A perfusion index change ratio of ≥0.27 was observed in group R , 0.636; p = 0.032). A perfusion index change ratio of ≥0.27 at 5 min after block is associated with, but does not predict improvement in, pain levels following lumbosacral transforaminal block.Transforaminal epidural injection is used to treat radicular pain. However, there is no objective method of assessing pain relief following transforaminal injection. Perfusion index is a metric for monitoring peripheral perfusion status. This study evaluates the correlation between perfusion index change and analgesic efficacy in transforaminal blocks for lumbosacral radicular pain. We retrospectively analyzed data of 100 patients receiving transforaminal block for lumbosacral radicular pain. We assessed perfusion index before treatment and at 5, 15, and 30 min following the block. We defined responders (group R) and non-responders (group N) as those with ≥50% and <50% pain reduction, respectively, 30 min following block. Clinical data and perfusion index of the groups were analyzed. Ninety-two patients were examined, of whom 57 (61.9%) and 35 (38.0%) patients reported ≥50% and <50% pain reduction, respectively. Group R had a significantly higher perfusion index change ratio 5 min following the block ( Epidural injection of local anesthetics and steroids is one of the most common methods of managing chronic low back pain and radicular pain ,2. Hyaluhttp://cris.nih.go.kr/cris/index.jsp, ref: KCT0003318).We retrospectively reviewed the electronic medical records of 100 patients with lumbosacral radicular pain who underwent transforaminal block from April to August 2018 at two tertiary care hospitals. The patients ranged in age from 20 to 83 years. All patients had low back pain and radicular pain for more than 3 months. The inclusion criteria were as follows: (a) a primary diagnosis of low back pain radiating to the lower limbs; (b) a diagnosis of spinal stenosis, herniated nucleus pulposus, and/or a degenerative spinal disorder on a cross sectional imaging study (either CT or MRI) of the lumbosacral spine. The exclusion criteria included lumbosacral epidural injection within the previous 2 weeks and any history of lumbosacral surgery, lumbosacral neuroplasty, neoplastic diseases, peripheral vascular disease, or use of medications affecting the vascular system. The lesion level for transforaminal injection was determined based on clinical manifestations, physical examination, and review of imaging studies. Lesion severity was categorized as one of three different degree levels  by reviewing imaging data. This study was approved by our departmental ethics committee (ref: SMC 2018-08-178) and registered with CRIS  was injected to confirm that the needle tip was appropriately placed in the epidural space. After confirming that the contrast had spread throughout the epidural space, a total volume of 5 mL  was infused. Following the procedure, patients were observed for any adverse effects. PI was monitored using pulse oximetry  on the toe of the affected limb. We assessed PI prior to treatment (T0), and at 5 (T5), 15 (T15), and 30 (T30) min following transforaminal injection. Temperature was assessed using a touch thermometer  on the dorsum of the foot of the affected limb. Room temperature was maintained at 23–25 °C. Pain was scored using a numerical rate scale  and cold sensation of the affected limb  was recorded at T10 and T30. PI, temperature, pain severity, and cold sensation at T0 were recorded after 5 min of bed rest and before skin infiltration with 1% lidocaine.All procedures were performed under fluoroscopic guidance and standardized. Patients were placed in the prone position, and anteroposterior and lateral view images were obtained with a C-arm  to ensure proper site of entry. Following aseptic preparation and application of 1% lidocaine, a 23-gauge Tuohy needle  was inserted into the skin surface over the upper quadrant of the target foramen. Aspirations to assess for the presence of blood or cerebrospinal fluid were routinely performed. When negative for aspirate, 0.5–2 mL of contrast medium . Data are expressed as the mean ± standard deviation (SD) or number (proportion), as appropriate. Demographic data for the two groups were compared using a Chi-square test, T-test or Fisher’s exact test. To minimize individual variance in PI absolute values, we calculated PI change ratios (PI at each time point—PI at T0/PI at T0) and temperature changes (temperature at each time point—temperature at T0) at T5, T15, and T30. The PI change ratios, temperature change, pain severity, and cold sensation over time were compared using the Wilcoxon rank sum test. In each group, the differences in PI change ratios over time were compared using a generalized estimating equations analysis. A receiver operating characteristic (ROC) curve was constructed to investigate the cut-off PI change ratio at T5 to correctly predict analgesic efficacy at the maximum area under the curve (AUC), which ranged from 0.5 to 1.0. A n = 6) or failed transforaminal injection due to epidural venogram (n = 2). Thus, a total of 92 patients were analyzed. We defined responders, or group R, as patients who showed a reduction of ≥50% on the numeric rate scale for pain, 30 min following the block, and non-responders, or group N, as those who showed a reduction of less than 50%. Demographic and clinical data are summarized in p = 0.029). There were no significant differences in PI change ratios over time in group R (p = 0.351) or in group N (p = 0.654). The ROC curve of PI change ratios at T5 is shown in p = 0.032). The change in temperature was not different between the two groups (Of the 100 patients assessed for eligibility, eight were excluded due to insufficient medical records (o groups . Cold seo groups . None ofLumbosacral radicular pain is caused by irritation or compression of the affected nerve root . It is cIn this study, we found that PI change ratios at T5 in group R were significantly higher compared with those in group N. We also found that a PI change ratio of ≥0.27 can be a useful marker of improvement of pain. The sensitivity of 75.4%, specificity of 51.4%, and AUC of 0.636 in the current study were relatively lower than these parameters in previous studies ,22,24,25This study had several limitations. First, we did not measure the PI of the contralateral limb. Second, we categorized patients using only a numerical rate scale. In addition, we did not include an evaluation of functional disability. Third, the follow-up period of 30 min was too short to sufficiently evaluate block efficacy. Joswig and colleagues  reportedThis study shows that PI change ratios are associated with successful pain relief following lumbosacral transforaminal block, with a PI change ratio of ≥0.27 at T5 reflecting an improvement in pain. PI change ratios can provide a simple and easy way of monitoring overall changes in pain levels, but they cannot predict improvement in pain owing to the low AUC. Future prospective randomized studies are needed to determine whether PI change ratios can provide superior diagnostic value in the long-term period after injection and for the treatment of other forms of chronic pain.


The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases.This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least − 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life.This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases.NCT02773966 (Registration date: 05/16/2016).Registered with ClinicalTrials.gov, number:  Due to optimized therapies, life expectancy of patients with metastasizing cancer will continue to rise. Bone metastases affect 10–30% of all cancer patients, especially those located in the vertebral column. The main clinical problems are severe back pain and an increased risk of pathological fractures. Therefore, optimized palliative treatments to improve quality of life are necessary.External beam radiotherapy (EBRT) is a well-established treatment option for patients with spinal metastases. EBRT results in adequate pain relief with acceptable local tumor control . Of the The two most common schemes are either 10 fractions of 3 Gy  or a single-shot irradiation with 8 Gy . Based oBalloon kyphoplasty is a valuable treatment option for patients with painful and instable metastases to the vertebral column. In the CAFE trial , 134 patHowever, kyphoplasty alone has no documented anticancer effect and thus EBRT is required to avoid early tumor regrowth. As this may take another 2–4 weeks , this prolonged treatment poses an unacceptable mental and physical challenge to patients. These considerations also apply for 1times 8Gy, albeit not that distinct. Moreover, patients with progressive or simultaneous  metastases may also urgently require chemotherapy, which cannot be applied concurrently to radiotherapy due to the risk of potentiated toxicity.p < .001) and a persistent pain reduction beyond the first postoperative day of ≥3 points in 34 (79.1%) patients. As the 3, 6, and 12 month local progression-free-survival (L-PFS) was excellent with 97.5, 93.8, and 93.8%, we set up this randomized phase III trial to investigate whether this new technology may have the potential to replace the current standard of care.To reduce treatment time and at the same time increase quality of life, novel techniques like kyphoplasty combined with  anticancer methods are required. Our group developed a novel approach to deliver intraoperative radiotherapy during kyphoplasty (Kypho-IORT) –10. In aThis protocol  describes a prospective, multicenter, randomized phase III study set up to assess pain reduction after Kypho-IORT (Arm A) or EBRT (Arm B) for spinal metastases  at the first post-interventional day (i.e. one day after Kypho-IORT in Arm A and one day after the begin of fractionated or single-shot EBRT in Arm B).percentage of patients with a pain reduction of at least 3 points on VAS at week 2 and 6 weeks after start of treatmentlocal tumor control, measured by longitudinal CT/MRI scans done at FUs by assigning one of the following lesion states: stable, osteoradionecrosis, pathological fracture, sintering progression, local relapsefrequency of re-intervention or salvage therapies to the treated sitesecondary fractures/sintering progressionoverall progression-free survivaladverse eventsincidence of cement leakage skin toxicity/wound healing, documented by regular imaging of the scarquality of life, assessed by completion of EORTC QLQ C30 and BM22 questionnairesSecondary objectives arePatients ≥50 years of age with up to 4 treatable vertebral metastases and a localized pain of VAS ≥ 3/10 are eligible to participate.Age ≥ 50 yearsKarnofsky Performance Index ≥60initial pain score (VAS) of at least 3 under standard pain medication (change of the pain medication will me monitored)documented history of cancer painful osteolytic metastases involving a maximum of 4 vertebrae of the thoracic/lumbar spine, which are accessible for Kypho-IORTwritten informed consentany prior treatment  of the target lesion(s)Lesions cranial to T3 Tumors infiltrating dorsal vertebral structures  or intraspinal  extensionpathologic fracture with sintering of > 50%purely osteoblastic/osteosclerotic metastasishigh likelihood for cement leakage (e.g. erosions of the bony borders of the vertebrae), which cannot be controlled otherwise by operating surgeonPregnancy/lactationAfter informed consent, all patients will be screened for inclusion and exclusion criteria and obtain a patient ID. A baseline visit will then be performed, which includes the assessment of the KPS and VAS scores, comorbidities and medication, a gross neurological exam, the documentation of the underlying primary cancer and the completion of the QoL questionnaires to obtain baselines. If not performed before, a CT or MRI scan of the spine will have to be performed. After fulfilment of all inclusion criteria and in the absence of exclusion criteria, patients will then be allocated into any of the two arms by block randomization (block sizes of 2 or 4 and stratification by institute). Patients randomized into Arm A will undergo Kypho-IORT, patients randomized into Arm B will undergo standard EBRT (10 × 3 Gy or 1 × 8 Gy).The intervention (Arm A or B) should begin within a time frame of 14 days after randomization.Kypho-IORT will be carried out under general anaesthesia as extensively described before –11. All The cement augmentation can be performed either as kyphoplasty or in a vertebroplasty technique. Each patient must receive early post-operative imaging of the treated vertebra to assess any leakage of cement. The direction of leakage and the clinical symptoms associated (symptomatic vs. asymptomatic) must be documented at this stage.Patients randomized into arm B will receive conventional external beam radiotherapy, either as fractionated radiotherapy with 30 Gy delivered in 10 fractions of 3 Gy or as single-dose irradiation with 8 Gy. Each center must select and adhere to one treatment option (fractionated or singe-dose irradiation). Radiotherapy can be given as per established local standards . Patients will need to be seen at least once weekly by physicians and evaluated for adverse reactions.Pain will be assessed at baseline (screening) and then at day 1 , week 2, and week 6 week after treatment and at each follow-up visit there will be an evaluation of pain intensity measured by the visual analogue scale (VAS) together with the current pain medication. Any re-intervention or salvage therapies to the treated site will be also documented.increase in size of osteolytic areasdevelopment of epidural diseaseprogressive sintering/fracture of the treated vertebral bodyAt each follow-up visit , there will be either a MRI or CT scan of the (complete) spine to determine the response of the treated lesion  and to monitor for new metastases to other regions of the spine . Local control is defined as time span between randomization and local progression. Local progression is assessed either by serial CT or MRI scanning. Indicators for local progression in CT scans are:increase in the T2-signalepidural diseaseOnce progression is suspected in CT scans, a contrast-enhanced MRI should be performed, whereas indicators of progression areIt has to be considered that MRI and PET may show false-positive signals when the time to surgery is less than 6 months, whereas an epidural disease is the clearest indicator. When in doubt the PI and the steering committee have to decide on the case.Overall progression-free survival is defined as time from randomization to any (confirmed) tumor progression or death by any cause.At day 1, week 2, week 6, month 3 and each 6 m follow-up visit, a physical examination of the surgical scar /irradiation field will be performed to grade any of the following toxicities: dermatitis radiation, wound infection, scar, pigmentation, telangiectasia or other skin toxicity. In case of any skin toxicities, a photo will be acquired. A neurological examination will be performed to detect paresthesia, sensory numbness, motor weakness and paresis. An adverse event (AE) is then defined as any unfavorable and unintended sign , symptom, or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure . Ongoing AEs will be followed until recovery. Wherever possible, adverse events will be reported on the basis of CTC-AE v4.0.A pre-existing disease or symptom  will not be considered an adverse event unless there will be an untoward change in its intensity, frequency or quality. This change will be documented by an investigator.Serious adverse events (SAEs) are defined as any event that is fatal, life threatening, causes or prolongs hospitalization; causes disability or incapacity or requires medical intervention to prevent permanent impairment or damage, or any grade 4 toxicity. Only SAEs that are judged to be related to surgery or irradiation by the local study center are reported.In case of death an autopsy should be done to clarify the cause of death.QoL will be determined using the EORTC quality of life C30 and the bone metastasis module questionnaire (EORTC-QLQ-C30/BM22). The questionnaires should be completed before.treatment and during follow-up visits. The questionnaires have 30 respectively 22 questions and require approx. 10 min to complete. Even if the patient progresses or recurs before the last scheduled QoL assessment, QoL forms should still be completed.This study is designed to test if the analgesic efficiency of Kypho-IORT is superior to standard-of-care EBRT in patients with painful vertebral metastases by comparing percentages of patients with a pain reduction of at least 3 points on VAS at defined points in time .Assuming a pain reduction of VAS-3 points at day one  for 40% of the patients after Kypho-IORT vs 5% of the patients after EBRT under standard pain medication (no change of the pretherapeutic pain medication 12 h after Kypho-IORT or 24 h after the first EBRT), the study will require 22 patients in each arm in order to have a two-sided alpha of 0.05 and a power of 0.817. Including a dropout rate of 20% at least 54 patients have to be recruited. The effect size was estimated on the basis of the results of the preceded phase I/II trial  and the Data will be analysed on an intention to treat basis. All variables will be described by descriptive statistics . The Chi-square test or Fisher’s exact test will be used for categorical data. For continuous data, parametric or non-parametric mean comparison tests will be used. The Kaplan-Meier method with log-rank tests will be used to estimate relapse-free survival and overall survival.The trial will be carried out in compliance with the protocol, the principles laid down in the declaration of Helsinki, version as of October 1996 , in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP), the harmonized standards for Medical Devices (ISO 14155) and all other applicable regulatory requirements . Standard medical care  remains in the responsibility of the treating physician of the patient. This study was approved by the local ethics committee  and the Federal Office of Radiation Protection (Z5–22462/2–2013-116). All patients participating in the study need to provide written informed consent at least 24 h prior to the intervention.The trial is registered with ClinicalTrials.gov, number NCT02773966.revocation of the patient’s declaration of informed consentlack of compliancediscontinuation of the therapy for other reasons deemed necessary by the responsible physician (e.g. unfavorable intraoperative geometry)Grade IV skin toxicity, i.e. skin necrosis that require surgical interventionGrade IV bone toxicity, i.e. aseptic bone necrosis that require surgical interventionGrade IV nervous system toxicity, i.e. paresisTreatment of the patient must be discontinued if one or more of the following criteria apply:When therapy is discontinued, the reasons for discontinuing patient participation in the study must be listed in the patient’s file.The steering committee is allowed to close the study ahead of schedule.insufficient patient recruitmentunexpectedly severe toxicities (second Grade IV toxicity within the study)unexpected findings which prevent the continuation of the study for ethical and/or medical reasons Other termination criteria include:Kypho-IORT is a technically feasible new treatment option that provided immediate pain relief, structural stability and excellent local tumor control without severe side effects in a phase I/II trial . As the EBRT is an integral part of local therapy, but, as seen in several studies pain control is achieved in weeks (or even months) . In the


Despite numerous guidelines, nearly one of two patients with cancer pain remains undertreated, thereby affecting their quality of life. Active patient involvement through Therapeutic Patient Education (TPE) is considered as a relevant strategy to overcoming hurdles in pain management. The aim of the EFFADOL study is to assess the effectiveness of a TPE program in improving cancer pain management.The EFFADOL study is a stepped-wedge randomised controlled trial. A total of 260 cancer patients with unbalanced background pain will be randomised over the institutional level, i.e. stepped-wedge cluster design. Six clusters will be formed, one at the regional level of “Basse-Normandie” for patients receiving the educational approach by health providers already trained to TPE. Then, five additional centers will be gradually included at the national level, making it possible to compare the “conventional” management of pain  with the educational approach (after being trained). The main study parameter is pain interference on daily life assessed with the self-administrated and validated Brief Pain Inventory questionnaire. Secondary objectives comprised the evaluation of patients’ adherence to pain education program, the description of pain intensity, pain relief, analgesic adherence and pain emotional impact. Educational dimension of the program will be evaluated through the patients’ acquisition of knowledge and skills about their pain and treatment as well as their self-efficacy to participate actively in pain management. The patient’s feeling of pain changes will be measured. Finally, the satisfaction of participants and educators will be reported. We hypothetise active involvement of patients in TPE will lead to an improved pain management compared to standard care.Analyzing the impact of a TPE program in cancer pain patients will improve their pain management and quality of life. We expect that the dissemination of our project educational approach through the French territory will be accompanied by long term change in clinical practices with mutual benefit to patients and caregiver-educators.NCT03297723, registered: 09/28/2017.Protocol version: Version n°1.1 dated from 2016/09/08. Pain remains a prevalent symptom in patients with cancer despite the availability of opioids and current guidelines . Based oThe management of cancer pain encounters various obstacles, including patient-related barriers , 6 such Active patient involvement through Therapeutic Patient Education (TPE) is considered as a relevant strategy to overcoming obstacles in cancer pain management . TPE, asEnsemble, Faire FAce à la DOuLeur”), structured in 5 successive phases, each of them briefly described in the paper developing the EFFADOL combined approach from practice to research ),Among the other criteria (assessed only in PEP group), emotional repercussions will be assessed by the Hospital Anxiety and Depression Scale , a regional body whose particular mission is to harmonise TPE practices and their evaluation . The queThe assessment of the program and its benefits for patients will be also conducted with the caregiver-educators. It will evaluate the PEP impact on the educational team in terms of functioning, changes in practices and incorporation with the offer of local care, including communication with the attending physician.Patients’ relatives willing to participate to the PEP will have their own QoL evaluated by a self-questionnaire specifically developed in oncology and validated in French . AnalgeThe main judgement criterion in this study is the impact of pain on daily activities measured with the BPI. A score will be established by averaging the response on the 7 items of the subscale 9. The benefit of TPE on the impact of pain will be defined as a 2-point-decrease  between the values measured before and at the end of the PEP (at 8 weeks after inclusion). A 2-point decrease on the BPI scale correspond to a clinically significant improvement .The first secondary endpoint is the proportion of patients adhering to the whole PEP (3 sessions), adherence being defined as the achievement of these 3 sessions for patients who undertook to follow them.Other secondary endpoints are based on:- Pain intensity and relief (BPI), its impact on QoL , qualitative characteristics of pain (QDSA) and pain adherence.- Patient’s knowledge and skills about pain, patient’s self-efficacy to actively manage pain, patient-reported impression of improvement.- Participants’ satisfaction and educators’ satisfaction with PEP.The calculation of the number of subjects needed for statistical significance is based on the main judgement criterion and on the first secondary endpoint.To meet the first primary objective (Step 5 of the study) building on a stepped-wedge design, the calculation of needed number of patients is based on a ≥ 2-point decrease of the mean score of the BPI subscale 9 at 8 weeks after inclusion, in the experimental PEP group compared to the control group . The calculation takes into account that randomisation is done by clusters (patients belonging to a same cluster are not independent). Based on bilateral test and common-factor variances  it is estimated that 45 patients per arm equitably distributed between the 6 clusters, for a total of 90 assessable patients . It will be therefore possible to compare, at the region scale, the effect of TPE implementation on daily activities.To meet to the objective of the Step 4, the judgement criterion is the proportion of patients recruited in Basse-Normandie area adhering to the whole PEP.0 = 0.70, p1 = 0.85, α = 5%, and β = 10%, 80 patients are necessary  in order to best characterize adhesion to the PEP in the region .Overall, 230 evaluable patients are required; it is therefore planned to recruit 260 patients in order to anticipate some non-assessable patients.At every stage of the analysis, exploratory data will provide, for quantitative variables, mean, its standard deviation, median, quartiles, and missing data; for qualitative variables, frequencies and 95% confidence interval. Statistical tests and confidence intervals will be calculated with an overall error significance level of 5%. For the main objective (Step 5), statistical analysis will be done on the per-protocol population: it will concern assessable patients who have completed the whole program .Pain interference with daily life scores at 8 weeks post inclusion will be first compared between experimental PEP group and control group, in consideration of the correlation of data .For the first secondary objective (Step 4), patients’ adherence to the PEP at the regional scale will be assessed using one-sided test comparing a proportion to a reference value.For all the steps, a global analysis will be performed, taking into account the different periods of the study, clusters, and the care provided for each period, using a generalized linear mixed model for scales scores and for qualitative results obtained from questionnaires. This analysis will be adjusted to the patients’ demographic and clinical characteristics.The choice of the BPI subscale 9 as main endpoint is based on different scientific arguments.Cronbach alpha reliability ranges from 0.77 to 0.91). It has been translated and validated in French [BPI-sf is one of the most widely used pain assessment instrument. Besides pain severity, this questionnaire evaluates the impact on interference. The IMMPACT  panel recommended that this criterion should be included in all chronic-pain clinical trials , 34. Thin French  and the n French .Nearly one of two patients with cancer pain is undertreated . PatientIn this context, we developed a 5-step project responding to some objectives of the regional health policy and of to third French cancer plan . The conIn clinical trials, RCT are considered the gold standard of evaluation and as such are mainly used to validate the impact of PEP , 38. TheThis paper therefore presents the design of a stepped-wedge cluster randomised controlled trial to investigate the effectiveness of TPE in improving cancer pain self-management. The impact and benefit of PEP will be evaluated by comparing the educational approach and the “conventional” management of pain.The most commonly used criteria to evaluate pain improvement in PEP is pain intensity . NeverthWe also took a special interest in educational specifically addressed parameters. Besides patients’ knowledge and attitudes, patients’ communication skills and active participation in their pain management will be assessed.Satisfaction with treatment might act as a contributor to other outcomes and encourages patient involvement in pain management. Patient satisfaction with cancer pain care strongly correlates with retrospective ratings of overall improvement . PatientIn addition, evaluation of participants’ and educators’ satisfaction with the program will be used to further optimize the latter by adjusting the followed procedures in necessary.In conclusion, the originality and strength of this project are based on collaborative work between healthcare professionals and a research approach building on robust methodologies that seek to demonstrate the effectiveness of TPE in improving the patients’ skill in cancer pain management. Dissemination of this educational approach  will likely be accompanied by a long term change in practices that should provide mutual benefit to patients and caregiver-educators.Besides the benefit of PEP for individuals, cancer pain is a national challenge and better managing it is a major public health issue. In this regard, TPE, by giving an impetus to changing patterns of behaviors and attitudes, constitutes an asset to allow better assessment, treatment, and understanding of the problem.


Attachment theory provides a useful framework for understanding individual differences in pain patients, especially with insecure attachment shown to be more prevalent in chronic pain patients compared to the general population. Nevertheless, there is little evidence of attachment-informed treatment approaches for this population. The present study compares outcomes from two different attachment-informed treatment modalities for clinicians, with outcomes from treatment as usual (TAU). In both intervention groups (IG1 and IG2), clinicians received bi-monthly training sessions on attachment. Additionally, clinicians in IG1 had access to the attachment diagnostics of their patients. All treatments lasted for four weeks and included a 6-month follow up. A total of 374 chronic pain patients were recruited to participate in this study (TAU = 159/IG1 = 163/IG2 = 52). Analyses were carried out using multilevel modeling with pain intensity as the outcome variable. Additionally, working alliance was tested as a mediator of treatment efficacy. The study was registered under the trial number DRKS00008715 on the German Clinical Trials Register (DRKS). Findings show that while IG2 was efficient in enhancing treatment outcomes, IG1 did not outperform TAU. In IG2, working alliance was a mediator of outcome. Results of the present study indicate that attachment-informed treatment of chronic pain can enhance existing interdisciplinary pain therapies; however, caveats are discussed. Chronic pain syndromes are a result of complex interactions between biological, psychological, and social influences, including patients’ beliefs about their self-efficacy, hypervigilant monitoring of bodily sensations, and familial conflict or social support ,2,3. DueAttachment theory provides a useful framework to classify patients’ relatively stable cognitive, emotional, and behavioral response styles to stressors (such as pain). These attachment-related response styles, or attachment patterns, have been linked to disease processes in general ,6,7,8 anBased on their dominant response patterns, adults can be classified into one of four attachment styles—one secure style, and the three insecure styles: dismissing, preoccupied, and fearful ,13 see . AttachmEvidence in the pain literature suggests that these attachment styles relate to patients’ stress response, beliefs about their ability to cope with the experience of pain, perceptions of the pain as threatening, and specific interaction patterns with partners and health care personnel ,17. In gGiven available evidence, it is likely that insecurely attached patients have different needs in terms of both their relationship with the clinician and the treatment . Example(1)Patients in IG1 and IG2, who both receive an attachment-informed multidisciplinary treatment, will report a larger mean reduction in pain intensity between pre-treatment, post-treatment, and follow-up assessments than patients in the TAU group who receive state-of-the-art multidisciplinary treatment.(2)As the interventions (IG1 and IG2) are specifically designed to improve the working alliance, we expect higher ratings for the working alliance in IG1 and IG2 compared to TAU.(3)The quality of the working alliance will be the core mechanism of change in IG1 and IG2; that is, it will be the mediating variable between intervention and outcome.(4)As patients with higher levels of insecure attachment might not profit from the alliance in the same way as securely attached patients, we expect this mediation effect to be moderated by insecure attachment.In the present study, clinicians in a four-week interdisciplinary multimodal pain treatment program at the Heidelberg Orthopedic Hospital, Heidelberg University Clinic, were trained in: attachment theory, attachment-related individual differences, related clinical implications, and suggestions for building a meaningful working alliance. This training was expected to facilitate the attainment of the program’s aims by enhancing the working alliance, the therapists’ ability to provide a secure base for patients, and the therapists’ understanding and support of their patients’ individual attachment-based motivations and needs. The aims of this study were to examine whether: (a) there is a main effect of group (two attachment-informed groups (IG1 and IG2) versus treatment as usual (TAU)) on treatment outcome; (b) group effect is mediated by working alliance; and (c) working alliance is moderated by insecure attachment. The main hypotheses are that:Of the 545 patients attending the Heidelberg Orthopedic Hospital, University Clinic Heidelberg, between March 2012 and January 2016, 127 patients did not meet the inclusion criteria to be treated in the clinic (see below) and another 44 patients declined to participate. Therefore, a total of 374 (68.6%) were recruited to this study. As seen in the flow chart in All participants were enrolled as day-clinic patients in the orthopedic clinic of the Heidelberg University Hospital, and participated in a four-week outpatient multidisciplinary pain treatment program, including physiotherapy, occupational therapy, music and dance therapy, and individual and group psychotherapy. To attend this clinic they must: (1) have experienced chronic pain for at least six months, for which pain intensity, location, and spreading was not fully explained by specific somatic pathology; (2) be between 18 and 80 years of age; (3) have previously received standard treatment consisting of at least one rehabilitation program or two inpatient treatments, which did not yield lasting effects; and (4) have a diagnosis of somatoform disorder according to DSM-IV. In order to check whether or not these inclusion criteria were fulfilled, comprehensive diagnostic imaging and examination by an orthopedic specialist was conducted, as well as an interview with the structured clinical interview for DSM-IV (SCID) by a trained psychologist.High C-Reactive Protein (CRP) levels as an indicator of rheumatoid arthritis;Acute inflammation of the spine;A tumor;A diagnosis of psychosis;A diagnosis of a bipolar or neurological disorder;Insufficient ability to communicate in German.Exclusion criteria were:Use of medication was discouraged throughout the treatment, and the number of patients taking opioids or equivalent drugs in the outpatient clinic was very low (only 8.6%). While information regarding medication usage (including antidepressants and antiepileptics) was gathered at all time-points, it was not part of the exclusion criteria.All study procedures were approved by the Institutional Ethics Review Board of the Medical Faculty, University of Heidelberg. All procedures were in accord with the newest version of the Declaration of Helsinki , as wellAfter a briefing about the study procedures and aims, all participating patients provided written consent. The study was conducted in a block design with three patient groups  and three assessments times  general directions for building a meaningful working alliance; and (b) guidelines for the clinicians to enable them to tailor treatment to the specific needs of individual patient attachment styles and behaviors. More attachment-related training sessions, alternating with supervision meetings, were held on a monthly basis to assist clinicians in the practical application of this approach during interventions for the second (IG1) and third (IG2) study samples. Further, “situations” , which are perceived to be critical for forming a working alliance, were discussed at the weekly meetings. These situations were subsequently used to structure case discussions in the bi-monthly 90-min training sessions.The only difference between the IG1 and IG2 interventions was that, in IG1 only, weekly team meetings incorporated case reviews with discussion regarding the attachment diagnostics  of each patient. The IG2 group also had weekly team meetings, but the clinicians were not informed about the specific attachment style of each patient. Instead, it was expected that after receiving the attachment-based training sessions, the team would be more sensitive to the individual attachment behavior of patients without knowing the specific attachment style.The interdisciplinary multimodal pain therapy provided to the patients in the TAU group consisted of an intensive, structured interdisciplinary program provided in an outpatient setting with five hours of treatment per day, five days per week, for four weeks. The treatment included physiotherapy, occupational therapy, psychotherapy, and medical treatments in both individual and group modalities. Additionally, patients could participate in Nordic walking and dance and music therapy, as well as relaxation training and guided physical activity supervised by physiotherapists.not aim to modify underlying insecure attachment patterns, which would have been unrealistic within four weeks in this setting.In the attachment-informed approach, the same clinicians received training about attachment theory and attachment-informed treatment principles . The priThe motive-orientated working alliance (former known as complementary therapeutic relationship)  informedIn the interdisciplinary setting, it was necessary that the attachment-based approach be readily employed by healthcare professionals with diverse professional backgrounds ; therefore, all guidelines needed to be easily incorporated into all professional approaches.Current pain was assessed by a VAS, asking the patients to rate their acute pain during the present day on a scale ranging from 0 to 100. Similarly, average pain over the previous week was assessed using a visual analogue scale ranging from 0 to 100. For rating purposes these scales were collapsed to indicate values between 0 and 10. Visual analogue scales have been proven to provide a valid and reliable way of measuring chronic and acute pain ,42. VAS The Oswestry Low Back Pain Disability Questionnaire is a self-report measure of the functional disability of the patients and consists of 10 items assessing pain and disability in specific contexts of life to measure functional disability due to pain . The iteThe ECR-RD12 is a German short version of the ECR-RD scale, which has previously revealed very good internal consistency . The ECThe TSEB is a self-report questionnaire with 35 items, which assesses various facets of the working alliance specifically designed for day-clinic patients . Seven sd = 0.5, a power analysis was computed for an ICC of 0.2 for three time-points. According to the power analysis, 95% power was achieved at a group size of n = 160. Unfortunately, due to the nature of the block design and complications in recruitment, IG2 had only n = 52 willing participants. Thus, IG2 was underpowered at only 51% power.SPSS 22  was usedp > 0.001 for the χ2 value of the Mahalanobis distance as a measure of multivariate outliers, no outliers were identified.The data contained 9.82% missing values. The group of complete cases did not differ from the group with missing values on one or more variables in mean or standard deviation on any variable of interest. All analyses were conducted assuming the data was missing at random (MAR). Under MAR, observation missingness is assumed to be unrelated to the dependent variable at dropout . MultiplHLM7 software was used for multilevel modeling . We usedSince there was prior evidence from another study conducted at the Orthopedic Hospital that patient trajectories would be markedly different during treatment as opposed to during follow up, we decided to use a piecewise modeling approach. In the earlier study, symptoms declined steeply during treatment, and started increasing again during follow up. Change in each piece of the model was estimated using the technique outlined by Smith and colleagues  by proviFull maximum likelihood was used as the estimator in all models. Significance values and standard errors for fixed effects were computed using Kenward-Roger approximation . PlottinTo test mediation and moderated mediation effects, we used PROCESS macro version 2.11 for SPSS version 22.0 . For theIn terms of descriptive statistics, there were no significant differences between the three groups in terms of the core study variables see .p < 0.05), in favor of IG2 (see p < 0.05), patients with high attachment anxiety achieved the lowest scores of pain at follow-up  = −1.78, p = 0.08), although this effect did not reach significance.Concerning Hypothesis 1, the conditional model including average pain as the outcome variable showed no difference between either IG1 or IG2 to TAU at post-treatment see  but a si IG2 see . Additio IG2 see . While hAlthough there was no significant difference between TAU and the two intervention conditions, mediational analyses were conducted to see if there was an indirect effect of treatment condition on outcome by working alliance, as specified in Hypotheses 2 and 3. For these models we used a dummy variable as the independent variable comparing IG2 with TAU . IG2 was compared to TAU, since previous analysis hinted that these groups provided the greatest potential to explore this mediation effect by way of being conceptually different and also boasting bigger outcome differences than IG1 vs. TAU. The working alliance with team score provided by the TSEB was introduced as the mediator. For outcome variables we used the estimated score at post-treatment and at follow-up, as well as the slope (weekly rate of change) of pain intensity, leading to a total of six mediation analyses.p < 0.01). Patients in IG2 revealed a TSEB score of an estimated 0.23 units higher than patients in the control group. Furthermore, TSEB scores were significantly related with average pain at follow-up  = −2.183, p = 0.03) and the weekly rate of change in average pain  = −2.227, p = 0.03). Overall, the indirect effect of treatment condition by TSEB scores was significant for average pain at the end of follow-up, but not for the weekly rate of change in average pain.Regardless of the model, the treatment condition was significantly related to scores at TSEB  = 2.003, p < 0.05) and the weekly rate of change in current pain  = −2.075, p = 0.04). There was a significant indirect effect of treatment by TSEB scores on current pain at the end of follow-up; however, the indirect effect of treatment by TSEB scores on weekly change in current pain was not significant. On the other hand, there was no significant direct effect of treatment on current pain at follow-up  = −0.616, p = 0.54) or in current pain weekly change  = −0.596, p = 0.55).In the mediational models for current pain, we again found that TSEB scores were significantly related with current pain at the end of follow-up  = −1.986, p < 0.01) and the weekly change in average pain  = 2.650, p < 0.01).We conducted moderated mediational effects analysis to check if the mediational effects reported (indirect effect of treatment by TSEB scores) were, in turn, moderated by patient attachment pattern (Hypothesis 4). As presented in In summary, the mediation analysis indicated a difference in pain reduction between IG2 and TAU that is mediated by working alliance, measured by the TSEB. This effect, in turn, is dependent on attachment insecurity, as shown in not informed of patient attachment style, outperformed IG1, where therapists knew the attachment styles. Thus, this additional knowledge seemed to have had an adverse effect. There are a number of possible explanations for this phenomenon. Most likely, with therapists at the IG1 stage being new to attachment theory, they will have been consolidating information and gaining new perspectives throughout the IG1 stage, which would presumably support practice during IG2. The clinicians in IG1 may have felt overwhelmed, having access to a large amount of new information and to the patients’ attachment style, and trying to integrate these components “on the job”. The changed role of the therapist, in which they serve as a form of substitute attachment figure for the patients that has to attune to each individual attachment pattern by addressing the specifically related needs [The primary aim of this study was to examine whether providing attachment-informed training to clinicians in an interdisciplinary pain program could influence pain outcomes compared to treatment as usual (TAU). According to Hypothesis 1, it was anticipated that this would be the case. Results only partially supported this hypothesis, however. Patients in IG2 reported a larger mean reduction in average pain intensity between pre-treatment and post-treatment assessments compared to patients in both IG1 and TAU groups. Perhaps surprisingly, IG2, in which therapists were ed needs , also taThe interdisciplinary pain therapy includes physical activation, improvement of mobility, the ability to relax, occupational therapy, psychological pain management, reduction of pain killer intake, and coping-related interventions. An ordinary treatment can last up to 4 weeks for a full-time intensive outpatient treatment. Due to the limited time available, it is generally very difficult to build a stable and trusting work-alliance between the therapist and the patient to allow the patient to properly take in the content of the therapy. Even though it is much harder for insecure patients to establish and maintain a stable and trusting working alliance ,65, the The second hypothesis was that the intervention groups (IG1 and IG2) would produce stronger average working alliances compared to TAU. This was partly supported, with patients in IG2 reporting significantly better working alliances compared to those in TAU. Working alliances for patients in IG1 did not differ from those in TAU.The third hypothesis suggested that the quality of the working alliance would be the core mechanism of change in IG1 and IG2 . As expected, working alliance was found to be a strong mediator between the intervention effect and treatment outcome, suggesting that training staff in attachment theory and its implications for people in pain can help to improve the working alliance, and therefore strengthen outcomes. This is consistent with expectations based on parent-infant attachment-based interventions, where training in attachment theory enhanced maternal-sensitivity and infant-security . LiteratAs expected in Hypothesis 4, the link between working alliance and pain outcome was moderated by insecure attachment. Patients with higher levels of insecure attachment reported poorer working alliances compared to securely attached patients, with implications for pain outcome. This finding was evident despite attachment-informed intervention provided in this study, suggesting that this intervention did not counter the effects of attachment insecurity on pain outcome. While anticipated, based on previous research, this finding suggests the need for attachment-informed modifications to treatment that extends beyond the therapeutic alliance. The mentalization-based approach  has beenFindings support working alliance as a mechanism of change linked to patient attachment. Nevertheless, the path model also indicated that the insecure patients in IG2 were the only insecure patients who did not experience deteriorations in pain during the post-treatment phase. Although the mean difference in pain at the 30-week follow-up was non-significant, this trend hints at the attachment-specific training having a positive effect on post-treatment adjustment to pain ,77. The The primary limitation for this study can be found in the study design. The block design was chosen even though the optimal design for the study would have been a randomized controlled trial (RCT), with patients being randomly assigned to one of the treatment arms with separate groups of treating clinicians. However, this was not feasible in this orthopedic hospital setting. The very limited number of clinicians working at the outpatient department would have made it impossible to divide the clinicians into more than one interdisciplinary pain treatment at a time. A future study replicating the results of the current study might use a multicenter trial in order to control for spillover effects, while providing an adequate number of clinicians for an RCT design.Another limitation is the failure to control for therapist adherence to the treatment guidelines. While the clinicians were regularly asked during the weekly team meeting whether or not they implemented the training contents into their treatment routine, no adherence data is available. Future studies might profit from development of an intervention manual with clearly defined treatment characteristics and working mechanisms to support development of systematic adherence ratings. These might then be ascertained either from expert rated videos of therapy sessions, or a comparable approach, such as a manualized adherence rating. This information could be used as a control variable or descriptively to support interpretation of findings.While the main objective of the present study was to compare the three treatments, i.e., investigating between-person effects, we were also interested in the trajectories of treatment over time in our treatment groups. The short duration of the treatment combined with relatively long assessments at each measurement point has resulted in having only the minimum number of time points needed for longitudinal modeling. This, combined with large standard errors for our estimates of within-person effects, render low levels of certainty in those estimates. For future studies of multimodal pain therapies with attachment focus, a shorter assessment battery with more time points is needed to properly investigate the trajectories in patients’ symptoms over time.t-tests across dropouts and non-dropouts suggest that dropout is not systematically related to outcome, the question remains why the dropout at T3 was so high. Although significant effects between treatments were found, the results of the present study need to be replicated in a future study with all treatment arms being powered equally.A further methodological issue is the sample size of IG2 and the high dropout rate at follow-up across all treatment arms. While the non-significant Finally, the intervention was provided over only a four-week period. If adapted for longer outpatient settings, more pronounced differences may be seen over time as, hypothetically, attachment patterns might slowly alter over the course of therapy, increasing the positive effect of the working alliance on pain over time.The results of the present study provide preliminary support for the utility of incorporating attachment-informed interventions with existing multimodal pain therapies in short-term outpatient settings. Although the clinicians trained in the attachment-informed treatment only had four weeks to implement the treatment, this approach was more effective in reducing perceived pain intensity in IG2 relative to TAU. Findings suggest that one reason for this was the facilitation of a more stable working alliance between the therapist and the patient in the attachment-informed treatment. Findings also suggest that classifying patients into one of the four attachment categories prior to treatment may not be needed to build a stable working alliance. As a result of this study, a number of needs are identified. First, there is a need for a written manual with a detailed description of the intervention to support clinicians to adhere to and integrate the new techniques of the intervention into their daily treatment routine. Second, based on this manual, measures of treatment adherence by clinicians should be developed. Finally, more in-depth attachment-informed treatments should be developed, manualized, and evaluated. It is anticipated that these steps will contribute to even greater and more lasting clinical improvements, especially for those with insecure attachment patterns.


To compare the effects of high-intensity laser therapy (HILT) and a combination of transcutaneous nerve stimulation (TENS) with ultrasound (US) therapy on pain and functionality in patients with chronic lumbar radiculopathy.This prospective randomized comparative study was conducted in Department of physical medicine and rehabilitation, Turgut Ozal Medicine Center, Malatya, Turkey from April 2016 to September 2016. A total of 54 patients with chronic lumbar radiculopathy were enrolled in this study. The patients were randomly divided into two groups: Group 1 (n:27) received 10 sessions of a combination of hot pack, TENS, US and exercise, and Group 2 (n:27) received hot pack, HILT and exercise. The outcomes measured were low back with unilateral leg pain level measured by visual analog scale (VAS) and functionality measured with the Oswestry Disability Index (ODI) at the end of the therapy and four weeks later. p-value less than 0.05 considered statistically significant.In two groups, VAS  and ODI scores showed significant changes. At the end of the 2 weeks intervention, participants in Group-1 showed a significantly greater decrease in pain than participants in Group-2. Statistically significant differences in pain variation and functionality (VAS and ODI) were observed four weeks after treatment sessions for participants in the TENS+US therapy group compared with participants in the HILT group.HILT and TENS+US combined with exercise were effective treatment modalities in decreasing the VAS and ODI scores. TENS+US combined with exercises were more effective than HILT combined with exercise. Low back pain is one of the most common musculo-skeletal system pains that cause loss of work power and negatively affects quality of life. The prevalence of low back pain, observed in every culture and ethnic group, is reported as nearly 84%.2Discogenic low back pain, whether accompanied by radicular symptoms or not, is one of the common causes of low back pain.4Laser is a pain-free and non-invasive treatment modality.11In the literature there is no consensus on the application duration, pulse power, energy dose and frequency to be used for laser treatment of patients. There are a few studies to date on the effects of HILT therapy on cervical radiculopathy, frozen shoulder, lateral epicondylitis, carpal tunnel syndrome, myofascial pain syndrome, low back pain, gonarthrosis, post-mastectomy and lumbar discopathy pain.13There are studies in the literature showing the efficacy of physical therapy modalities and HILT in patients with chronic low back pain.In this study we aimed to compare TENS and Ultrasound combination, commonly used in routine practice, with the new non-invasive treatment method of HILT in terms of effects on pain and functionality for patients with chronic lumbar radiculopathy. At the same time, we aimed to suggest an appropriate and effective treatment proposal for patients with chronic lomber radiculopathy for HILT, which is one of the new treatment options.This prospective single-blind randomized study included patients, visiting the Department of Physical Medicine and Rehabilitation, Turgut Ozal Medicine Center, Malatya, Turkey from three 3 months low back with unilateral leg pain and clinical signs of radicular lesion in dermatomal distribution and/or myotomal muscle weakness and/or diminished reflexes in lower limbs. Lumbar spinal root pressure was detected by MRI.The local hospital ethics committee approved the study. Patients agreeing to participate in the study provided an informed consent form. Exclusion criteria for the study were previous history of spinal surgery, sequestrated disk hernia on MRI, steroid injection and/or physical therapy for the lumbar region within the last four weeks, inflammatory rheumatic disease, cardiac pacemaker, continuing or previous malignancy history and pregnancy.Patients included in the study were randomly divided into two groups. The patients in Group 1 had a total of 10 sessions of hot pack, TENS and ultrasound treatment applied over two weeks for five days each week. Patients had hot pack applied to the lumbar paravertebral area for 20 minutes, along with TENS application in conventional mode for 20 minutes at 70 Hz frequency and 100 microsecond wave length. Later again in the lumbar paravertebral region, patients had therapeutic ultrasound treatment of 1.3 watt/cm2 power, 1 mHz frequency applied with a US device (BTL-4825S Kombi Topline) for 10 minutes continuously.The second group had high intensity laser device (BTL 6000) used after 20 minutes hot pack application for five days per week over two weeks for a total of 10 sessions of high intensity laser treatment. The device was set to 25 Hz frequency, 10 watt power with 12 j/cm2 dosage to the lumbar region over 25 cm2 area for four minutes biostimulation mode, followed by continuous mode for 6 minutes with 7 watt power and 120 j/cm2 dosage.In addition, an isometric lumbar exercise program was initiated by the same physiotherapist to be performed with five repetitions in each set (modified straightening and pelvic tilt exercises) in Groups-1 and 2 during the therapy duration. The repetitions of both sets were increased up to ten, provided that this did not increase the patient’s pain.The patients were assessed with the visual analog scale (VAS) for low back with unilateral leg pain at rest, when moving and at night. Accordingly on a 10 cm line, the 0 point was accepted as no pain while the 10 point was accepted as maximum pain. Patients were asked to indicate the severity of low back pain on this line. Later the distance between the 0 point and the marked point was measured with a ruler.This comprises 10 questions assessing pain, personal care, lifting, walking, sitting, standing, sleeping, social life, travel and degree of pain variation, with each scored from 0 to 5. Maximum points are 50 and total score is multiplied by two to provide a percentage result. The evaluation is made with the formula: point/total score (50) x 100 = %. This form used to assess treatment results and compare different treatments in chronic low back pain patients and Turkish validity and reliability has been proven.17The pateints were assessed by the same blinded doctor before treatment, after treatment and four weeks later for pain with VAS and for functional state with ODI. Flow diagram of the study has been given It was calculated that a total of 54 individuals should be taken, with at least 27 subjects from each group when α = 0.05 and 1-β = 0.80 were taken in the power analysis performed.For statistical analysis of research data, SPSS for Windows version 17.0 software was used. Data related to quantitative variables are given as arithmetic mean ± standard deviation (sd) and min-max, while data related to qualitative variables are given as number (n) and percentage (%). The one-way ANOVA test was used for comparisons of the parametric continuous data. The Kruskal-Wallis test was used for the nonparametric continuous data. A repeated measures ANOVA was used to analyze the changes in variables. Significant differences were determined by Bonferroni post hoc tests. A value of p<0.05 was accepted as statistically significant.2 in Group-1 and 26.7±3.65 kg/m2 in Group 2. There was no difference between the two groups in terms of age and BMI (p>0.05). In terms of pain duration, there was no difference between the two groups   consisted of 27 patients with mean age 50.14±15.55, while Group 2 (HP+HILT) consisted of 27 patients with mean age 53.40±10.57 years. The female/male distribution was 20/7 in Group-1 and 16/11 in Group 2, while BMI was 26.9±3.65 kg/m p>0.05) .The VAS and ODI scores were similar in the two groups before treatment (p>0.05) . The comAssessment of the two groups at the end of treatment and 1 month after treatment found that the moving VAS score and ODI score were statistically significantly lower in Group 1 (HP+TENS+US) (p<0.05) .In this present study, patients with chronic lumbar radiculopathy in the high intensity laser treatment (HILT) and ultrasound (US) with transcutaneous nerve stimulation (TENS) combination groups were compared in terms of VAS scores and Oswestry Disability Index (ODI) score. In the two groups, VAS and ODI scores showed significant changes. However, patients receiving TENS+US treatment had a greater reduction in VAS scores and ODI score at the end of treatment and 1 month later compared to the HILT group.In recent years, high intensity laser treatment has been used for a wide range of painful conditions. The efficacy of the pulsed Nd:YAG laser has been proven in the treatment of many musculoskeletal diseases and it is believed to have anti-inflammatory, anti-edema, analgesic, and reparative effects.202 to the L1-S1 region three times per week after conservative treatment for four weeks. The response to treatment was assessed with VAS and ODI scores before treatment and after treatment and they concluded that the addition of HILT treatment to conservative treatment was more effective on pain and function for chronic low back pain patients. However, the low number of patients in the groups and the lack of assessment of long term efficacy of treatment were given as limitations of the study.21A recent study by Choi et al. randomly divided patients with chronic low back pain into two groups. One group received conservative treatment (HP+TENS+US), while the other group received 10 minutes of HILT with 1378 mJ/ cmA study by Fiore et al. compared the efficacy of high intensity laser treatment and ultrasound for patients with low back pain.23Non-pharmacological methods including a variety of physical therapy agents are the cornerstone of management of chronic low back pain. Therapeutic ultrasound (US) is among the commonly used physical modalities for treating soft tissue injuries. There is some evidence that therapeutic ultrasound has a small effect on improving low-back function in the short term, but this benefit is unlikely to be clinically important. Evidence from comparisons between other treatments and therapeutic ultrasound for chronic low back pain were indeterminate and generally of low quality.The results of this study show that in addition to the TENS and US combination, among physical therapy agents ensuring reduction in pain and disability for chronic low back pain patients, the new modality HILT treatment is effective; however it was concluded that there is a need for long term monitoring and controlled studies.Small number of patients because of economic reasons, the lack of evaluation of long term results and the lack of a control group.EK, RB and FE conceived, designed and did statistical analysis & editing of manuscript.EK and RB did data collection and manuscript writing.SA and YE did review and final approval of manuscript.


Post Mastectomy Pain Syndrome (PMPS) is a common postoperative condition for breast cancer, but has been ignored. The aim of this study was to investigate the prevalence of PMPS and the risk factors in women submitted to surgical treatment for breast cancer. The study included 532 postoperative breast cancer patients in a hospital for five consecutive years period, of whom 473 were considered eligible and included in the study. A total of 420 people completed a questionnaire survey, which revealed that 152 (36.2%) had ever suffered from PMPS and 18 (11.8%) sought treatment. Of the patients with PMPS, 34 (22.4%) had a history of chronic pain. Patients with PMPS were younger than patients without PMPS (50.5 ± 10.4 vs 53.5 ± 11.1). Univariate analysis showed that age, history of chronic pain, tumor staging, number of lymphadenectomy were significantly different between the two groups. Multivariate analysis shows that age and history of chronic pain were independent risk factors. The incidence of PMPS in postoperative breast cancer patients can reach 36.2%, and age as well as previous history of pain are independent risk factors for PMPS. The combination of prevention and treatment may be an effective way to reduce PMPS. About 255180 people were diagnosed with breast cancer in the United States in 20172. In China, breast cancer is the most common cancer among women and expected to account for 15% of all new cancers in women3. Mastectomy remains the main treatment for breast cancer, and nearly 37–40% of women with breast cancer receive the surgery4. About 20–68% of these patients experience post-mastectomy pain syndrome (PMPS), which is characterised as a dull, burning and aching sensation in the anterior chest, arm and axilla and exacerbated by movement of the shoulder girdle, continues more than three months after the surgical procedure5. PMPS seriously affects the physiological, psychological and quality of life of breast cancer patients6, and these patients are a large group and should attract our attention.Breast cancer is the most frequently diagnosed cancer globally and the leading cause of cancer-related death in women7, and early studies underestimated the incidence of PMPS for a variety of reasons. Although there is no uniform standard for its incidence, most studies have indicated that its incidence is high. Still, many doctors do not think it is a common symptom and ignore its prevention and treatment. A large number of patients with PMPS who have sought outpatient consultation did not know that there are treatment methods available and never were treated for the pain. Many gave up the idea that their pain could be alleviated8. Although some surgeons engaged in breast cancer practice recognized the incidence and duration of PMPS, sufficient treatment had not been provided to the patients, and the treatment effects were insufficient9.It has been decades since the first case of PMPS was reportedPMPS’s research in China is lagging and neglected. Due to the differences in race, disease prevalence, surgical techniques, and timing of surgery, it is necessary to study the prevalence and risk factors of PMPS in China. The aim of this study was to investigate the prevalence of PMPS and the risk factors in women submitted to surgical treatment for breast cancer.The experimental design was a retrospective study. We investigated all breast cancer patients who underwent mastectomy in the Guangxi Zhuang Autonomous Region Second People’s Hospital between January 2011 and December 2016. Patients who had experienced any of the following were excluded from the study: male patients, preoperative pain around the affected breast, bilateral breast cancer, with an operation history, with mental illness and unable to communicate. Patients who met the requirements were informed of the purpose of the study and informed consent was obtained from all participants. The study was approved by the ethics committee of the Guangxi Zhuang Autonomous Region Second People’s hospital. The methods involved in the study were carried out in accordance with the relevant guidelines and regulations.The definition of PMPS was based on the results of previous studies and pre-experiments, which included the following three criteria: character of the pain should be typical of neuropathic pain, such as numbness, needle, burning; location of pain should be in the ipsilateral axilla, arm, shoulder or chest wall; timing of the pain lasted more than three months.Relevant data was collected from medical record. Risk factors such as residence , marital status, occupation, education, preoperative body mass index, tumor staging, surgical procedure, lymph node dissection, chemotherapy, chemotherapy regimen, hormone therapy, were recorded.A self-designed questionnaire based on the Short-Form of McGill Pain Questionnaire (SF-MPQ) was used to survey the patients involved. The questionnaire determines whether postoperative pain exists or not. For patients with postoperative pain, duration of pain, pain grading, characteristic of pain and location of pain were recorded. Only those postoperative pain that meet the three criteria we have defined, as mentioned above, are considered PMPS. A body chart is attached to the questionnaire, on which participants can mark the pain position directly to avoid ambiguity. The contents of the investigation also included: aggravation or not when moving shoulder, intervention or not, relief or not after intervention, and impact or not on life.The survey was conducted by the trained professionals who instructed participants to complete the questionnaire. Patients included in this study received a telephone interview to be informed the purpose of the study. Further study can be carried out with the consent of the patient. Then, a questionnaire with a cover letter and a stamped addressed reply envelope be sent to the patients. Those patients who failed to respond within two weeks were contacted again for reasons, if necessary, mailed the questionnaire again or inquired to complete the questionnaire on telephone. And some patients completed questionnaires at outpatient visits. Pilot studies of these procedures and of the questionnaire were undertaken prior to the main study.Statistical computations were performed in SPSS 24.0. The measurement data were expressed as mean ± standard deviation, the counting data were expressed as examples and percentages, and the t test and chi-square test were carried out respectively. Factors with statistical significance in univariate analysis were included in Logistic multivariate regression analysis. P < 0.05 was considered as statistically significant.All data generated or analysed during this research are included in this published article.A total of 532 patients underwent mastectomy procedures in our hospital over a six year period, 473 patients met the requirements and were sent questionnaires. 420 questionnaires were completed, and the reasons for not completing the questionnaire included: 1. The patient died, 2. The patient could not complete the questionnaire, 3. The patient or his family did not cooperate with the questionnaire 4. The patient could not be reached. The following analysis was based on the 420 questionnaires. The vast majority of which were total mastectomy (96.4%); Excision of pectoralis major and/or pectoralis minor in 10 cases (2.4%); Four patients underwent a second operation in six years; The number of patients with PMPS was 152 (36.2%).The age ranged from 32 to 80 years old, the average age of 52.4 ± 11.0 years. The urban population was 168 and the rural population was 252, representing 40.0% and 60.0% respectively. The number of people with higher education was 190 (45.2%), and those without higher education was 230 (54.8%). 358 (85.2%) were currently married and 62 (14.8%) without spouses. 167 (39.8%) were unemployed, and the remaining 253 (60.2%) had full-time or part-time jobs. 66 (15.7%) patients had a history of chronic pain. 162 (38.6%) patients were at an early stage, while 258 (61.4%) in advanced stages. The number of lymph nodes removed ≥15 in 264 (62.9%) patients and <15 in the remaining 156 (37.1%) patients. Postoperative complications appeared in 42 (10%) patients. 377 (88.8%) received chemotherapy before and/or after surgery. 67 (16.0%) received radiotherapy prior to and/or after surgery. 272 (64.8%) took hormonotherapy before and/or after surgery.  patients reported the pain at this location. Chest wall pain was also more common, 49 (32.2%) patients reported pain at the location. There were 26 (17.1%) cases of ipsilateral arm pain, and 8 (5.3%) cases of pain in multiple location. Pain was characterized by numbness in 73 (48.0%) and burning in 45 (29.6%), followed by stabbing in 28 (18.4%) and Other indescribable pain in 6 (3.9%). In 47 (30.9%) cases, it was reported that pain could be aggravated by moving upper limbs, clothing friction, or tiredness. The duration of pain was quite different, from 3 months to more than a year. The pain in 26 (17.1%) patients was persistent, while the rest was intermittent. The frequency of occurrence also varied greatly, from 1 per month to more than 10 per month. 18 (11.8%) sought treatment, of which 12 took painkillers and 6 received physical therapy.There were 152 people reported postoperative pain consistent with the definition based on the characteristics, location, and time of pain. Another 83 had postoperative pain, which did not fit the PMPS definition. In the patients with PMPS, 22.4% (34/152) had a history of chronic pain, while in the patients without PMPS, the proportion was 11.9% (32/268). Patients with PMPS (average age 50.5 ± 10.4) were younger than patients without PMPS (average age 53.5 ± 11.1). In the patients with PMPS, the proportion of patient in advanced stage was 67.8% (103/152), while 57.8% (155/268) in those without PMPS. 106 (69.7%) patients removed more than 15 lymph nodes in the patients with PMPS, and 158 (59.0%) in those without PMPS.Univariate analysis showed that age, history of chronic pain, tumor staging, number of lymphadenectomy were significantly different between the two groups. The four factors were analyzed by Logistic step regression analysis and the difference was significant in history of chronic pain and age . It was indicated that the history of chronic pain and age has a great influence on the onset of PMPS, and was an independence risk factor for PMPS.  is believed to be implicated in both PMPS and permanent loss of sensory function in the region supplied26. The ICBN is a nerve classically originating from the lateral cutaneous branch of the second intercostal nerve and the most commonly injured nerve during mastectomy27. However, omission of axillary staging is not an appropriate approach to modifying pain risk, for the risks of omitting axillary nodal sampling include increasing the number of patients who are understaged and undertreated and who experience reduced survival28. Instead, modification of surgical procedures related to axillary dissection constitutes a promising stand-alone target for risk reduction. Preservation of the ICBN is an effective way to reduce PMPS29 and should be factored into operative plans. Differences in the neural division result in the fact that this method is not always effective, sometimes, nerves which are successfully identified and protected can still present with postoperative complications. It was noted that six months following the procedure, 20% of patients who had successful ICBN preservation still experienced numbness and paresthesia. Sentinel lymph node biopsy, rather than standard axillary treatment, may reduce the risk of chronic pain after breast cancer surgery with no increase rates of axillary relapse30 and be recommended for patients with early-stage breast cancer, followed by dissection only if the biopsy result is positive31.Axillary lymph node dissection is necessary in breast cancer surgery, irrespective of which type of operation is elected. Axillary lymph node dissection is associated with PMPS, which has been found in this and previous studies9. However, they might also work for neuropathic pain, because central sensitisation can be prevented by aggressive early pain relief32. In addition, epidural or regional blockade of the afferent input to the central nervous system can achieve similar effects, but unlike COX inhibitors, has a remarkable effect on reducing the incidence of PMPS in one year after operation34. Antidepressants and antiepileptic drugs have also been used in the treatment of PMPS and promising results have been obtained in the reduction of PMPS with perioperative administration of venlafaxine35 or gabapentin36. Instead of for inflammatory pain, these treatments are for neuropathic pain. Other studies found venlafaxine or gabapentin can only improved acute postoperative pain and further data were needed on reducing chronic postoperative pain38. Some physiotherapy, including acupuncture39, laser therapy40, autologous fat grafting41, etc., have also been used in the treatment of PMPS and achieved some results. Importantly, future studies of the effect of preventive analgesia on the risk of PMPS should focus on the completeness and appropriateness of the intervention rather than on the timing of analgesia.Facing such a high incidence, PMPS should not continue to be ignored by patients and doctors. Preservation of the intercostal brachial nerve could decrease chronic pain and the use of sentinel lymph node biopsy could reduce the need for axillary dissection and thereby intercostal nerve damage. COX inhibitors, which are considered not suitable for preventing neuropathic pain, can only alleviate the postoperative inflammatory painThe limitations of this study are its consideration of patients only at a single center, a retrospective study, nonrandomized design, and a relatively small sample size. Further high-quality, prospective, multicenter studies were necessary to fully elucidate the incidence.The incidence of PMPS in postoperative breast cancer patients can reach 36%, which should get doctors’ attention. Age and previous history of pain are independent risk factors for PMPS and the patients with younger age or a history of chronic pain women may be at a higher risk of developing PMPS. The number of PMPS patients treated is limited, and surgeons should give patients undergoing breast cancer surgery more information about PMPS and actively provide effective treatment.


However, the N1 and the N2-P2 amplitudes' night/day ratios after foot stimulation were increased in patients, as compared to controls . These results suggest that RLS patients present circadian modifications in the pain system, which are not present in healthy controls. Both sensory-discriminative and affective-emotional components of pain experience show parallel changes. This study confirms the structural integrity of Aδ nociceptive system in idiopathic RLS, but it also suggests that RLS patients present circadian modifications in the pain system. These findings could potentially help clinicians and contribute to identify new therapeutic approaches.Restless legs syndrome (RLS) is characterized by unpleasant sensations generally localized to legs, associated with an urge to move. A likely pathogenetic mechanism is a central dopaminergic dysfunction. The exact role of pain system is unclear. The purpose of the study was to investigate the nociceptive pathways in idiopathic RLS patients. We enrolled 11 patients  suffering from severe, primary RLS. We recorded scalp laser-evoked potentials (LEPs) to stimulation of different sites (hands and feet) and during two different time conditions (daytime and nighttime). Finally, we compared the results with a matched control group of healthy subjects. The A Idiopathic restless legs syndrome (RLS) is a large prevalent chronic sensory-motor disorder  and it iAlthough there is no agreement about the prevalence of pain in RLS, some RLS patients describe their sensations as painful . InvolveThe exact role of pain system in RLS is unclear and only few studies addressed this issue. In patients with RLS, both primary and secondary to large fiber neuropathy, Schattschneider et al. found an impairment of thermal perception threshold suggesting a small fiber involvement . Another2 laser pulses delivered on the skin activate the nociceptive Aδ and C fibers, without any stimulation of the nonnociceptive Aβ afferents [Laser-evoked potential (LEP) recording represents the most reliable neurophysiological technique to assess the human nociceptive system function (evidence level A) . CO2 lasfferents .To the best of our knowledge, only one previous study assessed the nociceptive function in RLS by using LEPs . No abnoThe aims of the present study were to investigate (1) the function of the A∂-fiber pathway in idiopathic RLS patients by recording LEPs to stimulation of different sites (hands and feet) and (2) possible modifications of the nociceptive system excitability linked to the circadian rhythm of the disease. To reach this purpose, LEPs were recorded at two different times (early afternoon and nighttime).We enrolled 11 patients . RLS diagnosis was reached by using a structured interview following the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria [Inclusion criteria were (1) primary RLS, (2) severe symptoms , (3) exclusive or prevalent involvement of lower limbs, and (4) presence of a definite circadian pattern of symptoms. Exclusion criteria were (1) other movement disorders, (2) other sleep disorders, (3) neurological or medical disease, (4) any condition associated with chronic musculoskeletal or neuropathic pain, (5) intake of dopamine agonists, antidopaminergic, as well as other neurological active drugs , (6) any condition possibly causing secondary RLS , and (7) history of alcohol or drug abuse. All patients underwent full medical and neurological examination and neurophysiological tests, including measurements of nerve conduction, somatosensory-evoked potentials, motor-evoked potentials during daytime and overnight, and laboratory-based polysomnography. The main clinical data concerning the patients are summarized in In both patients and controls, LEP recordings were performed in two separate sessions: daytime session  and nighttime session . LEPs were obtained to stimulation of both hand and foot. Right and left sides were stimulated. Two averages of 20 trials each were obtained for each session and each stimulation site.2 laser . The stimulation site was visualized by a He-Ne laser beam.During LEP recording, the subject lay on a couch in a warm and semidarkened room. Cutaneous heat stimuli were delivered by a COμV at any recording channel, including EOG. In order to ensure that the attention level of subjects did not change across the whole experiment, they were asked to count the number of the received laser stimuli silently. Any recording with a counting mistake higher than 10% would not be considered for further analysis.The location of the impact on the skin was slightly shifted between two successive stimuli to avoid the sensitization of the nociceptors. The sensory threshold (STh), defined as the lower stimulus intensity eliciting a distinct pinprick sensation, was determined by the method of limits in three series of increasing and decreasing stimulus intensities. To record LEPs, we used an intensity set at 2.5x STh , which was felt as a painful pinprick by all the subjects. The interstimulus interval (ISI) varied randomly between 8 and 12 seconds. All subjects underwent a standard recording session simultaneously gathered from 3 scalp electrodes placed on Fz, Cz, and contralateral temporal region (T3 or T4), defined according to the 10–20 International System of EEG recording. The reference electrode was placed at the nose and the ground on the forehead (Fpz). Eye movements and eye blinks were monitored by electro-oculogram (EOG). Signals were amplified, filtered (bandpass 0.3–70 Hz), and stored for offline average and analysis. The analysis time was 1000 milliseconds with a bin width of 2 milliseconds. An automatic artifact rejection system excluded from the average procedure all trials contaminated by transients exceeding ±65 After each LEP recording, all subjects were asked to rate laser pain by using a 101-point visual analog scale (VAS), in which “0” corresponded to no pain and “100” to the worst pain one may conceive.Scalp LEPs include two main components: (1) the N1 potential, which is recorded in the temporal region contralateral to the stimulated side, and (2) the N2-P2 complex, which shows its maximal amplitude on the vertex (Cz). For all LEP components, peak latencies were measured. The peak-to-peak N2-P2 amplitude was measured. Because in labeling the N1 reponse a certain difficulty may be caused by noise, the N1 amplitude was calculated offline by referring the temporal electrode contralateral to the stimulated side (T3 or T4) to the Fz lead .The following variables were included in the statistical analysis: VAS score, latencies, and amplitudes of N1, N2, and P2 potentials. All measures were compared between groups and within groups. Comparison between groups (patients vs. controls) was performed for each site of stimulation (hands and feet) and each stimulation session (day and night). Moreover, within each group (patients and controls), we compared the results of daytime vs. nighttime trials for each site of stimulation (hands and feet). Lastly, in order to evaluate modifications of the latencies and amplitudes of all LEP components between the sessions and compare these modifications between patients and controls, all neurophysiologic measures obtained in nighttime session were expressed as percentages of the corresponding values recorded in daytime session, according to the formula:U-test) were applied to comparisons between nonnormal distributed parameters; lastly, the parametric Student's t-test, or the one-way analysis of variance (ANOVA) was used to compare normal distributed variables.The statistical analysis was performed in successive steps. First, the normality of the distribution of all variables by means of the Shapiro–Wilk's test was verified; then, nonparametric tests  controls during day vs. controls during night, (2) patients during day vs. patients during night, (3) controls vs. patients during day, and (4) controls vs. patients during night; therefore, the significance level was set at p=0.05/4=0.0125). Statistics were performed using the SYSTAT 12 software, version 12.02.00 for Windows® (copyright SYSTAT® Software Inc. 2007).The significance level was set at U-test =21.0; p = 0.009) and hand stimulation  during night session.The mean VAS pain rating scores obtained in day and night sessions in patients and controls are reported in Nerve conduction study, somatosensory-evoked potentials, and motor-evoked potentials were normal in all RLS patients and controls. Polysomnographic data are consistent with a severe RLS in all patients; in particular, all patients showed high sleep-onset latency .Within-groups (day vs. night) and between-groups (controls vs. patients) comparisons of LEP latencies and amplitudes did not show significant differences     and sensory (dysesthesia) [Impairment of the nociceptive system in RLS has been hypothesized and investigated . The onlsthesia) .not sufficient to explain the variations seen in clinical pain.” In a more recent study with repeated sessions of LEP recordings in normal subjects, LEPs latencies did not show significant modifications in nocturnal versus diurnal recordings [Circadian oscillations in the pain system function are debated in healthy subjects. While a number of human studies on experimental pain documented significant circadian variation in pain perception, other studies failed in documenting any clinically relevant circadian variation in pain perception . In a pscordings . Our fincordings .On the other hand, circadian rhythms in the occurrence and intensity of pain may be present in various pathologic conditions, such as migraine, rheumatoid arthritis, toothache, cancer, and intractable pain . Also, iOur RLS patients showed higher LEP amplitude and higher pain perception to foot stimulation during the night than during the day session. These circadian amplitude modifications involved both the N1 and N2-P2 responses. Intracerebral LEP recordings demonstrated that the N1 potential is generated in the secondary somatosensory area (SII area) , while tIn RLS, the circadian variations of the symptoms are probably related to the molecular mechanisms involved in its development. There are 3 main hypotheses to explain the sensory symptom fluctuations. First, dopaminergic systems play a major role in RLS. Dopaminergic projections to the spinal cord originate supraspinally in dorsoposterior hypothalamic area A11 . The A11We have to mention a limitation of our study. Indeed, most our patients showed a high periodic limb movement (PLM) index. Therefore, we cannot be sure to what extent our findings could be related to PLM, rather than to RLS. However, PLM have been found in 80–89% of RLS patients ; thus, tδ nociceptive system in idiopathic RLS. However, RLS patients show an abnormal circadian modification of Aδ-fiber pathway excitability, possibly due to an impairment of the hypothalamic dopaminergic projections to the spinal cord.To the best of our knowledge, this is the first study evaluating nociceptive system in RLS patients, according to the circadian pattern of the symptoms. Our study confirms the structural integrity of A