptom drawings. However, software that is used in clinical care requires special attention to usability aspects and design to provide easy access for physically impaired or elderly patients.The aims of this project were to develop a new tablet-based software app specifically designed to collect patients’ and doctors’ drawings of pain and related bodily symptoms and test it for usability in 2 samples of chronic pain patients (Aim 1) and their treating doctors (Aim 2) as well as for test-retest reliability (Aim 3).In 2 separate studies, symptom drawings from 103 chronic pain patients and their treating doctors were collected using 2 different versions of the app. Both patients and doctors evaluated usability aspects of the app through questionnaires. Results from study 1 were used to improve certain features of the app, which were then evaluated in study 2. Furthermore, a subgroup of 25 patients in study 2 created 2 consecutive symptom drawings for test-retest reproducibility analysis. Usability of both app versions was compared, and reproducibility was calculated for symptom extent, number of symptom clusters, and the whole symptom pattern.P=.007) and the evaluation of symptom depth (P=.02), and the overall difficultness of the drawing process (P=.003) improved significantly. Doctors’ usability evaluation of the final app showed good usability with 75.63 (SD 19.51) points on the System Usability Scale, Attrakdiff 2 scores from 0.93 to 1.41, and ISONORM 9241/10 scores from −0.05 to 1.80. Test-retest analysis showed excellent reproducibility for pain extent  and good results for the number of symptom clusters (ICC=0.70) and a mean overlap of 0.47 (Jaccard index).The changes we made to the app and the body outline led to significant improvements in patients’ usability evaluation regarding the identification with the body outline (We developed a tablet-based symptom drawing app and improved it based on usability assessment in a sample of chronic pain patients and their treating doctors. Increases in usability of the improved app comprised identification with the body outline, symptom depth evaluation, and difficultness of the drawing process. Test-retest reliability of symptom drawings by chronic pain patients showed fair to excellent reproducibility. Patients’ usability evaluation is an important factor that should not be neglected when designing apps for mobile or eHealth apps. Bodily symptoms, such as pain, headache, discomfort, or paresthesias, are among the most common reasons to see a doctor ,2. QuantSeveral groups have developed symptom drawing approaches that were based on tablet computers -11. SuchThe aims of this project were to develop a new tablet-based software app and test it for usability in 2 samples of chronic pain patients (Aim 1) and their treating doctors (Aim 2) as well as for test-retest reliability (Aim 3). This app is specifically designed to collect patients’ and doctors’ drawings of pain and related bodily symptoms. Aiming toward high drawing precision, the app contains 4 different views of the human body, and the drawings were collected on a stylus-based tablet.Therefore, we developed and tested a prototype app (study 1) following in part the suggested design guidelines by Jaatun et al, that is, using action buttons instead of icons, limiting written textual instruction, avoiding rapid changes on the screen, and using a paper metaphor . UsabiliThe project comprised 2 consecutive studies: study 1 aimed at evaluating the usability of a prototype of our app. Study 2 was designed to evaluate the final app with all improvements that had been made. The final app version was also used to assess reproducibility of our symptom drawing approach in a test-retest design. The reproducibility study is reported according to the guidelines for reporting reliability and agreement studies see  15]..15].Participants of both studies were chronic pain patients and their treating doctors from a pain outpatient department. The project was conducted in accordance with the Declaration of Helsinki and had been approved by the Ethical committee of Hannover Medical School (#2987-2015). All participants were informed about the purpose of the project and gave written informed consent.Patients were asked to draw their pain and related symptoms before their appointment with the doctor. All of them were using the app for the first time. Following data entry, each patient filled out a usability questionnaire and continued with the routines of the pain outpatient department, namely, filling out standard pain questionnaires and having the appointment with the clinician.Doctors were asked to enter the findings of their anamnesis and bodily examination during or shortly after seeing the patient. All participating doctors had been briefly trained by one of the authors (TN) on how to use the app.In both studies, participants were recruited consecutively from patients of the Pain Outpatient Department of Hannover Medical School. Inclusion criteria were chronic pain (pain duration of ≥3 months), age ≥18 years , physical ability to draw symptom drawings on a tablet personal computer (PC), and ability to give written informed consent. Due to our consecutive recruiting approach, our sample should reflect the normal composition of patients in outpatient departments similar to ours.We screened 70 patients in study 1, of which 52 were included, 15 declined participation, and 3 had to be excluded because they did not fulfill the inclusion criteria. In study 2, we screened 58 patients, of which 51 were included, 5 declined participation, and 2 were excluded because they did not fulfill inclusion criteria.The mean age was 56.2 (SD 16.1) years in study 1 and 60.4 (SD 15.7) years in study 2. There were no significant differences between both study populations regarding age, sex, body mass index, educational level, number of pain clusters, years of pain treatment, number of previous therapeutic consultations, and usage frequency of tablet computers or comparable devices .All doctors who evaluated the app were anesthesiologists with at least 5 years of clinical experience. Moreover, 6 of them participated in study 1, of which 2 were pain specialists and 4 were in training for pain specialization. The specialists examined 48 of the study patients, whereas those in training examined 30.Of the 4 anesthesiologists involved in study 2, 2 were pain specialists and 2 were in training for pain specialization. This time the specialists examined all 51 patients, of which 35 were additionally examined by a specialist in training.All symptom drawing data were collected on a Samsung Galaxy Note 2014 edition 10.1 (SM-P600) tablet computer running on Android 4.1.2 (study 1) or Android 5.1.1 (study 2). This tablet has a 10.1-inch touch screen with a resolution of 800×1280 pixels and is equipped with an electronic pen (stylus) that was used for all data entry. In contrast to entering data by finger, which uses the capacitive touchscreen, the tablet records stylus interactions with a separate inductive digitizer, which allows for a higher resolution while eliminating unwanted activation of the screen, for example, by the palm.The software app was organized into 3 different modules: drawing instructions, symptom specification, and drawing . App verThe first screen instructed the user how to make a correct symptom drawing. Following the suggested design guidelines by Jaatun et al , we usedAfter acknowledging the drawing instructions, a new screen was displayed asking users to specify any pain-related symptom in an iterative process. They were first asked to choose the type of sensation from the following list of descriptors (in German): burning, cold, cramping, dull, electric, heavy, hot, numb, pressing, pricking, radiating, shooting, stabbing, tearing, tender, throbbing, tingling, and tugging. In the next step, they rated the intensity of the sensation on a VAS, ranging from “no sensation” to “strongest imaginable intensity.” Next, they entered the perceived depth of the sensations by choosing one of the following descriptors: skin, muscle, organ, and bone. The initial version of the app contained an additional classification of the symptom into major or minor symptom. Following this textual specification, the drawing module was initialized.The doctors’ version of the app had an additional variation of the symptom specification module to enter common diagnostic findings in a bodily examination. This screen contained German translations of the following findings: allodynia, anesthesia, atrophy, dysesthesia, hyperalgesia, hyperhydrosis, and hypesthesia. The VAS and depth rating was similar to that of the symptom specification module.In the final module, users were shown a body outline to draw the location of the symptom or finding specified in the previous module. It had been specifically developed for this purpose based on photographs of a human body. The sex of the initial version was undetermined. Although previous screens allowed data entry by finger, drawings could only be made using the tablet’s stylus. Users were free to choose from a set of drawing tools . Drawing was restricted to within the borders of the body outline. After finishing the drawing, users could either choose to end data entry or to add another symptom, which would bring them back to symptom specification.We made several improvements to the graphical user interface (GUI) of the prototype app, most of which were inspired by the results of the usability assessment of study 1 as well as requests from the doctors. Furthermore, we completely abandoned the use of pop-up windows as suggested by Jaatun et al .Changes to the drawing instructions largely reflect the changes made to the other modules, for example, the newly added VAS of the drawing module (see below). In addition, we added a short explanation of the different drawing tools. As a general rule, we tried to move as much information as possible from instructions to symptom specification, because it seemed a more natural place to explain the choice of descriptors, symptom depth, and the use of the VAS and reduced the amount of information that needed to be memorized by the user. Finally, we reduced ambiguity of the app results for patients by specifying the time interval of the symptoms to be drawn (last 4 weeks).Many patients asked for the possibility to choose more than one descriptor for the single symptom, which is why we added this feature in the final version. Patients were also allowed to add their own descriptors if they were not happy with the available choices. Furthermore, the list of depth descriptors was changed following patients’ requests. As many of them found it difficult to localize the depth of their symptoms in either “skin” or “muscle,” the term “skin” was split into “on the skin” and “beneath the skin,” whereas the other terms were left unchanged.Symptom specification was expanded relative to study 1, which was largely motivated by considerations other than usability. Briefly, we asked for each symptom for the maximal and minimal intensity, if the symptom was currently present, the time of day when the symptom was worst , and the perceived burden associated with the symptom. The perceived burden replaced the classification into major or minor symptom, because for the majority of the patients all symptoms were rated as major symptom. Maximal and minimal symptom intensity as well as perceived burden were rated on a VAS ranging from 0 (“no symptom” and “no burden”) to 10 (“strongest imaginable intensity” and “strongest imaginable burden”) and anchored by numbers from 0 to 10. All changes were applied after consulting the participating doctors.In study 2, finding specification for doctors was also expanded. Besides the possibility to choose multiple symptom descriptors and depth categories, the second app contained an expanded list of findings . In addiSeveral profound design changes were made to the drawing module, all inspired by user feedback. To allow users to indicate local differences in symptom or finding intensity, we added a VAS to the drawing module. Different intensities in the drawing were indicated by different saturation values of the drawing color. We also changed the body outline and the way it was presented. First, we added the possibility to choose the gender of the outline . Sex-related changes to the outline were kept as small as possible to maintain comparability between the drawings from the different sexes.Second, we changed the mode of presentation. While the four views  of the body outline had been presented on one screen in the prototype , the finWe also changed the controls  at the bottom of the screen. Buttons for zoom (magnification glass) and scrolling (arrows) were removed because they had only been used by a minority of users. Furthermore, we reduced the line drawing tool to one thickness and added an eraser tool.Usability of the app and data acquisition method were assessed separately in patients (Aim 1) and doctors (Aim 2).To evaluate the app and the tablet-based data acquisition, we designed a usability questionnaire. It contained a common part aimed at comparing usability between studies 1 and 2 and an individual part with items specific to each of the studies. The common part consisted of 8 Likert-type questions (possible answers from 0 to 10) and 2 open questions with free text answers. The individual part contained 3 dichotomous and 1 multiple-choice question for study 1 and one Likert-type question for study 2. A translated version of the 2 questionnaires can be found in We observed doctors’ evaluation during data entry at several timepoints of the project and asked them to report any problems or ideas for improvement. These were collected in a list and later analyzed. Furthermore, a meeting with the participating doctors was arranged after the first study to discuss the study results and plans for app improvements.At the end of study 2, we evaluated usability from the doctors’ perspective through a Web-based survey comprising the following questionnaires:The System Usability Scale (SUS)  is a queThe Attrakdiff 2 questionnaire  measuresThe ISONORM 9241/10 questionnaire ,20 assesTo evaluate test-retest reliability of our acquisition method  for symptom drawings, we planned to include 25 of our patients in the second study. The rational for this sample size was that previous studies had shown excellent test-retest reliability of pain extent with intraclass correlation coefficients (ICCs) between 0.92 and 0.97 . Aiming t tests for all types of questionnaires for patients and doctors were calculated using Microsoft Excel .Mean values, SDs, and two-tailed We used a script written in Python 2.7 (Python Software Foundation ) to tranA total of 52 questionnaires entered the final analysis for study 1 and 51 for study 2. In study 1, 87% (45/52) of the study patients were content with the body outline. In total, 8% (4/52) of the patients proposed changes in its size and 4% (2/52) requested gender-specific changes. Moreover, 75% (39/52) of the patients agreed with the available choice of descriptors, whereas 23% (12/52) asked for additional or different terms to describe their sensations. In addition, 71% (37/52) of the patients were contempt with the terms to describe the depth of their sensations, whereas 27% (14/52) were not. Several patients used the free text option to suggest adding a multiselect option for sensations and depth descriptors. Furthermore, free text entries demanded the possibility to rate multiple symptom intensities over the day or criticized the restriction of the drawings to within the borders of the body outline. All translated free text answers of patients’ usability questionnaire can be found in P=.003), (2) the ability to identify oneself with the given body outline increased from 7.54 (SD 2.59) to 8.73 , and (3) the difficulty to select a depth descriptor decreased from 4.71 (SD 3.18) to 3.27 .The part of the questionnaire comparing the app versions of studies 1 and 2 showed significant differences for 3 of the 8 Likert-type items, indicating improved usability of the final app : (1) TheIn study 2, 4% (2/51) of the patients found the size of the body outline too small. One patient of 51 (2%) reported problems using the VAS while drawing and another one proposed to use a table to support the tablet during data collection. Finally, the difficulty of drawing the symptom pattern from different angles of the human body was rated as 1.78 (SD 2.16) on a Likert-type scale from 0  to 10 (“very difficult”).The results of the doctors’ usability assessment are displayed in . We collAssessment using the ISONORM 9241/10 questionnaire showed good results in the categories “suitability for learning,” “suitability for the task,” “self-descriptiveness,” “conformity with user expectations,” and “error tolerance.” Only in the categories “suitability for individualization” and “controllability” the results were slightly below the average.Results of the test-retest analyses are shown in We have developed a new tablet-based app (SymptomMapper) to collect electronic drawings of pain and related bodily symptoms. Following the suggested design guidelines by Jaatun et al , we limiUsability assessment comparing the pilot app from study 1 with the final app from study 2 showed 3 areas of significant improvement as rated by the patients: evaluation of symptom depth, identification with the body outline, and overall difficultness of the drawing process. Although we did not assess explicitly which changes of the app led to a particular improvement in usability, we will speculate in the following sections on the most likely causes and discuss them in the light of the relevant literature.Regarding the improvement in depth evaluation, we must note that unless the pain is entirely superficial, a pain map has to display the complex three-dimensional geometry of the painful area onto a flat, two-dimensional surface . It can Concerning identification with the body outline and overall difficultness of the drawing process, we believe that the improvements seen here were largely due to 2 major modifications we made to the drawing module, namely, the introduction of gender-specific body outlines and the consecutive rather than joint presentation of the single body views. The change from a genderless to a gender-specific body outline had been requested by patients and may have improved patients’ ability to identify themselves with the body outline. Egsgaard et al have shown that gender aspects of body outlines can influence the quality of the drawing as well as the patients’ drawing experience . In theiOn the other hand, the consecutive presentation of the body views constitutes a more guided approach compared with the joint presentation allowing patients to focus on one view at a time. This may also have improved identification with the body outline as compared with the pilot app. Finally, the size of the body outline was almost twice as large in the consecutive presentation approach as compared with joint presentation. Interestingly, however, the enlargement of the body outline did not have an effect on patients’ perceived exactness of the drawings.At the end of study 2, the 4 participating doctors were asked to evaluate the tablet app through a Web-based usability survey consisting of the SUS, Attrakdiff 2, and ISONORM 9241/10 questionnaires. A score of 75.63 on the SUS indicates an overall good usability of the final app ,32, whicThe ISONORM 9241/10-questionnaire evaluates several aspects of software usability including suitability for the task, controllability, conformity with user expectations, and error tolerance. All categories were evaluated above average by our doctors, except for “suitability for individualization” and “controllability.” Both categories received slightly negative ratings, which may reflect the fact that doctors and patients used the same app in our study that only differed in the lists of available symptoms. As one of the design goals of this app was to increase homogeneity and validity of symptom drawings, we tried to reduce sources of between-subject variability that are due to unnecessary freedom in the drawing process. Therefore, the final app version used a rather rigid succession of data entry steps, for example, by presenting all body views in a defined order of by fixing the symptom descriptor(s) once the drawing starts. A possible way to improve this in future releases would be to add features that allow doctors to circumvent some of the restrictions and to enter data more freely.After testing and improving the usability of our app, we used its final version to assess test-retest reliability of symptom drawings by a typical sample of chronic pain patients consulting a pain outpatient clinic. The analysis of pairs of consecutive drawings separated by 20 min and drawn by the same patients showed excellent reproducibility for symptom extent (ICC=0.92) and fair reproducibility for the exact symptom pattern (Jaccard index: 0.47). It is worth noting that we used 4 instead of the usual 2 views of the human. Although this complicates the drawing process, it allows for much more detailed assessment of lateral body regions. To our knowledge, this was the first study analyzing test-retest reliability for more than 2 body views.Our results closely replicate a study by Barbero et al , who in As in every study, we must note some limitations. Our attempt to quantify symptom depth relied on verbal descriptors, which may have led to mistakes arising from different interpretations of expressions, such as “beneath the skin,” whose German translation may have been interpreted by some as meaning “in every tissue layer beneath the skin.” Descriptors should be carefully checked for all possible meanings they convey. Furthermore, there are alternative approaches to assess symptom depth, for example, the aforementioned visual rating of the “percentage of depth to center” by Tucker et al  or depthOur test-retest results may have been biased by several uncontrolled factors. First, patients did not simply wait for 20 min between test and retest but used the time to fill out clinical pain questionnaires in preparation for their appointment with the doctors. The occupation with different aspects of their pain induced by the questionnaires may have influenced the second drawing, for example, by reminding patients of previously forgotten pain foci. Second, we cannot estimate the effect of learning. Roach et al showed that patients may complete pain drawings more reliably after they have been exposed to them several times . In our We developed an app for symptom drawing acquisition and assessed the usability of it in a sample of chronic pain patients and their treating doctors. We measured increases in usability of the improved app in terms of identification with the body outline, symptom depth evaluation, and difficultness of the drawing process according to patients’ evaluation (Aim 1). Furthermore, usability evaluation through treating doctors showed good overall usability and balanced hedonic and pragmatic values (Aim 2). Test-retest reliability of symptom drawings by chronic pain patients showed fair to excellent reproducibility for symptom pattern, symptom extent, and number of symptom clusters (Aim 3). Patients’ usability evaluation is an important factor when designing apps for mobile or eHealth apps and should not be neglected.


Chronic back pain (CBP) is a leading cause of disability and results in considerable socio-economic burdens worldwide. Although CBP patients are commonly diagnosed and treated with a focus on the “end organ dysfunction” , the evaluation of CBP remains flawed and problematic with great challenges. Given that the peripheral nerve injuries or diseases are insufficient to define the etiology of CBP in some cases, the evaluation of alterations in the central nervous system becomes particularly necessary and important. With the development of advanced neuroimaging techniques, extensive studies have been carried out to identify the cortical abnormalities in CBP patients. Here, we provide a comprehensive overview on a series of novel findings from these neuroimaging studies to improve our understanding of the cortical abnormalities originated in the disease. First, CBP patients normally exhibit central sensitization to external painful stimuli, which is indexed by increased pain sensitivity and brain activations in pain-related brain regions. Second, long-term suffering from chronic pain leads to emotional disorders, cognitive impairments, and the abnormalities of the relevant brain networks among CBP patients. Third, CBP is associated with massive cortical reorganization, including structural, functional, and metabolic brain changes. Overall, a deep insight into the neural mechanisms underlying the development and outcome of CBP through more sophisticated neuroimaging investigations could not only improve our current understanding of the etiology of CBP but also facilitate the diagnosis and treatment of CBP based on precision medicine. As a substantial worldwide health problem, chronic back pain (CBP) is one of the most frequent complaints and the second most common symptom reported by patients during their primary physical care visits . Being mIt is widely accepted that CBP can be caused by anatomical abnormalities or systemic diseases in/around the spinal cord , including lesions or degenerations in certain structures of the spine . TherefoTheoretically, the imprecise diagnosis of CBP could be caused by the possible dissociation between nociception  and pain (a conscious experience in the brain) . Pain caIn clinical practice, an integrated diagnosis strategy that not only assesses injuries or diseases in/around the spinal cord but also evaluates cortical abnormalities is highly needed to optimize the treatment strategies for CBP patients, especially for non-specific CBP patients. In the present study, we overviewed findings in recent research that evaluates cortical abnormalities in CBP patients using advanced neuroimaging techniques, and discussed some perspectives on how to improve the diagnosis of the disease .Several non-invasive neuroimaging techniques with different underlying physical principles are widely adopted to evaluate the cortical abnormalities in CBP patients , includiThe structural MRI could provide anatomical information of the brain with high spatial resolution, and the functional MRI (fMRI) is used to determine the location of the “activate” brain regions during cognitive tasks . Both teBy extracting morphological features from structural MRI through some advanced analysis techniques , several crucial anatomical changes have been observed in CBP patients. In a pilot study, CBP patients exhibited decreased neocortical gray matter (GM) volume , with the magnitude equivalent to the loss quantity caused by 10–20 years of normal aging . MeanwhiAs an effective technique to map white matter (WM) tractography in the brain , diffusiThe resting state fMRI and task fMRI are normally applied to investigate functional alterations in CBP patients by measuring the spontaneous blood-oxygen-level dependent (BOLD) activities of brain networks at resting state  and the Consistently, evidence from the task fMRI revealed that CBP patients exhibited abnormal brain functions related to pain processing . For exaDifferent from MRI techniques that could provide massive spatial information related to cortical regions/networks involved in pain processing, EEG/MEG techniques can measure the cortical changes with a high temporal resolution, thus giving a deep insight into the dynamic process of pain information processing . NowadayIn addition, CBP patients showed evident abnormalities in emotional and cognitive functions. For example, when being assessed the emotional decision-making abilities using the Iowa gambling task, CBP patients scored much lower than healthy controls did, and their performance was significantly influenced by the duration and intensity of their chronic pain . ConsistAccompanied by the long-term changes of cortical function, cortical reorganization in CBP patients due to the processes of neuronal plasticity was well documented . Demonstin vivo single-voxel proton MRS (1H-MRS), which is able to provide additional evidence on abnormal brain alterations associated with chronic pain (N-acetyl aspartate (NAA) was observed in several brain regions of CBP patients, including the dlPFC, orbitofrontal cortex (OFC), anterior INS, ACC, and thalamus  involving cortical dysfunction, more and more researchers shift their interests from the peripheral level to the cortical level. With the development of non-invasive neuroimaging techniques, a series of novel findings were obtained in this field.First, despite CBP patients have sensorimotor impairments , they have enhanced central sensitization to external painful stimuli, manifested by increased subjective pain sensitivity and increased brain activations in pain-related brain regions. It has been reported that increased pain sensitization and decreased sensitivity to innocuous stimuli in CBP patients are associated with increased catastrophizing, which is also linked with increased clinical back pain . This ceSecond, suffering from chronic pain, CBP patients commonly exhibited emotional and cognitive disorders, including depression, anxiety, catastrophizing, and sleep disturbances . In lineAdditionally, accumulating evidence has demonstrated that CBP is associated with clear cortical reorganization and neuronal plasticity, which is normally quantified by structural  , functioTo sum up, with the development of neuroimaging techniques, great progress has been made to improve our understanding of cortical alterations in CBP patients over the past few years. However, the neural mechanisms associated with the development of CBP remain largely mysterious, which hampers the improvement of the efficacy of CBP treatment. To address this issue, integration of neuroimaging techniques and other biotechnologies  would be important to achieve a comprehensive assessment of the risk factors  of the development and maintenance of CBP. In addition, longitudinal studies are highly needed to assess the temporal relationship between chronic pain and neural plasticity. It is worthwhile to note that longitudinal studies would not only improve our understanding of the neural mechanisms associated with the causes and outcomes of CBP but also provide theoretical bases for accurate diagnoses of CBP patients. Integrating the results obtained from comprehensive and longitudinal studies is a promising way to identify the causes of pain and pain-associated comorbidities and deepen our understanding of the mechanisms involved in chronic pain, and ultimately promotes the development of more appropriate and effective treatments in CBP management.LZa, XZ, LW, and LH conceived of this topic. LZa conducted the literature search and wrote the manuscript. LZa, LZo, QR, TM, LW, XZ, and LH revised the work. LZa, XZ, LW, and LH edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 54-year-old male patient with postoperative axillary lymph node, intrapulmonary, intracranial, and cervical spine metastases of left liver cancer was suffering from severe, persistent, and pricking pain in the right dorsal shoulder and right arm since 3 months. The drug dose of the fentanyl transdermal patch was gradually increased after admission and an adjuvant analgesic was also included, but neither treatment alleviated the pain. It was gradually alleviated after intramedullary analgesic infusion through intrathecal pump implantation in cistern magna. Terminally ill patients often have the desire to spend their remaining time at home, which however becomes a challenge in the face of refractory pain. At present, no palliative chemoradiation or ablative or stimulant neurosurgical options are available to manage pain in cancer patients. Based on the findings of this report, we concluded that an intramedullary drug infusion system can have a significant analgesic effect in patients with cervical metastasis and refractory cancer pain. Pain is very a common symptom in all stages of cancer patients. According to WHO's principle of three-step pain relief for cancer patients, oral analgesics should be given in the following order as per necessity: the nonopioids like aspirin, followed by weak opiates like codeine, then strong opiates like morphine, and adjuvant drugs such as opioids and nonsteroidal agents can be given to calm patient anxiety. The patient we discussed in the paper was refractory even to systemic opioid and nonopioid analgesics, and chemoradiation or ablative/stimulant neurosurgical procedures were not possible; there were limited options for palliative treatment when patients wish to spend their remaining days at home. The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines was held in 2017 to address the issue of refractory cancer pain and minimally invasive treatment such as intrathecal pump implantation [The patient was a 54-year-old male with multiple metastasis of axillary lymph nodes, lung, and intracranial and cervical vertebrae after liver cancer surgery. He had been experiencing severe, persistent needle-like pain in the right shoulder, back and right arm since 3 months. Other doctors treated the pain with fentanyl transdermal patch 29.4mg q72h and 100mg tramadol sustained release tablet q.d. oral prior to admission. However, neither analgesic therapy was effective in treating his pain. In addition, the patient had breakthrough pain (BTP) more than ten times in 24 hours, and NRS  score was 7. Due to the poor analgesic effect of the tramadol sustained release tablets, they were discontinued, and the patient's condition was reassessed after admission. The patient felt pricking, numbness, and electrical shocks, suggesting an ID Pain scale [NRS score was 4 at rest on day 2 of admission, BTP was 4 times at night, and NRS score was 7. One hour after administering 10mg morphine tablets, NRS score decreased to 3. Due to the weak effect of 29.4mg fentanyl, the concentration was increased to 42mg in the transdermal patch. At the same time, 5mg dexamethasone injection IV q.d., oral 25mg amitriptyline tablets 25mg q.n., and oral 2mg Clonidazepam tablets q.n. were given.2 saturation monitoring. The intrathecal pump parameters could be adjusted according to the degree of pain and drug reaction experienced by the patient. In the period between operation and 8:00am on day 8 after operation, the patient pressed bolus 15 times and the effective number was 8 times. Since the pain was not relieved even after pressing, the parameters were adjusted to Con of 0.3ml/h and bolus of 1ml with 0.25mg morphine. Meanwhile, fentanyl dose in the transdermal patch was reduced to 33.6mg. After adjusting the pump's parameters, the NRS score was 1 at rest, the time of BTP was 4, and the NRS score was 4. According to the equivalent dose of opioid drugs and related efficacy conversion, the intrathecal dose of morphine is about 300 times more than its intravenous form. When the pain stabilized, fentanyl dose in the transdermal patch was further reduced to 25.2mg after expiration, and the amount of morphine infused via the intrathecal pump was reduced daily. The degree of pain was significantly reduced compared with that before surgery. Taken together, administration of analgesic via intrathecal pump implantation in the cisterna magna reduced pain levels and reduced the number of BTPs. The patient experienced considerable pain relief (see On day 7 of admission, the patient still complained of obvious pain in the back, shoulder, and right arm, NRS score was 5 at rest, BTP was 3 times at night and NRS score was 8. In our patient, imaging showed multiple soft tissue masses in the neck space, corresponding to metastases. Since the spinal canal becomes narrow and results in cerebrospinal fluid reflux in such a condition, the tip of the catheter was inserted in the cerebellomedullary cistern. Intrathecal pump was implanted in the cisterna magna under DSA without any complications in the First Affiliated Hospital, Zhejiang University School of Medicine . Morphinlief see . HoweverCurrent data show that 53% of cancer patients experience pain at each stage of the disease, while 58% to 69% patients undergo pain as the disease progresses . Around  et al. [ et al. [ et al. [Complete implantable infusion pumps can inject analgesic drugs into the epidural or subarachnoid cavity in most patients. Some clinicians believe that the intrathecal infusion system must be placed lower than the neck region . However et al.  placed t[ et al.  reported[ et al.  also repAn implantable intrathecal pump has also been reported to be effective against intractable cancer pain , and we For a terminal cancer patient, a better analgesic effect can be obtained by infusing the drug via intrathecal pump implantation in the cisterna magna. In our case, a low dose of morphine was required for pain relief, with high efficiency and as per the needs of the patient. It is an ideal treatment for refractory cancer pain accompanying cervical or intracranial metastasis.


Evidence to support initiation of pharmacological treatment in patients with uncomplicated (low risk) mild hypertension is inconclusive. As such, clinical guidelines are contradictory and healthcare policy has changed regularly. The aim of this study was to determine the incidence of lifestyle advice and drug therapy in this population and whether secular trends were associated with policy changes.Longitudinal cohort study.Primary care practices contributing to the Clinical Practice Research Datalink in England.Data were extracted from the linked electronic health records of patients aged 18–74 years, with stage 1 hypertension (blood pressure between 140/90 and 159/99 mm Hg), no cardiovascular disease (CVD) risk factors and no treatment, from 1998 to 2015. Patients exited if follow-up records became unavailable, they progressed to stage 2 hypertension, developed a CVD risk factor or received lifestyle advice/treatment.The association between policy changes and incidence of lifestyle advice or treatment, examined using an interrupted time-series analysis.A total of 108 843 patients were defined as having uncomplicated mild hypertension . Patientsspent a median 2.6 years (IQR 0.9–5.5) in the study, after which 12.2% (95% CI 12.0% to 12.4%) were given lifestyle advice, 29.9% (95% CI 29.7% to 30.2%) were prescribed medication and 19.4% (95% CI 19.2% to 19.6%) were given both. The introduction of the quality outcomes framework (QOF) and subsequent changes to QOF indicators were followed by significant increases in the incidence of lifestyle advice. Treatment prescriptions decreased slightly over time, but were not associated with policy changes.Despite secular trends that accord with UK guidance, many patients are still prescribed treatment for mild hypertension. Adequately powered studies are needed to determine if this is appropriate. This study examined electronic health records from a large, nationally representative sample of the UK population.Analyses were undertaken according to a prespecified protocol which was reviewed and approved by an independent scientific advisory committee.Mild hypertension was defined consistently according to blood pressure readings, meaning that those with a diagnostic code for hypertension but no associated blood pressure values may have been excluded.Low-risk patients were defined according to individual risk factors, rather than an established risk calculator due to large amounts of missing data , potentially underestimating the number of truly low-risk patients available for analysis.The incidence of lifestyle advice was defined according to clinical codes but it was not possible to identify patients given lifestyle advice where it was either not coded or where it was only recorded in the free text consultation notes.High blood pressure (hypertension) is a key risk factor for the development of cardiovascular disease,9–14There is little evidence to support initiation of pharmacological treatment in patients with uncomplicated mild hypertension. A Cochrane review18Clinical guidelines often make recommendations based on ‘expert opinion’ where evidence is lacking or inconsistent. Such guidelines are predictably contradictory, with those in the UK promoting lifestyle modification in low-risk patients20The aim of this study was to use routine patient records from the Clinical Practice Research Datalink (CPRD)This was a longitudinal cohort study in conducted in Primary Care from 1998 to 2015 using data from the CPRD, a database of electronic health records from England.21Individual patient data were extracted from the medical records of all patients registered at general practices contributing to the CPRD in England. Patients were entered into the study on the date of the third consecutive blood pressure reading between 140/90 and 159/99 mm Hg occurring after the study start date 1 January 1998. The start date was chosen because it represents the date from which all relevant data linkages were first available. Patients exited the study if they had three consecutive blood pressure readings >160/100 mm Hg , developed a risk factor for cardiovascular disease, received lifestyle advice or treatment or follow-up records became unavailable (patient or practice left the CPRD) . The lasThe primary outcome of this study was evidence that lifestyle advice and/or pharmacological treatment had been given during follow-up. Lifestyle advice was defined as Read code for any lifestyle advice relating to smoking, alcohol, diet, hypertension, physical activity, weight, oral health or lipid disorders  deprivation), lifestyle factors , alcohol consumption (units per week), and body mass index (BMI)), pretreatment blood pressure readings (in the preceding 12 months), related comorbidities ) and all prescribed statin/antiplatelet medications were extracted from the CPRD database and used to define the study population.Ethnicity was classified into white, black, South Asian, mixed race, other and unknown groups. The Index of Multiple Deprivation (IMD) was provided as quintiles of deprivation in England, with the highest quintile indicating the highest level of deprivation. Smoking status was defined as never, previous or current smoker. Those with unknown smoking status were assumed to have never smoked. Where there was no record of blood pressure lowering, statin or antiplatelet treatment, it was assumed that patients were not prescribed treatment.Only patients with records deemed ‘acceptable for research purposes’ by CPRD were included in the analysis, and hence age and sex information was complete. Where there was no record of alcohol consumption, rheumatoid arthritis or hypercholesterolaemia, patients were assumed to be non-drinkers and have no history of these conditions. Where there was no record of blood pressure lowering, statin or antiplatelet treatment, it was assumed that patients were not exposed to any treatment. A total of 91 patients (0.001%) were missing IMD data and were excluded. To enable calculation of a cardiovascular risk score for sensitivity analyses, missing values for cholesterol and BMI were simulated once, assuming a normal distribution, and using means and SD in each age–sex strata from the 2011 Health Survey for England.22As a descriptive study, no formal sample size calculation was required. All patients from the CPRD fulfilling the eligibility criteria were included.Descriptive statistics were used to describe the study population and estimate the proportion of patients being offered lifestyle advice or therapy (or both) following a diagnosis of uncomplicated mild hypertension.The impact of the introduction of the NHS health check programme in April 2009As a post hoc analysis, the impact of the introduction of the QOF in 2004SS had access to the entire CPRD database from which eligible patients were identified and all data extracted. Where multiple blood pressure values appeared in the record on any one day, the lowest value was selected. Treatments/diagnoses of conditions were determined from the presence of at least one coded prescription/diagnostic code, respectively. Baseline data were extracted from within each patient’s up to standard registration period and were drawn from the latest available record prior to study entry. Values deemed a priori to be clinically implausible were excluded . Where there was evidence of prior smoking but the most recent smoking status recorded indicated no smoking, this was corrected by classifying patients as former smokers.To reduce the possibility of selection bias, all patients fulfilling the eligibility criteria for the study were included. Mild hypertension was defined according to measured blood pressure values rather than diagnostic codes, to reduce the potential for reporting bias, particularly in the pre-QOF era when coding was less standardised. For the primary analysis, breakpoints for the interrupted time-series analysis were prespecified based on policy changes thought likely to influence the giving of lifestyle advice and treatment, rather than trends observed in the data.Data linkage to the Office for National Statistics (ONS) mortality register was used to define patient mortality (patient exit from the study). Linkages to Basic Inpatient Hospital Episode Statistics (HES) were used in conjunction with CPRD records to define patient eligibility for the study , and define patient ethnicity (where unavailable in primary care records). A linkage to the IMD was required to acquire practice level indices of multiple deprivation.Patients were not involved in the development or design of this study.https://www.cprd.com/isac).The present study protocol (16_008R) was approved by this committee in March 2016, prior to obtaining the data cut . Results are presented as means, medians or proportions, with SD, IQR or 95% CIs, unless otherwise stated.Of the 7 416 968 individuals aged 18–74 years registered at linked, up-to-standard practices within the CPRD during the study period, a total of 108 843 patients  from 694 practices (333±192 patients per practice) met the criteria for having uncomplicated mild hypertension during the study period . IncludeIn the pre-NHS health check period from January 2000 to April 2009, the proportion of patients receiving lifestyle advice increased from zero by 0.04% per year (95% CI 0.04% to 0.05%) . The intTreatment prescriptions were given to approximately 1.29% (95% CI 1.23% to 1.34%) of patients with uncomplicated mild hypertension in the first month of the study, but the incidence then decreased by −0.05% (95% CI −0.06% to −0.05%) per year in the pre-policy period until 2009 . NeitherThe introduction of the QOF and clinical guidelines for the management of hypertension in 2004 was associated with a step-change increase in the incidence of lifestyle advice of 0.15%  . SubsequThe present study examined a large database of electronic health records to establish the incidence of guideline recommended lifestyle advice and non-guideline recommended treatment for uncomplicated mild hypertension in primary care. Across the study period, approximately one-third of patients received lifestyle advice while half were prescribed antihypertensive treatment. The introduction of pay-for-performance indicators in 2004,This study examined electronic health records from a large, nationally representative sample of the UK population.In an attempt to define mild hypertension consistently across the population, it is possible that some patients with a diagnostic code for hypertension but no associated blood pressure values may have been excluded. The focus of this study was on ‘uncomplicated’ low-risk patients, but for pragmatic reasons, no attempt was made in the primary analysis to exclude those with a high risk of cardiovascular disease according to an established risk calculatorThe incidence of lifestyle advice was defined according to clinical codes related to the giving of lifestyle advice which might be of relevance to the management of hypertension and cardiovascular disease risk , perhaps due to more accurate blood pressure measurement and targeting of treatment brought about by new National Institute for Health and Care Excellence guidelines and the introduction of out-of-office blood pressure measurement for diagnosis in 2011.The peak in prevalence of lifestyle advice coinciding with the inclusion of QOF indicators encouraging advice for physical activity, smoking cessation and diet in 2013,One could argue that the evidence for giving lifestyle advice in uncomplicated mild hypertension is as inconclusive as the evidence for pharmacological interventions, with many trials having short follow-up and exhibiting risk of bias36The present study shows that the introduction of pay-for-performance indicators and a cardiovascular risk screening programme have been associated with increased guideline recommended lifestyle advice being offered to patients with uncomplicated mild hypertension, although the overall prevalence remains relatively low. However, nearly half of the patients go on to be prescribed treatment, despite a lack of evidence suggesting benefit. This may be explained by a lack of clear evidence to guide treatment decisions. Adequately powered studies, perhaps using routine clinical data at scale, are required to accurately define the relationship between treatment and cardiovascular disease and death in patients with uncomplicated mild hypertension.


Chronic nonspecific low back pain is common and one of the most disabling conditions in the world. There is moderate evidence that chronic low back pain patients present altered functional connectivity in areas related to pain processing. Quantitative sensory testing is a way of clinical measure of these alterations. Although there is not enough evidence, there are some reports that electroacupuncture is supposedly more effective in relieving pain than acupuncture because the addition of electric current could optimize the effects of traditional technique. Thus, the objective of this randomized clinical trial was to verify if electroacupuncture treatment reduces pain and changes quantitative sensory testing responses in patients with chronic nonspecific low back pain. Patients were evaluated before and after 10 sessions regarding pain  and quantitative sensory testing . There were 1 treatment group (electroacupuncture (EA)) and three different control groups . A total of 69 patients participated in the study. No significant differences were found in pain intensity or quantitative sensory testing responses when comparing electroacupuncture group to the three control groups. There was a significant reduction in both resting and movement pain intensity in groups EA, CTR 1, and CTR3. Although ten sessions of electroacupuncture have diminished pain intensity in both resting and movement, it could not change significantly quantitative sensory testing and diminish central sensitization in patients with chronic nonspecific low back pain. The implications of this study involve the fact that, maybe, in chronic nonspecific low back pain, electroacupuncture should be associated with other treatments that target central sensitization. Chronic nonspecific low back pain is common and one of the most disabling conditions in the world , 2. AccoSome available and commonly used quantitative sensory tests in musculoskeletal disorders are the investigation of mechanical detection threshold, heat detection threshold, vibration detection threshold, and pressure pain threshold . They alWhile traditional acupuncture dates back at least 2,000 years ago, electroacupuncture is a relatively recent technique, since it has been started to be used in the last 50 years . One of Microinjection of the beta-endorphin antagonist into the periaqueductal gray matter (PAG) decreased electroacupuncture-induced analgesia, suggesting that this neurotransmitter is involved on its mechanism of action . In addiAlthough there is a lot of published systematic reviews, meta-analyses, guidelines, and increasing research funding on low back pain, patients' self-reported disability have not improved in the last years . RegardiIn addition, although acupuncture is an age-old therapy and has shown to have good results in the clinical practice, there are still some gaps in the clinical trials that make it unclear whether electroacupuncture differs from acupuncture or whether it is just a variation of the technique, or even if there is some advantage by adding an electric stimulus to the already inserted needles.This is a double-blinded and placebo controlled randomized clinical trial. Distribution was made with sealed opaque envelopes containing numbers 1 to 4, corresponding to the number of groups, performed in a blocked proportion of 1:1. For assuring the blinding process, there were two types of investigators in this study: investigator 1, responsible for evaluating patients and measuring all variables, before and after treatment; and investigator 2, responsible for applying the treatment during all sessions. Neither the patient nor investigator 1 knew in which group  subjects were allocated. Patients were treated at the Ambulatory of Laboratory for Research in Neurosciences, located at Federal University of Sergipe.This study follows Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) recommendations. angina pectoris, congestive heart failure, and decompensated hypertension) disease; (11) having heart pacemaker; (16) having auditory, visual, or communication disturbance.Patients were included if they had (1) low back pain diagnostic made by an orthopedics physician; (2) pain on the lumbar region for at least three months; (3) never been submitted to acupuncture or electroacupuncture treatment previously. Exclusion criteria were (1) doing physiotherapy or other treatment for low back pain; (2) being pregnant or postpartum women who had given birth in the past three months; (3) having deformities or important amputations on lower limbs; (4) having low back pain due to infection, tumor, osteoporosis, rheumatoid arthritis, vertebrae fracture, or radiculopathy; (5) having nervous or cutaneous tissue injury affecting lumbar region; (6) having active infectious processes; (7) having surgery or invasive exams on the spine on the past three months; (8) having inability to understand instructions or consent to the study; (9) having psychiatric or cognitive impairments; (10) having neurological , pulmonary ), or cardiac  and also registered on the Brazilian Registry of Clinical Trials (report number: RBR-3w2p32). It complies determinations of 466/12 Resolution from the Brazilian National Health Council. All subjects included assigned an informed consent before to be included in the study.Patients were randomly allocated into one of the four study groups and Traditional Chinese medicine style was used in all groups. Randomization was done with opaque sealed envelopes in the proportion 1:1. There were 1 treatment group (EA) and 3 control groups, considering electroacupuncture as a focus in this study. Patients in the treatment group received electroacupuncture (needle + electric current).μ and δ opioid receptors [A 10 Hz frequency was chosen because it decreases substance P; and at 100 Hz, dynorphin is released , 13. BotIn Control Group 1, electrical stimulus lasted only 45 seconds, but needles were still kept inserted during 30 minute-period. Patients in Control Group 2 received only had a needle inserted in, without electrical stimulus or device . In Control Group 3, needles were placed in the same other group's acupoints; however, they were withdrawn immediately after puncture. Patients in this group could not see that needles were removed.Acupoints were used in all groups. These points were chosen because they are commonly used to treat low back pain in clinical practice. As this study has a mechanistic approach, all patients received puncture in the same points. Sterile acupuncture needles, 25 x 30 mm sized , were inserted bilaterally during 30 minutes in 4 acupuncture points related to low back pain: (1) B22, located 1,5 cm laterally to L1 vertebrae; (2) B26, located 1,5 cm laterally to L5 vertebrae; (3) B50, located 3 cm laterally to T12 vertebrae; (4) B53, located 3 cm laterally to S2 vertebrae. In the CTR 3 group, needles were inserted in those same acupuncture points; however, they were immediately removed after puncture.2), that is why in needle could pass thru the skin or fat. Treatment was delivered three times a week  in a total of ten sessions. No additional components of treatment  were used. Patients were informed that different types of acupuncture were being compared in the study. All patients allocated in placebo groups received the same treatment as the active groups when all sessions and data collection have ended.This method has been previously tested by our group comparing different types of placebos and real acupuncture. No difference was found between groups when needling sensation was compared . In the Pain intensity was measured by using the 11-point numerical rating pain scale that ranges from 0 to 10, with 0 indicating “no pain” and 10 “worst pain imaginable”. Patients verbally classified their pain at rest (standing position) and during flexion-extension movement of lumbar spine (patient was in a standing position and then was instructed to try to touch his fingers on his toes).Brazilian version of McGill Pain Questionnaire  was usedFour quantitative sensory test measures were used to characterize patients' pain processing: (1) tactile detection threshold (TDT), (2) pressure pain threshold (PPT), (3) temporal summation of pain (TS), and (4) conditioned pain modulation (CPM).TDT was measured with a kit of twenty von Frey monofilaments . Monofilament was positioned perpendicularly to patients' skin and then a light pressure, sufficient to bend monofilament in a “U” format, was done . PatientTest was applied in two points bilaterally: (A) referent to the local of pain (primary hypoesthesia), located at the midpoint of paravertebral muscle belly, at the level of the third lumbar vertebrae and (B) distant point from pain area (secondary hypoesthesia), at the muscle belly of tibialis anterior muscle, at the level of tibialis anterior tuberosity . Three m2 . With algometer positioned perpendicularly to patients' tissue, a crescent pressure was done and patient was instructed to inform when pressure clearly became painful. An interval of one minute was done between each one of the three measures.In these same points and after TDT measures, PPT was evaluated with a pressure algometer with a probe area of 1 cm2 in a point 7,5 cm from wrist line. Pain intensity was asked verbally thru the 11-point numerical rating pain scale during the 1st, 10th, 20th, and 30th second of stimulation.TS was measured by applying a constant pressure of 4 kg/cmTo evaluate CPM, firstly, PPT was measured in the right forearm, 7,5 cm from wrist line. An ischemic compression of 270 mmHg was made in the contralateral arm with an sphygmomanometer  positioned 3 cm proximally to the cubital fossa, then patient opened and closed left hand 10 times. Pain intensity was asked and when it was equal or more than 4, PPT was measured in the right arm, during the ischemic compression. Five minutes after this procedure, PPT was again measured, now without compression.In all groups, patients were instructed not to take analgesics, anti-inflammatories, or opioids.Initially, data collected were transported to a spreadsheet in Excel for Windows 2010, where the descriptive statistics were performed, with measures of position  and dispersion (standard error of the mean). Subsequently, comparisons made between and within groups were made in the program Statistical Package for the Social Sciences (SPSS) version 16.0.All data were tested for normality by Shapiro-Wilk test. Categoric data were analyzed by qui-square test. In intragroup analysis, all variables were nonparametric and were analyzed by Wilcoxon test. When comparing groups, data that followed a normal distribution  were analyzed by ANOVA. All the other variables followed a nonnormal distribution and were analyzed using the Kruskal-Wallis test followed the Tukey post hoc test.In all comparisons, it was considered statistically significant difference when the p value of the analysis was less than 0.05. The values were expressed as mean and standard error of the mean.A total of 283 individuals were assessed for eligibility. 197 subjects were excluded because they did not met inclusion criteria or declined to participate. No significant differences were found between groups regarding demographic characteristics .Also, no significant differences (p≥0.05) were found in pain intensity or quantitative sensory testing responses when comparing electroacupuncture group to the three control groups . There wIn this study, electroacupuncture treatment could not change quantitative sensory testing responses in patients with chronic nonspecific low back pain. This treatment reduced pain intensity in both rest and movement; however it also occurred in CTR 1 and, curiously, in CTR3, where needle was immediately removed after puncture.According to the Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA), an extension of the CONSORT statement , this miDespite this, pain reduction in group CTR 3 may have happened not only because of the possible effect that minimal penetration can elicit, but also due to the placebo effect. Patient's beliefs that they might be receiving an active treatment can influence responsiveness of treatment such that, according to an overview of systematic reviews , some reSham and placebo procedures should be similar to real acupuncture and the ideal was that they still were physiologically inert. Meeting this both criteria is not easy for acupuncture studies . In our Conversely, an overview of systematic reviews and randomized clinical trials about noninvasive treatments for chronic low back pain found that acupuncture is associated with lower pain intensity than sham and no acupuncture, with moderate magnitude of effect and low strength of evidence for pain outcome . In thisOther systematic review  also attIn the present study, the addition of electrical current to needles was not superior to the other groups. A study by Napadow et al.  with a fIn the present study, it was expected to verify a reduction in both primary and secondary hyperalgesia, since a modulated frequency associating low stimulation frequencies, which reduce secondary hyperalgesia, while higher frequencies reduce primary hyperalgesia, was used .Nonetheless, even using modulated frequency in the present study, maybe ten sessions of electroacupuncture were not sufficient to reduce central sensitization. Studies have suggested that pain related to hypoesthesia is probably due to central plasticity, as a consequence of nociceptive activity  and MDT Interestingly, temporal summation of pain, a measure of central facilitation , had itsHowever, in general, electroacupuncture was not able to significantly alter quantitative sensory testing responses and diminish central sensitization in patients with chronic nonspecific low back pain in this study. Notably, there are a few noninvasive treatments with promising results for reducing central sensitization symptoms in musculoskeletal disorders, such as TENS  and exerIn the last years, most recent guidelines have been recommending self-management, active, physical, and psychological therapies, instead of surgical and pharmacological treatments. Acupuncture is suggested as second-line or adjunctive treatment option for some guidelines, but others do not recommend it at all , 29. HowTo our knowledge, this is the first randomized clinical trial that investigated the effect of electroacupuncture in central pathways of patients with chronic nonspecific low back pain. Hence, more efforts are needed to improve the internal and external validity of systematic reviews and randomized clinical trials about acupuncture and electroacupuncture in low back pain .Limitations of this study involve a lack of control group without receiving treatment, for example, waiting list. Also, a comparison with some usual care group should be interesting. Besides that, acupuncture and electroacupuncture have an individual approach. In clinical practice, acupuncture points are chosen according to individual/individuality characteristics. However, in trials with a mechanistic approach, as this study, standardization and methodological rigor are needed .Although ten sessions of electroacupuncture have diminished pain intensity in both resting and movement, it could not change significantly quantitative sensory testing and diminish central sensitization in patients with chronic nonspecific low back pain. The implications of this study involve the fact that, maybe, in chronic nonspecific low back pain, electroacupuncture should be associated with other treatments that target central sensitization.


Randomized, single-blinded, multi-center, parallel-group trial.To compare the effects of adding electrical dry needling into a program of manual therapy, exercise and ultrasound on pain, function and related-disability in individuals with plantar fasciitis (PF).The isolated application of electrical dry needling, manual therapy, exercise, and ultrasound has been found to be effective for PF. However, no previous study has investigated the combined effect of these interventions in this population.One hundred and eleven participants (n = 111) with plantar fasciitis were randomized to receive electrical dry needling, manual therapy, exercise and ultrasound (n = 58) or manual therapy, exercise and ultrasound (n = 53). The primary outcome was first-step pain in the morning as measured by the Numeric Pain Rating Scale (NPRS). Secondary outcomes included resting foot pain (NPRS), pain during activity (NPRS), the Lower Extremity Functional Scale (LEFS), the Foot Functional Index (FFI), medication intake, and the Global Rating of Change (GROC). The treatment period was 4 weeks with follow-up assessments at 1 week, 4 weeks, and 3 months after the first treatment session. Both groups received 6 sessions of impairment-based manual therapy directed to the lower limb, self-stretching of the plantar fascia and the Achilles tendon, strengthening exercises for the intrinsic muscles of the foot, and therapeutic ultrasound. In addition, the dry needling group also received 6 sessions of electrical dry needling using a standardized 8-point protocol for 20 minutes. The primary aim was examined with a 2-way mixed-model analysis of covariance (ANCOVA) with treatment group as the between-subjects variable and time as the within-subjects variable after adjusting for baseline outcomes.X2 = 9.512; P = 0.023) more patients in the electrical dry needling group completely stopped taking medication for their pain compared to the manual therapy, exercise and ultrasound group at 3 months. Based on the cutoff score of ≥+5 on the GROC, significantly  more patients within the electrical dry needling group  achieved a successful outcome compared to the manual therapy, exercise and ultrasound group . Effect sizes ranged from medium to large (0.53<SMD<0.85) at 3 months in favor of the electrical dry needling group.The 2X4 ANCOVA revealed that individuals with PF who received electrical dry needling, manual therapy, exercise and ultrasound experienced significantly greater improvements in first-step morning pain , resting foot pain , pain during activity , LEFS , FFI Pain Subscale , FFI Disability Subscale , and FFI Total Score  than those who received manual therapy, exercise and ultrasound at 3 months. No differences in FFI Activity Limitation Subscale  were observed. Significantly .Therapy, Level 1b. Plantar fasciitis (PF) is the most common cause of heel pain and is estimated to affect 10% of the general population during their lifetime. In 2007,PF is characterized by intense sharp pain over the medial plantar heel with intial steps in the morning or after inactivity, that increases with prolonged weightbearing activities., 20, 22 The Cochrane review on PF concluded that high quality evidence of efficacy for any one treatment modality is still lacking. MoreoverAdditionally, several needling approaches have been investigated for PF. For cases of persistent PF, physicians often recommend corticosteroid injections;, 31 howeAlthough the 2014 APTA clinical practice guidelines concludeIn the absence of high quality evidence for any one treatment modality, it may sThis randomized, single-blinded, multi-center, parallel-group trial compared two treatment protocols for the management of PF: manual therapy, exercise and ultrasound vs. manual therapy, exercise and ultrasound plus electrical dry needling. The primary end-point was first-step pain (when getting out of bed in the morning) as measured by the Numeric Pain Rating Scale (NPRS). Secondary outcomes were resting foot pain intensity (NPRS), pain during activity (NPRS), the Lower Extremity Functional Scale (LEFS), the Foot Functional Index (FFI), medication intake , and the Global Rating of Change (GROC).The current clinical trial was conducted following the Consolidated Standards of Reporting Trials (CONSORT) extension for pragmatic clinical trials.  The studFig 1has given written informed consent (as outlined in PLOS consent form) to publish a picture of their foot and lower leg.Consecutive individuals with PF from 10 outpatient physical therapy clinics in 6 different states  were screened for eligibility criteria and recruited over a 24-month period . For patients to be eligible, they had to meet the following criteria: 1, a clinical diagnosis of PF in accordance with the clinical practice guidelines from the Orthopaedic Section of the American Physical Therapy Association (APTA); 2, plantTen physical therapists  participated in the delivery of treatment for patients in this study. They had an average of 8.0 (SD 4.4) years of clinical experience, and all had completed a 54-hour post-graduate certification program that included practical training in electrical dry needling for PF. In addition, all physical therapists delivering treatment were Fellows-in-Training within the APTA-accredited American Academy of Manipulative Therapy Fellowship in Orthopaedic Manual Physical Therapy post-graduate program, and therefore received advanced clinical training in the diagnosis and treatment of PF. Similar to our previous study and to e1 nerve root impingement, fat pad atrophy, proximal plantar fibroma, fat pad contusion, calcaneal bone bruise, or calcaneal stress fractures. In  In ,[76], for the , for FFI , for FFI , for FFI Similar to the findings of the current study, another randomized controlled trial of patients with chronic PF reported a 69% reduction in foot pain and an 80% success rate following 10 sessions of electroacupuncture over 5 weeks targeting the most tender points over the medial plantar aspect of the calcaneus with 2 to 6 needles left in place for 30 minutes. LikewiseThe underlying mechanisms as to why the electrical dry needling group in the current study experienced greater improvements than the manual therapy, exercise and ultrasound alone group remains to be elucidated. However, mechanical and electric periosteal stimulation, peri-neural needling of the tibial and lateral plantar nerves, and the duration that the needles are left in situ may be important components to consider when using dry needling therapies in patients with PF.Although the etiology of PF remains unclear, the proximal attachment of the plantar aponeurosis at the medial tubercle of the calcaneus is most often reported by patients as the origin of symptoms and the site of greatest discomfort.–93 In faPeriosteal “pecking” or “peppering”, via mutliple penetrations with dry needles at or near the proximal attachment of the plantar fascia over the medial tubercle of the calcaneus, is intended to stimulate microtrauma and local inflammation, augment A number of peri-neural needle points were used with electric stimulation to target the posterior tibial nerve, medial plantar nerve, and lateral plantar nerve, which provide the sensory innervation to the plantar surface of the foot and the medial tubercle of the calcaneus. A recentAside from one cohort study that treated patients with PF with a single lidocaine injection in which the needle was immediately removed upon dispensing the injectate, other stElectrical dry needling (i.e. electroacupunture) has been found to cause the release of substance-P and CGRG predominantly from non-neural structures, facilitating a negative feedback loop to neural and neuroactive components of the target tissue., 109 In Major strengths of the current study include the inclusion of a large sample size with 10 treating physical therapists from 10 clinics in 6 different geographical states, and the use of the same standardized 8-point needling protocol and dosage paramenters. However, we only assessed mid-term follow-up; thus, we do not know if the significant between-groups differences observed at 3 months would be sustained in the long-term. We also cannot be certain that the results are generalizable to other dry needling protocols, dosages, techniques or needle placements. Additionally, we did not include a dry needling placebo group; which should be included in future studies. Lastly, therapist and patient treatment preferences were not collected and could potentially affect the results.The results of the current randomized clinical trial demonstrated that patients with PF who received manual therapy, exercise and ultrasound plus electrical dry needling experienced significantly greater improvements in first-step morning pain intensity, resting heel pain, pain during activity, function, related-disability and foot health-related quality of life, and medication intake as compared to the group that received manual therapy, exercise and ultrasound alone. Future studies should examine the effectiveness of different types and dosages of electrical dry needling and include a long-term follow-up.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.