In addition, a reduction of absolute power in the low-frequency band of HRV (t(13) = 2.536, p = 0.025) was detected. These findings indicate that this intervention may reduce pain intensity and modulate associated physiological parameters. As these results are limited by several factors, e.g., a small sample size and no control group, they should be validated in further studies investigating this novel intervention in these patients.Patients with chronic pain report reduced quality of life and high symptom burden while often responding insufficiently to treatment options. Mirror therapy has been proven to be effective in treating phantom limb pain and other conditions such as CRPS. This study was designed to investigate the efficacy of mirror therapy in patients with somatoform pain disorders on symptom severity and associated physiological parameters. Fifteen patients with persistent somatoform pain disorder (F45.40) or chronic pain disorder with somatic and psychological factors (F45.41) participated and received four weeks of tablet-based mirror therapy. Symptom severity was measured with established questionnaires, and their thermal detection, pain thresholds, and heart rate variability (HRV) were also assessed. After mirror therapy, pain intensity was reduced ( The prevalence of chronic pain in the general population is estimated to be as high as 40–50 percent ,2 and poIn accordance with ICD-10-GM . In addiPatients are generally treated using a multimodal treatment approach that can include pharmacological options, psychotherapy, mindfulness-based or biofeedback interventions, and exercise ,13,14,15Mirror therapy is an interventional treatment that was initially intended for patients with phantom limb pain ,19 but iTo the best of our knowledge, there has been no investigation into the efficacy of mirror therapy for patients with chronic somatoform pain disorders. As chronic pain disorders are often accompanied by distinct autonomous and physiological differences, such as abnormal autonomous functioning  and alteThe analysis of HRV is a powerful tool for investigating the central regulation of autonomic activity via the sympathetic (SNS) and parasympathetic (PNS) nervous systems . It alloIncreased sensitivity to painful stimuli has been found in several chronic pain conditions ,37, and The study was designed to provide preliminary evidence of the potential efficacy of mirror therapy in a clinical sample of patients with chronic somatoform pain disorders. First, this interventional study aimed to experimentally measure the change in pain intensity before and after using mirror therapy. To find out whether potential improvements were not only reflected in the changes in the self-reported pain intensity but also in more objective parameters, such as HRV and thermal pain thresholds, in which these patients presented distinct alterations, we secondly assessed pain sensitivity to painful stimuli before and after using mirror therapy. We, therefore, expected that if changes in the thermal thresholds occurred, the direction of the effect would be towards a reduced sensitivity to painful stimuli. Third, we examined if possible changes in the self-reported pain intensity were also reflected in alterations of the objective physiological measure of HRV. Here, our hypothesis was that if the pain symptoms were reduced by the intervention, the high-frequency and low-frequency HRV would increase and decrease, respectively.n = 15) patients with persistent somatoform pain disorder (ICD-10-GM: F45.40) or chronic pain disorder with somatic and psychological factors (F45.41) were enrolled in this study. All patients who presented at the Outpatient Clinic to the attending physician and had the necessary diagnosis were contacted individually by the study personnel and evaluated for their suitability to participate in the study. Participating patients were diagnosed by the attending physician according to ICD-10-GM and continued their respective individual multimodal treatment during their participation in the study. To reduce the variability in the data of pain symptoms and physiological parameters due to individual patient treatments , these were not allowed to change during participation in the study, and no new therapeutic treatment was allowed to be started.Patients were consecutively recruited from 2019 to 2021 at the Outpatient Clinic for Psychosomatic Medicine at the University Hospital Tübingen. Fifteen . Patients with the mentioned medications were excluded due to their effect on the autonomic nervous system. While other medications may also have an effect on cardiac functioning, we focused on the medications that have a clear adrenergic effect, for example, beta-antagonists show definite altering effects on HRV metrics [All measurements of this study were performed in the autonomous function laboratory of the Department of Psychosomatic Medicine at the University Hospital Tübingen. Baseline characteristics and demographics of the study sample were assessed at the beginning of mirror therapy (T0) digitally via a tablet. At the beginning of this first measurement session, the patients were informed about the study and its design and, afterwards, gave their informed consent for participation. Psychometric (questionnaires), physiological (HRV), and psychophysical  measurements were taken before (T0) and after (T1) the execution of the mirror therapy program. HRV measurements were obtained before measuring thermal detection and pain thresholds. At the end of the first measurement session, the patients were introduced to and familiarized with the mirror therapy program. During the four-week interval (between T0 and T1), the patients performed guided mirror therapy using a tablet at home for a duration of 15 min each day. All psychometric parameters  were assessed digitally with a tablet.In the first sessions, mirror therapy and its implementation were introduced and explained to all subjects by qualified study personnel. The therapy regimen consisted of separate exercises for the upper and lower limbs of the pain-dominant side of the body and were executed by the patients at home. Mirror therapy has been shown to be effective not only when performed in a clinic but also in a home-based setting, with patients showing high adherence to the regimen ,42,43. TThe exercises consisted mainly of fine motor tasks in which the extremities had to be moved precisely and unerringly. For example, number points seen in the mirror had to be traced in the correct order, the limbs had to be moved sensibly with or against the clock hand, or certain figures had to be traced. Lower limb exercises were carried out with the tablet utilizing its onboard camera system to reflect the patients’ own movements as conceptualized by a mirror . ExercisThe psychometric data collection was based on validated questionnaires and consisted of the German Pain Questionnaire (DSF), which is routinely used in clinical applications.current pain intensity and average as well as the greatest pain intensity during the last four weeks. With the exception of the wellbeing score, the following applies: the higher the corresponding values of the DSF scores, the higher the degree of impairment. High scores on the scale of wellbeing indicate higher functioning, i.e., habitual wellbeing.The DSF of the German pain association contains a detailed acquisition of subjective pain symptoms, severity, and associated restriction . In addiHeart rate variability (HRV) was recorded before testing the thermal detection and pain thresholds with eMotion Faros 180° . HRV data analysis was performed with Kubios HRV Premium . HRV was assessed during a five-minute sitting resting period in which participants were verbally instructed to relax and not talk or move (as described in ). The daThermal detection and pain thresholds were measured separately for cold and warm/hot stimuli with the Thermal Sensory Analyzer , overall resulting in four separate measurements. Using a thermode (3 × 3 cm) on the measured center of the volar forearms, the patients received thermal stimuli with an initial temperature of 32 °C. To avoid testing both cold and hot stimuli on the same area, we applied cold stimuli to the left and warm/hot stimuli to the right forearm. No patient presented with pain in the forearm region. The temperature was increased or decreased by steps of 1 °C/sec (according to the testing protocol in ). The stp < 0.05 for all statistical analyses.Statistical analysis was performed with SPSS Version 27.0.1.0  and R VeThe DSF included an assessment of pain characteristics at the first measurement session (T0) to allow for a description of the history of pain symptoms and their qualities in the study sample. The baseline characteristics and demographic data of the study sample are shown in Concerning the pain symptom duration of the fifteen patients, four patients (26.67%) reported having pain symptoms for more than five years, six patients (40%) had been experiencing their pain symptoms for two to five years, three patients (20%) reported a duration of one to two years, and two patients (13.3%) reported a duration of their pain symptoms for six months to a year.The patients were also questioned about their pain profile, i.e., if the pain was more experienced in the form of attacks or in a continuous manner, and if there were pain-free intervals or fluctuations in severity. Four patients (26.7%) reported having primarily pain attacks with pain persisting in between, one patient (6.67%) was also having pain attacks, but with pain-free intervals in between the attacks. Six patients (40%) reported having mainly continuous pain with severe fluctuations, and four patients (26.7%) were also having continuous pain but with only slight fluctuations.The main pain complaints of the patients were primarily localized in the back  and the upper extremities . The lower extremities , thorax , and head  were less often reported. As required by the inclusion criteria, the stated pain complaints were lateralized, i.e., they only appeared or were predominant on one side of the body.z = −2.878, p = 0.004, t(14) = 3.850, p = 0.002, p = 0.058, p = 0.070, z = −1.121, p = 0.262, ps > 0.05, A comparison of the DSF pain intensity scale before (T0) and after (T1) mirror therapy showed a significant reduction  = 8.638, p = 0.003, R2 = 0.702), with the following significant predictors: comorbidity depressive disorder  = 3.674, p = 0.004), disability (DSF)  = −2.476, p = 0.031), and depression (DASS)  = −2.710, p = 0.020), indicating that patients with depression as a comorbidity had a greater reduction in pain intensity compared to patients with somatoform pain disorder without depression. The model also suggests that patients with lower levels of disability and depressive symptoms at baseline may have been a predictor for a greater reduction in pain intensity. A visual inspection of the model residuals with a Q-Q plot indicated no violation of the assumption of normal distribution.The stepwise regression method used to identify the variables that predicted the improvement of pain symptoms yielded an overall significant regression model (t(13) = 2.536, p = 0.025, t(13) = 0.169, p = 0.868, ps > 0.05; Analysis of the parameters of HRV showed a decrease in the absolute power in the low-frequency band after the completion of mirror therapy  and after (T1) the therapy regimen  mirror therapy led to significantly reduced pain levels after four weeks of intervention, where, specifically, the average pain intensity in patients was reduced; (ii) the absolute power but not the normalized power of HRV in the low-level band was significantly decreased after the performance of mirror therapy; (iii) pain sensitivity to only cold painful stimuli increased after four weeks of mirror therapy; and (iv) patients with comorbid depressive disorder particularly benefitted, regarding pain reduction, from the mirror therapy.The overall pain intensity, as measured by the respective DSF scale, was significantly reduced through the therapy program. Our results are in line with studies on CRPS, which demonstrated the efficacy of the mirror beyond phantom limb pain ,60. The We also found that the cold pain threshold values were significantly increased after mirror therapy compared to the thresholds at baseline. This suggests that patients in this study became more sensitive to painful cold stimuli after completion of the therapy program. Achenbach et al.  conducteOur final finding was the reduction of absolute power in the low-frequency band of HRV. Previous research has shown that patients with somatic symptom disorders and functional somatic syndromes can show reduced HRV , and HRVrs(12) = −0.48, p = 0.084). As HRV is thought to have a normal or healthy range [Because the patients in our study showed a reduction in pain intensity and the absolute power of low-frequency HRV, our results could therefore be consistent with the assumption of a positive relationship between pain intensity and low-frequency HRV .To our knowledge, this study is the first of its kind to investigate the effect of mirror therapy as a novel therapeutic approach in patients with chronic somatoform pain disorders. New approaches are especially needed, as these patients often remain symptomatic even after extensive diagnostic and therapeutic interventions. However, several open questions and limitations remain with our study. As our study featured no control group, a clear causative attribution of the reduction in symptoms to our intervention cannot be made. Comparing mirror therapy to a treatment group with more unspecific training activity could further elucidate the specific mechanisms of mirror therapy that underlie its efficacy. Patients in this study did not exclusively report pain in the extremities. While mirror therapy is an intervention designed to facilitate improvement in pain or disabilities in the extremities, a possible mechanism of action in lateralized pain not localized in the extremities, such as in the shoulders, lower back, or hips, needs to be investigated, warranting further studies involving and comparing different groups of patients with chronic pain in various locations. Possible mechanisms of action may be an alleviation of symptoms via increased body awareness or states of mindfulness that occur during mirror therapy or unspecific effects of physical activity, which have been shown to reduce symptoms in patients with chronic pain ,76. AnotAdditionally, as our study also consisted of a rather small sample size and did not include follow-up measurements, the robustness and long-term effects of our findings remain unclear. Therefore, randomized controlled studies with larger cohorts are mandatory to further investigate the effects of mirror therapy in somatoform pain disorders. Lastly, as mirror therapy is relatively cost-efficient and low in side effects, it poses a promising addition to the existing therapy options in the multimodal treatment of patients with chronic somatoform pain. Since the intervention would be relatively inexpensive to implement, it would likely fit fairly seamlessly into treatments that already focus on the patient’s body, such as biofeedback therapy and mindfulness exercises.In summary, our pilot study provides the first evidence that mirror therapy may be an efficacious additional therapy approach within a multimodal pain therapy program for patients with chronic somatoform pain disorders. However, several limitations of this study remain that restrain its conclusiveness regarding the potential pain-reducing effects of mirror therapy in these patients.


Background and objectiveA degenerative joint condition mostly affecting the weight-bearing joints is osteoarthritis (OA). The majority of the time, it involves the knee joint. Pain and stiffness are common in grade 1 and 2 OA. And that's the main reason people ask for help. Physiotherapy treatment can be helpful for symptomatic management of early OA. Along with exercises, contrast bath therapy (CBT) is a therapeutic alternative to medication to alleviate pain and stiffness in OA. Many studies have been done using the traditional water immersion CBT. However, there is a paucity of studies on contrast therapy given using a device. This study intends to find the effect of a knee pad device (KPD) on pain, range of motion, and functional disability in knee OA patients when compared with CBT.MethodsAbout 60 patients having unilateral knee OA were selected and randomly divided into two groups: group A received CBT for 20 minutes, and group B was treated with a KPD for 20 minutes and the Otago exercise program was given in both groups for 30 minutes. Both groups received treatment for three sessions per week for two weeks. Outcome measures used for assessment at baseline and post-treatment were visual analog scale (VAS), knee range of motion, Western Ontario and McMaster Universities Arthritis Index (WOMAC) scale, and distance covered in a two-minute walk test.ResultsBoth the groups showed significant improvement post-treatment (p < 0.05). Group B showed more significant improvement when compared with group A. The enhancement in VAS , range of motion , WOMAC , and two-minute walk test  showed improvement in functional ability.ConclusionThe findings of this study showed that both groups showed improvement following treatment, but that the use of a KPD in combination with strengthening and balance retraining is more efficient in reducing pain and enhancing quality of life in patients with grade 1 or 2 knee OA than conventional CBT. One of the most enfeebling diseases that causes discomfort and functional impairment that affects quality of life is osteoarthritis (OA), also known as degenerative joint disease of the knee . It predThe level of severity of OA is rated from grade 0 to 4 depending on radiographic findings and the Kallgren and Lawrence classification . In 0-grA non-pharmacological treatment alternative for OA pain and stiffness reduction is contrast bath therapy (CBT). In this method, each limb of the body is immersed in warm water and then immediately immersed in cold water. Several times, this cycle is repeated. Furthermore, this can be used to alleviate swelling . Warm waThe knee pad device (KPD) based on vibration and alternate heating and cooling by using an ice pack is used to treat pain. The heating pads inside this device are designed to provide a temperature of 40-45°C. It is feasible to alter the heating and vibration modes according to the need. It is loaded with a 3000 mAh battery which can withstand 6-7 hours.Through vibrations of molecules, infrared releases heat and can enter the skin up to 2-3 cm without irritating the outer layer of the skin. Heating enhances the tissues' supply of nutrients, blood flow, and intra-cellular fluid as well as removing metabolic waste. This results in decreased pain and muscle spasms. The use of an ice pack during cryotherapy enhances the threshold for pain and reduces its intensity .The most frequently prescribed treatment for knee OA is likely to be exercise therapy. Numerous treatment guidelines endorse exercise therapy since the evidence suggests that it is beneficial for people with knee OA, even though its effects are limited .Exercise therapy is the most often used method of managing OA of the knee. Land-based exercise programs have shown good effects on pain and life quality. In people with knee OA, proprioceptive exercises can increase proprioceptive acuity, reduce discomfort, and improve functional impairment in both weight-bearing and non-weight-bearing positions . Otago eAt the musculoskeletal outpatient department of the Acharya Vinoba Bhave Rural Hospital and Ravi Nair Physiotherapy College, Wardha, India, a randomized controlled trial was carried out. Approval was obtained from the Institutional Ethical Committee of Datta Meghe Institute of Higher Education & Research (Deemed to Be University) with Ref. No. DMIMS(DU)/IEC/2022/797 and Clinical Trial Registration of India (CTRI/2022/05/042506). The research protocol is published in the Journal of Clinical and Diagnostic Research, before initiating the study. The study only included participants who were permitted to participate. A total of 60 people were included through simple random sampling and sorted into group A and group B using the sequentially numbered opaque sealed envelope method.Under the supervision of a professor in the Department of Musculoskeletal Physiotherapy, the primary researcher, a postgraduate resident in physiotherapy, completed the randomization and allocation. A postgraduate resident in physiotherapy with the same level of experience who was aware of the trial and blinded to the intervention evaluated outcomes before the beginning of the research and just after it was completed.Inclusion and exclusion criteriaPatients both male and female having age groups between 40 and 60 years, grade 1 or 2 unilateral knee OA, and suffering from stiffness less than 30 minutes were included in the study. Patients having grade 3 or 4 OA, superficial or deep sensory impairments, systemic illnesses, patients with severe disabilities, participating in other interventional studies, and not willing to participate were excluded from this study. Each participant gave their written, informed consent. The methodology of the research is illustrated in a flowchart in Figure ProcedureGroup A received treatment with CBT. It was given in a sitting position, with the lower limb immersed in water up to the knee. The water in two immersion baths was adjusted to a temperature of 12˚C-14˚C and 38˚C-40˚C, respectively. The lower limb was soaked in warm water for four minutes, and then for one minute in cold water. The cycle was repeated for a total of 20 minutes, beginning with a warm water immersion.Group B received treatment with a KPD. Over the knee joint, this device was placed. Depending on the patient's needs, the heating and vibration mode was altered. After four minutes of application, this was followed by one minute of cryotherapy using an ice pack. For 20 minutes, this therapy was given as shown in Figure In both groups, the Otago exercise program (OEP) was carried out. The OEP takes about 20-30 minutes to complete. It starts with a gentle five-minute warm-up that includes flexibility exercises, then moves into lower-limb strengthening and balancing drills. Exercises to strengthen the knee extensors and flexors, the hip abductor, the ankle plantar flexors, and the dorsiflexors were performed. Resistance was provided by ankle weight cuffs with 10 repetitions in one set, three sessions per week for two weeks. In this program, balance retraining exercises included knee bending, walking and turning around on a figure-of-eight mark, sideways walking, backward walking, tandem stance, tandem walking, and one-leg stance. About 10 repetitions in one set, of each balance retraining exercise, were given for three sessions per week for two weeks.Visual analog scale (VAS), Knee flexion range, Western Ontario and McMaster Universities Arthritis Index (WOMAC) scale, and distance covered in a two-minute walk test were taken as outcome measures pre and post-treatment.Statistical analysisThe level of significance for the statistical analysis was set at p < 0.05, and descriptive and inferential statistics were calculated using the chi-square test, student-paired and unpaired t-tests, and the software used was IBM SPSS Statistics for Windows, Version 27  and GraphPad Prism 7.0 .Participants were enrolled in all 68, and each participant's eligibility was determined. Of those, 8 failed to fulfill the criteria for inclusion. Groups A and B, each with 30 patients, were made up of 60 patients who matched the study's criteria. Patients in both groups were 40-60 years old. With a gender distribution of 9:7 males and 21:23 females in groups B and A, respectively. Along with this, 9:11 samples with grade 1 OA and 21:19 samples with grade 2 OA were seen in groups B and A, respectively. There was no statistically significant disparity in the patient ages, gender, or grade of OA between the two groups, according to the chi-square test results. Table Table The VAS score before and after treatment is shown in Figure Figure In group A, CBT was given along with the OEP. Regarding pain, this group showed that many of them suffered from moderate pain which, post-treatment showed significant improvement. Similarly, a study by Abd EL Fatah et al., stated that contrast hydrotherapy effectively reduces pain and improves quality of life . AnotherEndorphins and encephalin hormones, which help reduce pain, enhance comfort, and obstruct the transmission of pain input, are released when heat is applied. Applying cold reduces inflammation, which has an impact on pain inhibition, by causing vasoconstriction, which reduces cellulite permeability, cellular diffusion, and neutrophil migration .In this study contrast therapy in both groups was given in the ratio of 4:1 which is a four-minute hot application and a one-minute cold application alternately. Similarly, a study by Shadgan et al. also used the ratio of 4:1 minute of hot-cold immersion for treatment and concluded that the contrast bath application improves oxygenation and tissue hemodynamics and supports its therapeutic effects .Group B received treatment using a KPD along with the OEP. The device used in this study is self-operatable as it has a touched screen, displaying three modes of vibrations and heating which according to the patient’s requirement was managed. Similarly, a study by Priya et al., on individuals with knee pain using a smart knee pain relief pad which gives alternate heating and cooling along with vibrations, showed significant improvement in reducing pain. This device was connected to a smart smartphone to operate the intensity of heating, cooling, and vibrations according to the needs of the patients which was psychologically good for reducing pain. They could operate the required intensities on their own according to the pain .This study showed improvement in scores on VAS post-treatment in both groups. Because physiological effect of heat therapy includes the reduction of pain, an increase in blood flow and metabolism, and an improvement in connective tissue elasticity . WarmingA sympathetic vasoconstrictive reaction is triggered by the skin and muscle losing heat, which lowers blood circulation to the cooled tissues. A local anesthetic effect known as cold-induced neurapraxia results from the reduction of the activation threshold of tissue nociceptors and the conduction velocity of pain-signaling nerve signals during cold therapy ,24. A stBoth groups received contrast therapy, but group B additionally received a vibration effect along with alternate heat and cold treatment. When vibrations are administered locally, vibratory analgesia predominantly reflects a spinal mechanism, since signals from low-threshold mechanoreceptors suppress the activity of wide dynamic range neurons in the dorsal horn, which transmit information about stimulus pain to the brain. This helps to block the pain sensations . BecauseIn this study improvement in the WOMAC score of both the groups was seen because of improvement in pain, range, and stiffness. Heating improves the extensibility of the tissues. The alternate hot and cold application removes the metabolic waste that stimulates the nociceptors thus alleviating pain.The OEP is also included in this study and was given in both groups. A study by Cederbom and Arkkukangas concluded that the OEP could be a suitable evidence-based pain management and fall prevention program . One of This study demonstrated that, when assessed using the VAS for pain, the range of knee flexion on a goniometer, functional impairments on the WOMAC, and two-minute walk test after treatment sessions, both groups exhibited significant improvement. When the means of the two groups were compared for all outcome measures, group B, which was treated with a KPD, significantly outperformed group A, which received CBT.Since this was a time-limited trial, follow-up was not feasible, indicating that the effects over time were not examined and that no control group did not receive any treatment. In this study, patients having unilateral grade 1 or 2 OA were included. So, in the future the study can be performed in grade 3 or 4 OA, patients with bilateral knee OA, and another pain-reducing intervention can be added to this treatment.This study intended to find the effects of CBT and KPD along with OEP in patients with OA knee. Statistical analysis showed post-treatment improvement in all the outcomes that is VAS, range, WOMAC score, and two-minute walk test of both the groups. Group B showed better results when compared with group A.The study concluded that both groups improved after treatment, but using a KPD combined with strengthening and balance retraining was found to be more effective than conventional CBT in reducing pain and improving functional ability in patients with grade 1 or 2 knee OA.


BackgroundLow back pain (LBP) is a global health concern. Management of LBP aims at pain relief facilitating improvement of functional ability. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line of therapy. However, the selection of NSAIDs is challenging given the range of underlying etiologies and severity. The current study aimed to compare the efficacy and safety of two available fixed-dose combinations (FDCs), namely, a dual FDC (DFC) of etoricoxib (60 mg) and thiocolchicoside (4 mg) versus a triple FDC (TFC) of chlorzoxazone (500 mg), diclofenac (50 mg), and paracetamol (325 mg).MethodologyA total of 200 eligible adult subjects aged 18-70 years with a history of LBP and muscle spasm for ≤14 days and Wong-Baker Faces Pain score >4 were enrolled after obtaining written informed consent and randomized in a 1:1 allocation ratio to be treated with either DFC or TFC for 28 days. Efficacy was assessed based on the change in score from baseline (before treatment) to day 28 on the Wong-Baker Faces Pain Scale and the Oswestry Disability Index (ODI) questionnaire, as well as the proportion of subjects who improved upon treatment. Safety was assessed based on adverse events and clinical laboratory test results.ResultsA significant decrease in pain intensity (p < 0.001) and significant improvement in functional ability (p < 0.001) was observed after treatment with either DFC or TFC. The decrease in Wong-Baker Faces Pain score and ODI, from baseline, was comparable between the treatment groups. However, more subjects with very severe pain at baseline showed ≥30% improvement upon treatment with DFC than with TFC . Also, significantly more crippled subjects with very severe functional disability showed improvement in the DFC group compared to the TFC group . No adverse events or clinically relevant laboratory test results were evident.ConclusionsBoth DFC and TFC were comparable in efficacy and safety for the management of recent-onset LBP. However, significantly more subjects with very severe pain or functional disability showed improvement after 28 days when treated with DFC compared to TFC. Low back pain (LBP) is a spectrum of pain disorders that might be overlapping, often with distinct sources ,2. GlobaA large proportion of LBP cases resolve without formal diagnosis; however, diagnosis is recommended based on physical examination, recording of history, response of patients to questionnaires, and medical imaging. Prevention strategies are not widely in practice primarily due to a lack of acknowledgment of non-anatomical factors in the onset and progress of LBP. Therefore, management strategies are of paramount importance . The aimThis study was designed to investigate the cumulative effects of the administration of NSAIDs and muscle relaxants in patients with LBP. The test medication of this study is a fixed-dose combination (FDC) of the NSAID etoricoxib 60 mg) and the muscle relaxant thiocolchicoside (4 mg). Etoricoxib is a selective cyclooxygenase-2 inhibitor that also confers gastroprotection. Thiocolchicoside acts on inhibitory neurotransmitters; it has anti-inflammatory and analgesic effects and does not cause sedation . The use0 mg and At the initiation of this study, there were no reports, to our knowledge, of an FDC of etoricoxib and thiocolchicoside. However, a recent study published from India reported faster relief of recent-onset painful muscle spasms upon treatment with an FDC of etoricoxib and thiocolchicoside compared to thiocolchicoside monotherapy in adult patients . In our This open-label, randomized controlled trial (RCT) was conducted from July 2022 to January 2023 at two sites in India, namely, Maulana Azad Medical College (New Delhi) and Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital (Kolkata). The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines for clinical trials on Pharmaceutical Products in India, as mentioned in the New Drugs and Clinical Trials Rules 2019 , as well as in compliance with the requirements of the clinical study protocol approved by the Ethics Committees of the study sites. Written informed consent was obtained from all subjects before enrollment. The trial was registered with the Clinical Trials Registry of India on July 4, 2022 (reference number: CTRI/2022/07/043690).To detect a difference of 13% in pain severity on the Wong-Bakers Faces Pain scale between the two treatment groups, assuming a power of 80%, a level of significance of 5%, and considering a dropout rate of 5%, 100 subjects were required in each treatment group and a total population of 200 subjects was required in the study. Eligible subjects were of either sex, aged 18-70 years (both inclusive), having a history of LBP and muscle spasm for ≤14 days, and with a Wong-Baker Faces Pain score >4 at baseline. Subjects with back pain due to fractures, malignancy, infection, abnormal metabolism, osteoarthritis of the hip or any other disease, or with back pain originating or referred from other organs were excluded from the study. Subjects with asthma or other allergic disorders, those with a history of peptic ulceration or gastrointestinal bleeding or severe dyspepsia, or those with a known allergy to NSAIDs/skeletal muscle relaxants or any component of the study product were also excluded. Eligible subjects were randomized using permuted block randomization by 1:1 allocation to be treated with either DFC (etoricoxib (60 mg) + thiocolchicoside (4 mg)) or TFC (chlorzoxazone (500 mg) + diclofenac (50 mg) + paracetamol (325 mg)). Both medications were consumed orally once daily in the morning for 28 days.Efficacy was assessed based on the Wong-Baker Faces Pain Scale , which eAll statistical methods were based on the International Conference on Harmonization E9 document Statistical Principles for Clinical Trials and all statistical analyses were done using SPSS version 28.0.1.1 . All hypothesis testing was performed at the 5% significance level. The Central Limit Theorem was assumed for data normality. This theorem states that the distribution of sample means approximates a normal distribution as the sample size gets larger, regardless of the population’s distribution. Sample sizes ≥30 are often considered sufficient for the theorem to hold true. An independent t-test was used to compare demographic variables between the two groups. Repeated-measures analysis of variance and post-hoc pairwise (with Bonferroni correction) was used to analyze scores on the Wong-Baker Faces Pain scale and ODI. Categorical data between treatment groups was analyzed using Z-test.A total of 200 subjects were screened who met the eligibility criteria and were randomized. In total, 100 subjects were enrolled in each of the two treatment groups  and 56/100 (56%), respectively. Most subjects (33%) were 41-50 years old. The demographic characteristics of subjects in both groups were comparable at baseline, with no statistically significant differences between the groups  completed all visits and were considered for efficacy analysis  and a significant improvement in functional ability . The same was true for early improvement in pain intensity and functional ability on day 14 (p < 0.001 for both groups) Tables .The overall percentages of decrease in Wong-Baker Faces Pain score  and ODI (~25% in both groups) were comparable between the groups. There were a total of 174 responders ; TFC, 89/98 (~91%)) with respect to Wong-Baker Faces Pain score and 162 responders with respect to ODI (DFC 79/92 (~86%); TFC, 83/98 (~85%)). The proportion of responders in each component of the ODI questionnaire is presented in Table We analyzed the proportion of responders with ≥30% improvement among subjects classified based on the severity of pain and functional disability. For subjects with pain of moderate-to-severe intensity at baseline (Wong-Baker Faces Pain score of 6), the proportion of responders with ≥30% improvement was more in the TFC group compared to the DFC group, although the difference was not statistically significant . However, a higher proportion of subjects with very severe pain (baseline Wong-Baker Faces Pain score of 7-8) in the DFC group showed ≥30% improvement compared to the TFC group . Among subjects with moderate disability (baseline ODI of 21-40), the proportion of responders with ≥30% improvement was comparable between the treatment groups, while only one subject with severe disability (baseline ODI of 41-60) showed ≥30% improvement. However, among subjects who were classified as crippled (baseline ODI of 61 -80), the proportion of responders with ≥30% improvement was significantly more in the DFC group compared to that in the TFC group . Thus, the DFC proved to be beneficial to more subjects with very severe pain compared to the TFC  in Wong-Baker Faces Pain score and ODI was significant in both treatment groups and comparable between the groups. However, a higher proportion of subjects with very severe pain or functional disability showed improvement when treated with the DFC compared to the TFC. We have come across only one study that reported the efficacy of the test DFC used in this study. Priyanka et al.  in 2022 In this study, we followed subjects for 28 days which is longer than the earlier studies from India that evaluated patients for seven days ,14. FurtBased on the results from this study, it can be concluded that the FDC of etoricoxib (60 mg) and thiocolchicoside (4 mg) is effective and safe to be used in adult patients with recent-onset LBP. The overall efficacy of the DFC was found to be comparable to that of the reference TFC used. However, the data support an advantage of the DFC over the TFC in patients with very severe LBP.


In a recent study methadone has been reported more effective witha 3-day switch (3DS) was more effective than the stop and go strategy (SAG). Many shorcomings, however, are of concerns. The poor selection fo patients with low level of pain intensity, the incomprehensibile choice of of SAG or 3DS, and considerations reported in a previous controlled study with evident methodological limits, make their conclusion inaccurate. Controlled studies are fundamental in research. However, a pragmatic approach reflecting daily practice should be carefully taken into consideration. A more flexible use of SAG strategy and strict clinical observation to change doses according to the clinical response may provide the optimal treatment in patients receiving high doses of opioids. A retrospetive study of Ding et al.  reportedFirst, given that most patients were switched for uncontrolled pain, I wonder if patients were under this condition. In fact the median pain score was 4/10 (presuming that some of them had even less than 4), a level that is not exactly considered a condition of “poor pain control”. A decrease in pain intensity to 2/10 does not seem clinically relevant, although it apparently means a reduction of 50%. Secondly, being a retrospective study, the modality of switching to methadone reflects the practice of the local institution. So, it is difficult to understand why some patients were assigned to 3DS or SAG.Third, more importantly, they quote a randomized study that revealed that the SAG approach was associated with compromised pain control, a higher number of dropouts, and more serious adverse events than the 3DS approach [3). There are some considerations that could help in making clear some points, regardless of data reported with the strict protocol dictated by the rules of a randomized controlled study.They do not report how long they needed for achieving the benefit in pain control (regardless of the low level of pain intensity). The rationale of 3DS was based on concerns about the safety of switching to methadone, due to poor information about conversion ratios existing at that time. However, the SAG strategy argues that an unfavorable clinical condition associated with a drug, can be optimally changed, stopping the offending drug and providing a new one. In fact there is no reason to maintain a drug used in more than half of patients at high doses /day). These dose levels are often associated to states of hyperalgesia which suggest to discontinuing the offending drug, rather than providing a certain amount for three days. In addition, the 3DS approach may take time, ranging from 3 to 11 days, which is inconvenient in circumstances of uncontrolled symptoms, resulting in avoidable prolonged suffering.The SAG strategy has gained popularity for the obvious pharmacokinetic advantages, producing rapid changes of plasma concentration of the two opioids, and consequently of the clinical effects produced by them, rather than facing the effects of two drugs together .But the most relevant point that has been omitted is that while providing a more rapid effect, SAG also requires expertise and flexibility in the subsequent days in managing methadone doses according to the clinical picture, particularly when the switching is started with high opioid doses and requires careful monitoring in a protected environment (such as in the case reported in the Deng’s paper). The rationale of 3DS seems to be already overcome, as there is no advantage in reducing the doses of a drug which is poorly effective or toxic. It is obvious that SAG cannot provide the best performance with a protocol in which doses are not flexible in the subsequent days. In other words SAG requires a high level of experience to carefully monitor the clinical effects, balancing the benefits of pain relief and the occurrence of adverse effects. I reported the many bias of this paper . NorwegiWhile we agree that methadone is an optimal and cost-effective choice for patients who do not respond to previous opioids, a more flexible use of SAG strategy and strict clinical observation to change doses according to the clinical response may provide the optimal treatment in patients receiving high doses of opioids. Retrospective comparison studies have relevant limitations and data gathered from this kind of study may be misleading and requires careful interpretation.


To unravel the complexity of the neuropathic pain experience, researchers have tried to identify reliable pain signatures (biomarkers) using electroencephalography (EEG) and skin conductance (SC). Nevertheless, their use as a clinical aid to design personalized therapies remains scarce and patients are prescribed with common and inefficient painkillers. To address this need, novel non-pharmacological interventions, such as transcutaneous electrical nerve stimulation (TENS) to activate peripheral pain relief via neuromodulation and virtual reality (VR) to modulate patients’ attention, have emerged. However, all present treatments suffer from the inherent bias of the patient’s self-reported pain intensity, depending on their predisposition and tolerance, together with unspecific, pre-defined scheduling of sessions which does not consider the timing of pain episodes onset. Here, we show a Brain-Computer Interface (BCI) detecting in real-time neurophysiological signatures of neuropathic pain from EEG combined with SC and accordingly triggering a multisensory intervention combining TENS and VR. After validating that the multisensory intervention effectively decreased experimentally induced pain, the BCI was tested with thirteen healthy subjects by electrically inducing pain and showed 82% recall in decoding pain in real time. Such constructed BCI was then validated with eight neuropathic patients reaching 75% online pain precision, and consequently releasing the intervention inducing a significant decrease (50% NPSI score) in neuropathic patients’ pain perception. Our results demonstrate the feasibility of real-time pain detection from objective neurophysiological signals, and the effectiveness of a triggered combination of VR and TENS to decrease neuropathic pain. This paves the way towards personalized, data-driven pain therapies using fully portable technologies.The online version contains supplementary material available at 10.1007/s13311-023-01396-y. Furthermore, the experimental protocols are extremely heterogeneous in terms of time and duration of treatment, frequency, and intensity. As a consequence, the effectiveness of these approaches remains an undecided issue [Chronic neuropathic pain is a distressing health problem affecting up to 6.9% of the general population  which ised issue , 43. In ed issue , 44. A ced issue .To address these problems, we purposely developed a Brain-Computer Interface (BCI) detecting pain in real time through neurophysiological recordings of EEG and SC to deliver a novel multisensory intervention combining VR and TENS.Eighteen healthy subjects  were enrolled to test and validate the system feasibility, while nine patients affected by chronic neuropathic pain  participated in the BCI proof-of-concept study. The patients were diagnosed by their neurologist with painful diabetic peripheral neuropathy (8/9) or pain caused by idiopathic neuropathy (1/9). A more detailed characterization of the clinical sample is in Table A RehaMove3 (Hasomed GmbH) TENS device was employed to deliver biphasic pulses at 50 Hz frequency targeting the tibial and peroneal nerves Fig. a, thus iWe performed an experimental validation of the intervention Fig. a on fiveOnce we validated the intervention, we built and tested the Brain-Computer Interface to event-lock the release of the intervention based on EEG and SC signatures of pain. We used a 24-channels portable EEG device  with a sampling frequency of 500 Hz, and an eSense MINDFIELD sensor for SC with a sampling frequency of 5 Hz . Simultaneously, the SC electrodes were placed on the subject’s left-hand palm. Afterward, given the crucial importance of an optimal calibration to elicit intuitive and electro-tactile widespread sensation , 48, thrz-scored and then fed into a support vector machine (SVM) Classifier with Radial Kernel (C = 1 and γ = 0.01), which was employed due to its suitability for BCI applications [C = 1 and γ = 0.01). Offline performances were again evaluated with a four fold cross-validation both for 3-classes and 2-classes outlines, following the same method described for EEG.EEG data collected during offline recordings was band-pass (3–40 Hz) filtered through an FIR windowed (Hamming) sinc filter of order 2000. Six electrodes in the centro-parietal area were then selected  to focus the analysis on the central area of the somatosensory cortex, known as one of the crucial areas involved in pain processing. Within each of the 4-s stimuli duration, Running Observation Windows (ROW) of 500 ms with 80% overlap were extracted and labeled according to the epochs from which they were taken . The choice of 500 ms ROW ensured a reasonable compromise between adequate frequency resolution and loss of signal stationarity . Windowsications , we traiFor the online phase, the EEG and SC 2-classes trained models were loaded. Since EEG and SC work on two different classifiers (due to different communication protocols), we implemented a pipeline to merge information from both signals. Here, 500 ms EEG and 2 s SC chunks are processed to produce a classification every 500 ms each. The final classification is made every second and relies on the last 4 classifications according to a probabilistic approach (see Supplementary Section: Probabilistic approach). To evaluate the online performances of the BCI detection framework we considered a painful stimulation (P) as correctly classified if the BCI released the intervention within 4 s from the end of the stimulation; non-painful stimulation (NP) and no stimulation (R) as correctly classified if the BCI did not release the intervention within 4 s from the end of the stimulation.C = 1 and γ = 0.01) to distinguish between P and R conditions. SC signal was discarded from the analysis since the two conditions (P and R) did not produce any significant difference in the signal  by slightly changing some of its characteristics due to the intrinsically different nature and manifestation of their pain. Patients were asked to fill out the Neuropathic Pain Symptom Inventory (NPSI)  the mornnal Fig. . During t-test. The statistical analysis of the extracted EEG and SC features was performed in Python. Normalized (z-scored) feature values for the three conditions  among healthy subjects were compared with the Friedman one-way repeated measure analysis of variance by ranks, followed by the Siegel-Castellan post hoc test. For patients, features across P and R conditions were compared with a paired t-test.For each of the analyses, the normality was tested using the Shapiro-Wilk tests . When the null hypothesis was rejected, non-parametric tests were employed. In the intervention validation analysis, the reported NPRS across the four conditions were compared in MATLAB R2021a using a non-parametric Friedman test (Fisher’s post hoc). For patients, the perceived pain intensities (NPRS) during the “focus on pain” and “rest” conditions, as well as the NPSI scores the day before and after the intervention, were compared in MATLAB R2021a using a paired p-value < 0.05, Friedman test, all p < 0.05) lower perceived pain intensity with respect to all the other conditions . Moreover, by evaluating the temporal evolution of reported pain, we found that the VR + TENS condition is associated with the highest slope of decrement  to extract EEG and SC features Table  trainingp-value > 0.05; one-tail paired t-test, p-value = 0.014, Cohen’s effect size = 1.29, statistical power = 0.95)  Fig. c.p < 0.05). Therefore, to keep the analysis consistent, non-parametric tests were used for all features. EEG alpha power was significantly lower in P with respect to NP (p < 0.001 Friedmann) and R (p < 0.01) conditions, while no statistical difference was found for the NP vs R comparison  and R (p < 0.05). Again, no statistical difference was found for the NP vs R comparison conditions  and to NP (p < 0.05)   (Table p < 0.05) and NP (p < 0.05) conditions , thus highlighting an overall decrease of the signal power in these bands as a possible signature of increased perceived pain  Fig. . Similar01) Fig. , while s5) Table . Finallyns Table . Almost ns Table . Graphicns Table   . Even though the detection framework showed promising results for patients as well (75 ± 7% precision), BCI online performances were higher for healthy subjects compared to patients. This is likely linked to how patients had to focus on their pain, rather than receiving experimentally induced pain as in healthy. The absence of a transient and fast stimulus prevented a clear signature of pain in SC, which was therefore discarded in the patients’ processing pipeline. As a result, a functional and effective integration between the two neurophysiological signals (EEG and SC) was possible in healthy subjects only.In the EEG features analysis, our results showed a common trend of decreased alpha power in the centro-parietal area following a painful electrical stimulation. This is consistent with the majority of pain-related studies, which report a decrease of the alpha band as a biomarker of pain perception after experimentally induced pain –24, 26. Despite the different pain protocols employed for healthy subjects and patients, common trends emerged from the offline features analysis. Indeed, also for patients and similar to previous studies , 31, 61,Moving towards the effectiveness of the intervention, we proposed a novel therapeutic approach based on the combination of TENS and VR. Before implementing the real-time BCI system, the efficacy of the proposed intervention was demonstrated on healthy subjects by showing that the combination of TENS and VR provided a significant decrease in pain with respect to the unimodal approaches. It is worth noticing that contrary to the VR condition, the unimodal TENS condition led to a significant improvement with respect to the control. However, when this technology is coupled with VR, pain perception decreases even further. This result highlights the VR potential as a complementary element to conventional pain therapy rather than as a stand-alone therapeutic solution.When the intervention was implemented in the BCI framework and tested on neuropathic patients, there was a significant decrease in pain (50% NPSI score decrease) the day after the session, showing the potential of this novel, safe, and non-invasive intervention. Due to the absence of a control condition, we can only speculate on the reasons behind the effectiveness of the proposed intervention. Given the importance of attention modulation in our experimental settings, the VR scenario likely played a role in patients’ pain decrease. However, while VR has shown also in other studies to be able to decrease pain through attentional mechanisms, it is known to have an analgesic effect while, or at least immediately after that, the patient is immersed in the VR environment . TherefoFinally, the benefits of this intervention could be further expanded to beneficially impact altered body representations. Indeed, recent research has shown that patients with diabetic neuropathy have a cortical reorganization similar to the one found in amputees . While tTo the best of the authors’ knowledge, this study has shown for the first time the possibility of detecting pain and delivering a purposely designed intervention in real time for neuropathic patients. However, it presents some limitations. Firstly, the proposed BCI relies on two different communication protocols for EEG and SC signals (LSL and OSC respectively). The use of two different protocols does not allow the precise synchronization of the streamed signal and therefore requires two different processing pipelines, discarding the possibility of building a unique classifier for both signals. On the other hand, to limit the potential negative outcomes of this failed integration, a versatile probabilistic approach merging weighted information from SC and EEG classifiers was built and yielded successful results.Moving towards the efficacy of the intervention, it is necessary to stress that, despite noticing a significant pain reduction 1 day after the BCI testing, we cannot completely rule out a placebo effect nor indicate which intervention between TENS and VR had the higher effect. Indeed, despite having validated the intervention on healthy subjects using proper control conditions , these have to be performed in the future with patients. In this proof-of-concept study for time purposes, we tested the complete intervention only.Furthermore, the different protocol employed for healthy subjects and patients is another important limitation. While in healthy subjects we elicited a transient arousal with a painful electrical stimulation, for patients, we did not induce pain but rather modulated their attention to pain. These changes explain why SC recording in patients did not yield significant results. As of today, the BCI structure developed for healthy would perfectly fit neuropathic patients with sharp, episodical attacks of pain, or patients who have painful/pain-free phases. This would allow the integration of SC decoding for neuropathic patients as well and therefore more coherent and consistent results. However, to test the performances of the system with such patients, it would be necessary to monitor, for instance in a home-use scenario, electrodermal and brain-related activity over several hours or days and train the classifier on the features extracted from these recordings. Since we performed the BCI testing onsite at the laboratory, we validated the BCI by slightly changing some of its characteristics to fit the patients’ pain profile. Despite possible spontaneous pain attacks, we chose to target the attentional component of pain to avoid daunting sessions waiting for a pain attack to occur. Nevertheless, we want to highlight that our final aim is not to propose an intervention where the patients must focus on their pain . Instead, this was a methodological choice that could simulate their pain attacks, to make the experiments more uniform as possible among patients and temporally feasible. Indeed, given that the patients reported to have several pain fluctuations, we envision the possibility of using our system in a home scenario, where the BCI would then detect pain attacks rather than focusing on pain. In this view, we need to stress that the current setting of this proof-of-concept BCI is not ready for real-life clinical contexts and future studies with a longitudinal design should investigate the feasibility and potential of training and testing the BCI on spontaneous pain attacks..Continuing with the future implications, while the current BCI cannot discriminate between various components of pain, this represents an interesting perspective towards the personalization of the intervention. More specifically, future studies with a high sample size could aim at distinguishing biomarkers for the sensory and attentional components of pain. For example, if the BCI would be able to detect specifically the attentional component of pain in hypochondriac patients , it could fine-tune the intervention targeting that specific component, which in our case would be the VR modulationFinally, for future use, our system could be exploited as an objective automatic detection system for pain for several real-time applications. The intervention we designed is indeed specific for neuropathic patients. Nevertheless, VR and TENS output could be substituted with other treatments for different etiological conditions of pain.Supplementary file1 (DOCX 538 kb)Below is the link to the electronic supplementary material.


Chronic spontaneous urticaria (CSU) is a condition that is associated with recurrent pruritic hives and/or angioedema lasting for more than 6 weeks and is known to affect 1% of the population. Neuropathic pain can be defined as abnormal pain in the peripheral or central nervous system following injury and results from dysfunctions in the peripheral or central nervous system without peripheral nociceptor stimulation. Histamine appears in the pathogenesis of both the CSU and diseases of the neuropathic pain spectrum.To evaluate the symptoms of neuropathic pain in patients with CSU using scales.Fifty-one patients with CSU and 47 sex- and age-matched healthy controls were included in the study.The results of the short-form McGill Pain Questionnaire revealed the scores in the sensory and affective domains, Visual Analogue Scale (VAS) scores and pain indices to be significantly higher in the patient group , while the overall pain assessment and sensory assessment based on the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale were also significantly higher in the patient group. Based on the assumption that scores of > 12 indicated neuropathy, 27 (53%) of the patients in the patient group and 8 (17%) in the control group were found to have neuropathy (p < 0.05).Cross-sectional study, small patient sample and use of self-reported scales.In addition to itching, patients with CSU should be aware of the potential for the association of neuropathic pain. In this chronic disease that is known to affect the quality of life, using an integrated approach with the patients and identifying accompanying problems are as important as treating the dermatological disorder. Chronic spontaneous urticaria (CSU) is a condition that is associated with recurrent pruritic hives and/or angioedema lasting for more than 6 weeks, and is known to affect 1% of the population.Neuropathic pain can be defined as abnormal pain in the peripheral or central nervous system following injury and results from dysfunctions in the peripheral or central nervous system without peripheral nociceptor stimulation.Histamine appears in the pathogenesis of both the CSU and neuropathic pain spectra of disorders. The present study investigates the symptoms of neuropathic pain in patients with CSU using scales, as the simplest and easiest method.This cross-sectional, questionnaire-based and case-controlled study was approved by the local ethics committee (Decree nº 2017-KAEK-189_2019.07.10_04) and was conducted in accordance with the principles of the Declaration of Helsinki.After obtaining their informed consent, 51 patients with CSU and 47 sex- and age-matched healthy controls were included in the study. All of the participants were above the age of 18 years. Excluded from the study were those with pregnancy, lactation, alcohol consumption, presence of a major central nervous system disease, cognitive impairment and psychiatric comorbidity. Only CSU patients were included in the study. Patients with chronic inducible urticaria and acute urticaria were excluded.The body weight and height measurements were obtained for the calculation of Body Mass Index (BMI), as well as sociodemographic data, disease duration, comorbid diseases, drug use, presence of angioedema and clinical examination results of patients with CSU presenting to dermatology outpatient clinics.Is an established and widely accepted patient-reported outcome tool for the prospective measurement of CSU activity. UAS7 scores of ≤ 6 indicate well-controlled, 7–15 mild, 16–27 moderate and 28–42 severe urticarial.The main component of the SF-MPQ comprises 15 descriptors  that are rated on an intensity scale of 0 = none, 1 = mild, 2 = moderate or 3 = severe, and three pain scores are derived from the sum of the intensity rank values of the words chosen for sensory, affective and total descriptors. The SF-MPQ also includes the Present Pain Intensity index of the standard MPQ and a Visual Analogue Scale (VAS).Aims to identify the pain of predominantly neuropathic origin, distinct from nociceptive pain, without the need for clinical examination. The S-LANSS is a 5-item questionnaire related to symptoms of pain and with two items related to clinical signs involving self-administered sensory tests for the presence of allodynia and decreased pin-prick sensation. The scores range from 0 to 24, with a score of 12 or greater suggesting neuropathic pain. The validity and reliability of the Turkish version of these scales were developed.t-tests were used to compare the means between the two groups. For categorical variables, a Chi-Square test was used to test the differences between groups. Spearman’s correlation analysis was used for the correlation between neuropathy tests and disease characteristics. Unless otherwise stated, p < 0.05 was set as the level of significance.All statistical analyses were performed using the IBM SPSS Statistics  software package program. Continuous variables were expressed as mean ± SD, and Student’s The study included 51 patients  and 47 controls , and the two groups had similar sociodemographic characteristics (p < 0.05). In the patient group, 18 were on omalizumab and 18 were on antihistamines, while the remainder were not receiving treatment at the time of admission .Table 1GAn assessment of the results of the short-form McGill Pain Questionnaire revealed the scores in the sensory and affective domains, VAS scores and pain indices to be significantly higher in the patient group , while the overall pain assessment and sensory assessment based on the S-LANSS pain scale were also significantly higher in the patient group. Based on the assumption that scores of > 12 indicated neuropathy, 27 (53%) of the patients in the patient group and 8 (17%) in the control group were found to have neuropathy (p < 0.05). An analysis of the results of the questionnaire revealed the median total neuropathy score in the patient group to be 14, which was statistically compatible with the neuropathy findings (range: 0–33) .Table 2EAn analysis of the correlations between the disease activation findings  and neuropathy revealed a statistically strong positive correlation, especially with the urticaria activity score  .Table 3CIn the present study significantly, higher scores were identified in the sensory and affective domains of the short-form McGill Pain Questionnaire, as well as the VAS scores and pain indices in the patient group. The overall pain assessments and sensory assessments identified from the S-LANSS pain scale were also significantly higher in the patient group. Neuropathy was detected in 27 and eight of the patient and control groups, respectively. There was a statistically strong positive correlation between the urticaria activity score, and the neuropathy test scores.Neuropathic pain is a common problem in clinical practice that affects many aspects of daily life, and that is associated with poor overall health, reduced quality of life, poor sleep, and higher levels of anxiety and depression. The quality-of-life measurements of those with chronic neuropathic pain were found to be as low as in those with depression, coronary artery disease, recent myocardial infarction or uncontrolled diabetes mellitus.Mast cells are immunological cells that are distributed throughout different parts of the body with reported roles in several pathological conditions, such as hypersensitivity, atherosclerosis, pulmonary hypertension and infertility. There have also been studies reporting the importance of their roles in the pathogenesis of neuropathic pain of various etiologiesIt has been well established that sensitized mast cells can cause allergies and anaphylaxis, and mast cells are also known to contribute to several biological and pathological processes, such as vascular physiology, pain, itching and cancer.Atopic dermatitis presents with severe itching, similar to CSU, and recent studies have reported accompanying pain symptoms in addition to itching in patients with atopic dermatitis, identifying a need to question patients in this regard.Wallis et al. examined 35 patients with pachyonychia congenital – a rare autosomal dominant disorder – and assessed the severity and type of pain, as the main symptom in these patients, through questionnaires and quantitative sensory tests. The authors reported that 62% of the patients had neuropathic pain and the rest had nociceptive pain symptoms.This study has some limitations, the main ones being its cross-sectional study design, the small patient sample and the use of self-reported scales. Comorbidities such as type 2 diabetes could be associated with neuropathic pain, but these were present in only a small proportion of the sample, and there was no difference in the comorbidities of the two groups. Furthermore, no electrophysiological screening tests could be performed, as a further limitation. The questionnaires applied can be considered valid and reliable for use in screening tests, and in some cases, they may help identify disorders that cannot be detected by electrophysiology.In addition to itching, patients with CSU should be aware of the potential for accompanying neuropathic pain. In this chronic disease that is known to affect the quality of life, using an integrated approach with the patients and identifying accompanying problems are as important as treating the dermatological disorder. There is a need for prospective studies of this issue in which descriptive and methodological methods are applied together in large patient series to support the findings of the present study.None declared.Gülhan Gürel - Designed the study; recruited the participants; participated in the data collection; interpreted the data; drafted the first manuscript and all authors critically reviewed the paper.Hikmet Saçmacı - Designed the study; participated in the data collection; did the statistical analysis; interpreted the data.None declared.


Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system (CNS) occurring typically in younger patients, usually between 20 and 40 years of age. There are different clinical manifestations associated with MS, including visual impairment, sensory impairment, spasticity, urinary dysfunction, and pain. With advancing disease, the treatment of pain in MS patients becomes, along with MS-associated disability, the most problematic issue because there are different types of pain, such as thalamic or cortical deafferentation pain, extremity pain, and trigeminal neuralgia (TN) associated with MS, that can dramatically worsen the quality of life of these patients  sequences. In a recent report, these thin-cut sequences, offering a good contrast between the CSF (hyperintense), cranial nerves (isointense), and cerebellar arteries (hypointense due to the flow voids), have shown good reliability in predicting the neurovascular conflict in patients with TN . Regarding the complications, one patient developed transient mild facial nerve palsy after MVD and completely recovered after 2 months, while another patient developed transient diplopia after the percutaneous treatment and totally recovered after 4 weeks. At the latest follow-up (FU), we observed no recurrence in the MVD group and only three recurrences (13.63%) in the percutaneous balloon compression group.We systematically applied this flowchart in January 2021. We treated 30 MS-related TN patients. Of them, 22 were submitted to percutaneous balloon compression, and eight were treated with MVD. The clinical and outcome data of patients are reported in In conclusion, the surgical treatment of drug-resistant TN in MS patients is a challenge for neurosurgeons. The full knowledge of the pre-operative neuroanatomy of each patient can help the neurosurgeon choose the correct surgical procedure, improving the quality of life of these patients.NM: Conceptualization, Writing—original draft, Writing—review & editing. AR: Investigation, Writing—review & editing. QD'A: Formal analysis, Writing—review & editing. MD'E: Investigation, Methodology, Writing—review & editing. AI: Validation, Writing—review & editing.


This review covers the current evidence regarding the treatment outcomes and limitations of conventional periodontal therapies and provides information based on the available experimental and clinical studies related to the HY mechanism of action and effects following its use associated with subgingival instrumentation and other types of dental treatments.Periodontitis is one of the most common oral polymicrobial infectious diseases induced by the complex interplay between the altered subgingival microbiota and the host’s dysregulated immune-inflammatory response, leading to the initiation of progressive and irreversible destruction of the periodontal tissues and eventually to tooth loss. The main goal of cause-related periodontal therapy is to eliminate the dysbiotic subgingival biofilm in order to arrest local inflammation and further periodontal tissue breakdown. Because, in some cases, subgingival mechanical instrumentation has limited efficiency in achieving those goals, various adjunctive therapies, mainly systemic and locally delivered antimicrobials, have been proposed to augment its effectiveness. However, most adjunctive antimicrobials carry side effects; therefore, their administration should be precociously considered. HybenX Periodontitis is one of the most common chronic infectious-inflammatory diseases in humans and a major public health concern ,2 that cThe subgingival mechanical instrumentation is the gold standard of periodontitis treatment and determines a significant shift in the subgingival microbiota ,7 as wel® (HY)  , ectively .p = 0.018). However, at the three-month follow-up, after two repeated treatment sessions, there was no significant difference in the anaerobic bacterial burden between the group treated with HY and ultrasonic instrumentation and the group treated only with ultrasonic instrumentation [A randomized clinical study followed over three months the microbiological outcomes after different subgingival therapeutical regimens used for periodontitis treatment. HY used as monotherapy was equally effective as ultrasonic instrumentation in reducing the subgingival bacterial load. After six weeks, the combination of ultrasonic instrumentation and HY determined a superior reduction of the anaerobic bacterial load compared to the mechanical instrumentation alone  (p < 0.001) and all bacteria of the red complex (p < 0.001), the levels of all investigated inflammatory mediators IL-1β (p < 0.05), IL-10 (p < 0.05) and TNF-α (p < 0.05) as well as of the IL-1β/IL-10 ratio (p < 0.001) from the gingival crevicular fluid after one year [Porphyromonas gingivalis, Tannerella forsythia, Treoponema denticola) has also been reported after a single subgingival HY application in periodontitis patients [Another split-mouth randomized clinical study reported that as compared to subgingival mechanical instrumentation alone, the association with HY significantly reduced the proportion of some bacteria of the orange complex  or silver nanoparticles , resulting in areas of partially opened dentin tubules of around 3–4 µm alternating with areas of continuous smooth, compact smear layer [®) and silver nanoparticles (Perioflush®), as seen in the elongated, well-attached gingival mesenchymal stem cells cultured on HY-treated samples [The SEM analyses showed that applications of HY onto instrumented roots coated by a continuous smear layer eliminated the smear layer more efficiently than sodium hypochlorite  [p < 0.05) and clinical attachment gain  in patients treated with combined therapy as compared to subgingival mechanical instrumentation alone [Three randomized controlled clinical trials reported the effects of HY on different periodontal parameters after its adjunctive use in periodontitis therapy. A pilot study with a split-mouth design reported a significantly greater reduction of the dental plaque and bleeding on probing scores as well as of the gingival indices in periodontitis patients after supra- and subgingival mechanical instrumentation combined with the topical administration of HY (combined therapy) as compared to those receiving only mechanical instrumentation. After three months, there were no considerable differences in the pocket depth reduction between sites treated with the combined therapy and those mechanically instrumented  . On the on alone .p < 0.001) was covered by residual plaque and calculus deposits in the group treated with combined treatment  as compared with sub-gingival mechanical instrumentation alone . Considering the percentages of soft and calcified deposits, a significantly reduced percentage of root surface covered by residual plaque (p < 0.001) was observed in the group treated with the combined approach (10.63 ± 12.79%) as compared to the group treated with the single approach (17.32 ± 10.68%). However, a significantly higher percentage of residual calculus (p < 0.001) was detected in the group treated with the combined therapy (46.90 ± 33.76%) as opposed to the other group (23.65 ± 18.27%). In addition, the mean cleaning depth was significantly lower (p < 0.001) for the teeth treated with the combined therapy (4.41 ± 2.96 mm) as compared to those treated by mechanical instrumentation alone (2.67 ± 2.70 mm). These results suggest that HY may enhance the efficacy of biofilm removal but does not bring any additional benefits to the calculus deposits removal in deep periodontal pockets of teeth with more complex morphology [A more recent parallel, randomized clinical trial, in which multirooted teeth with deep periodontal pockets indicated for extraction were treated with combined therapy or only with subgingival mechanical instrumentation, evaluated on photographs the total area and the percentage of root surface covered with residual dental plaque and calculus as primary treatment outcomes. A significantly reduced root surface area (rphology .Secondary effects after HY applications have also been evaluated in these clinical studies. Thus, fewer patients reported pain during the second-step therapy or post-operative dentinal hypersensitivity when the combined therapy was applied as opposed to the subgingival mechanical instrumentation alone . ModeratHY has been promoted as a potential therapeutical agent to manage peri-implantitis  since noA one-year follow-up clinical study assessing patients with severe peri-implantitis, treated with open flap debridement and one-time decontamination with HY, reported an obvious improvement of the peri-implant status as revealed by the mean probing depth reduction of 3.1 mm, a mean attachment gain of 3.6 mm, and a mean bone fill of 58.6% .The main limitations of some of the cited clinical studies, mainly case reports, are the small number of recruited patients, the lack of comparison groups, the risk of selection bias, the lack of standardized assessment protocols, and the inability to generalize the results. Thus, further randomized controlled clinical studies are needed to assess the clinical efficacy of HY as part of periodontal and peri-implant therapy.Due to its proven antibacterial properties, HY may be a promising therapeutical agent for the non-surgical and surgical treatment of periodontitis, peri-implantitis, endodontic infections, and even mucosal ulcers.The adjunctive use of HY can bring additional clinical benefits, reduce the need for invasive therapeutical procedures and enhance the healing of the tissues in treating both periodontal and peri-implant lesions. Moreover, HY has the potential to partially remove the smear layer from root surfaces more efficiently than other locally adjunctive antimicrobial agents, which can facilitate, to some extent, periodontal tissue reattachment at the intervention sites.Nevertheless, more in vitro studies with different designs and larger sample sizes are needed to precisely determine the influence of the sulfonic/sulfuric acid-based decontaminating agent on the root surfaces and cell adhesion and to provide additional information on the biocompatibility of this product. Moreover, long-term clinical studies with larger samples of patients are needed to determine the product’s effectiveness in humans.


Screening trials before full implantation of a spinal cord stimulation device are recommended by clinical guidelines and regulators, although there is limited evidence for their use. The TRIAL-STIM study showed that a screening trial strategy does not provide superior patient pain outcome at 6-month follow-up compared with not doing a screening trial and that it was not cost-effective.To report the long-term follow-up results of the TRIAL-STIM study.The primary outcome of this pragmatic randomized controlled trial was pain intensity as measured on a numerical rating scale (NRS) and secondary outcomes were the proportion of patients achieving at least 50% and 30% pain relief at 6 months, health-related quality of life, and complication rates.Thirty patients allocated to the “Trial Group” (TG) and 36 patients allocated to the “No Trial Group” (NTG) completed outcome assessment at 36-month follow-up. Although there was a reduction in NRS pain and improvements in utility scores from baseline to 36 months in both groups, there was no difference in the primary outcome of pain intensity NRS between TG and NTG , EuroQol-5 Dimension utility values , or proportion of pain responders (33% TG vs 31% NTG). No differences were observed between the groups for the likelihood of spinal cord stimulation device explant or reporting an adverse advent up to 36-month follow-up.The long-term results show no patient outcome benefit in undertaking an SCS screening trial. AEadverse eventCONSORTConsolidated Standards of Reporting TrialsEQ-5DEuroQol-5 DimensionEQ-VASEuroQol Visual Analog ScaleFDAFood and Drug AdministrationIPGimplantable pulse generatorMCIDminimal clinical important differenceMDmean differenceNRSnumerical rating scaleNTGno trial groupPSPS-T2persistent spinal pain syndrome type 2RCTrandomized controlled trialSCSspinal cord stimulationTGtrial group.1 A number of randomized controlled trials (RCTs) and economic evaluations support the clinical and cost-effectiveness of SCS for neuropathic pain.15The use of spinal cord stimulation (SCS) for inhibition of pain was first described in 1967.18 target neural tissue,20 and feedback technology,6 common to all RCTs to date is that patients are required to undergo a screening trial to evaluate early response to therapy before full implantation of the SCS device. Screening trials are recommended by clinical guidelines and regulators including the Food and Drug Administration (FDA) in the United States.24 Such a screening trial allows patients to experience the sensation generated by SCS and potential pain relief to be achieved. A successful trial has been defined as the patient reporting ≥50% pain relief with stable or reduced pain medications and with stable levels of daily activity.23Despite many advances in SCS waveforms,26Although a successful screening trial should help to identify those patients who would most benefit from SCS and obtain long-term pain relief, there are drawbacks to such a screening trial strategy. Duplication of a clinical procedure at screening and full implant increase patient exposure to infection . Higher infection rates have been reported for 28-day trials compared with screening trials with shorter durations.27 Qualitative results of the TRIAL-STIM also indicated that the patients were not supportive of the concept of a trial.28Furthermore, the results from the TRIAL-STIM RCT showed there was no evidence that a screening trial provides superior patient outcomes or is cost-effective compared with not doing a screening trial.An important limitation of the TRIAL-STIM RCT results was that follow-up was limited to 6 months and therefore too short to evaluate long-term response to SCS. The aim of this report is, therefore, to report the long-term results of the TRIAL-STIM trial.29 The study was approved by the UK Health Research Authority North East Research Ethics Committee (17/NE/0056). The trial was conducted and reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines.30TRIAL-STIM was a multicenter, single-blind, parallel 2 group randomized trial . The study was conducted across 3 participating sites in the United Kingdom: South Tees Hospitals NHS Foundation Trust , Basildon and Thurrock University Hospitals NHS Foundation Trust, and Leeds Teaching Hospitals NHS Trust. The full study protocol has been published previously.21: neuropathic pain of intensity of at least 5 on a numerical rating scale (NRS); had endured pain for longer than 6 months despite receiving suitable conservative medical and surgical management; had undergone a satisfactory multidisciplinary assessment by a team with experience in providing SCS; and had the capacity to provide informed consent. Full eligibility criteria have been previously reported.29Participants were eligible for SCS if they met the following criteria according to NHS guidance (NICE TA159)29Participants were allocated (1:1) to 1 of 2 groups: trial group (TG) with a screening trial followed by SCS implantation in light of the screening trial result, or no trial group (NTG) with a strategy of SCS implantation only. Patients were randomized to groups through a password-protected web-based system developed and maintained by the Exeter Clinical Trials Unit. The allocation was stratified by center, and minimized on patient age (≥65 or <65 years), sex, and presence of persistent spinal pain syndrome type 2 (PSPS‐T2). The methods for randomization and masking have been previously described.Type of device and stimulation were not restricted, and devices from 4 major SCS manufacturers were used.29 Considering the RCTs31 listed in the NICE TA15921 clinical evidence section along with international guidelines,23 a screening trial was defined as successful when a patient obtained ≥50% pain relief and satisfactory on table paresthesia coverage (≥80%) of the pain area, observed a reduction in pain medications or reported improvement in quality of life and function, and successful location of leads at anatomic target for paresthesia-free therapies. Patients who did not have a successful screening trial did not receive an implant but all patients were followed up. Patients who had a successful trial had the implantation of the implantable pulse generator (IPG) on a separate occasion.Patients who were randomly assigned to the TG arm underwent a screening trial that involved passing an external or an internalized tunneled SCS lead, or leads, to an external stimulator in accordance with the center's standard operating procedure.32 and satisfactory anatomic lead location for paresthesia-free devices.In the NTG group, all patients received a permanent implant in one surgery when the following was observed: satisfactory on table paresthesia coverage (≥80%) of the pain area, no dislike of sensations,33 Secondary outcomes assessed at 36-month follow-up were the proportion of patients achieving at least 50% and 30% pain relief as measured on the NRS,33 health-related quality of life using the EuroQol-5 Dimension (EQ-5D)-5L tool,34 and complication rates.The primary outcome was pain intensity assessed on the NRS.29 The mean time to follow-up was 37.3 (range 36-40 months) and 37.1 (range 36-40 months) for the TG and NTG groups, respectively. The follow-up time is subsequently referred to as 36-month follow-up.The sample size calculation has been described elsewhere.27 No imputation of missing data is conducted for the analyses at 36 months to avoid making assumptions over long-term follow-up periods. A complete case assessment was considered to be more appropriate than conducting an intention-to-treat analysis with or without data imputation at 36 months to avoid making assumptions about missing data over long-term follow-up periods.The primary analysis compared primary and secondary outcomes between randomized groups including patients who completed the 36-month follow-up assessment.Linear regression methods with adjustment for baseline outcome scores and stratification/minimization variables were used to compare continuous outcomes. Logistic regression analysis adjusting for stratification/minimization variables were used to compare binary outcomes.All analyses were performed using STATA v14.0 (StataCorp LP).From June 2017 to September 2018, 137 patients were assessed for eligibility, with 105 patients proceeding to enrolment. Of the 105 participants, 54 were randomized to the screening TG. Seven of the patients in TG withdrew before the screening trial; of the remaining 47, an unsuccessful screening trial was observed for 5 (11%) patients and 42 (89%) patients had a successful screening trial and were implanted with an SCS system. Forty-nine of the 51 NTG patients received an SCS implant. Thirty TG patients and 36 NTG patients completed the follow-up at 36 months . Loss to follow-up in all instances was due to failure to reach the patients via telephone (maximum of 3 attempts), email, and letter.The only difference between the TG and NTG groups' baseline characteristics and outcome ratings was the duration of pain, which was slightly longer in the NTG group. Participants in the study had a mean NRS pain score of 7.5, an average age of 50.4 years, and fairly equal sex representation. The most frequent primary diagnoses in both groups were PSPS-T2  and radiculopathy .36 or recently suggested MCID ranges from 0.9 to 2.7,37 there were no clinically relevant differences in pain intensity at 36 months or change from baseline between TG and NTG groups. There was evidence of clinically significant reductions in mean NRS pain from baseline to 36 months for both TG (7.03-4.63) and NTG (7.58-5.47).At 36-month follow-up, there was no difference in the primary outcome of clinic-assessed NRS score between TG and NTG  and NTG (0.24). Similarly, for EQ-VAS, there were no significant differences between TG and NTG groups .Improvements were seen in EQ-5D-5L and EuroQol Visual Analog Scale (EQ-VAS) from baseline to 36 months in both groups. There was no evidence of difference between TG and NTG groups for EQ-5D utility scores . The mean change from baseline at 36-month follow-up for EQ-5D utility scores observed was around 0.2 for both TG and NTG groups. Considering a MCID of 0.074 for the EQ-5D utility scores,The proportion of patients who were responders considering a ≥50%  or ≥30% 53% TG; 42% NTG) reduction in pain from baseline were not statistically different between the TG and NTG groups  corresponding to fractured leads for 2 patients (1 TG and 1 NTG) and 1 patient in TG reporting problems charging the device; none of these AEs resulted in device explant. Overall , the likelihood of having an explant was not significantly different between TG  and NTG groups . Similarly, no difference was observed for the likelihood of reporting an AE .27 The results further support that the patients' preference to undergo an SCS implant as a single-stage procedure28 may not be detrimental to obtain benefits from SCS. It is also noteworthy that at 36- to 40-month follow-up, we observed no difference in the number of explants between the groups.The results of this study demonstrate that SCS screening trials do not provide superior patient outcomes in the long-term when compared with not doing a screening trial. These findings support the initial conclusions at the 6-month primary end point.40 Although superior to a MCID of 2 points in the NRS,36 the pain reduction obtained by patients in our study is less than previously reported. RCT samples are usually highly selected with frequent exclusion of participants with a higher risk profile, and therefore, less representative of clinical practice.42 TRIAL-STIM was a pragmatic RCT, the eligibility criteria used reflects clinical practice in the United Kingdom and is in line with NICE guidance for SCS.21 Therefore, we consider that our study provides an overall more realistic representation of the impact of SCS in clinical practice than RCTs that adopt eligibility criteria not reflective of clinical practice. Although it may be argued that the smaller effect of SCS reflects poor patient selection, it is useful to note that a multidisciplinary assessment was part of our inclusion criteria and that this included a psychological assessment at all 3 centers. Furthermore, the low rate of AEs reported in the study compares favorably to other RCTs and supports the expertise of the implanters involved.Clinically important reductions in pain intensity and improvements in health-related quality of life were observed at 36-month follow-up for both groups, confirming the long-term effectiveness of SCS. Previous long-term follow-ups of RCTs have reported similar effects of SCS for patients with neuropathic pain.Supplementary Material 1, http://links.lww.com/NEU/D381.Although our study was not powered for a comparison between the 3 waveforms used in this study , we did not observe clinically relevant differences between these waveforms at 6 or at 36 months. Discussion considering a smaller MCID is presented in 43 high frequency (10 kHz) vs paresthesia-inducing stimulation,44 high frequency (5 kHz) vs placebo,45 and burst vs different frequencies .46 However, superior pain reduction has been observed for tonic subthreshold stimulation at 500 Hz vs burst or placebo,47 high frequency (10 kHz) vs paresthesia-inducing stimulation,17 burst vs tonic stimulation,16 or 5882 Hz vs 1200 Hz, 3030 Hz, and sham.48 Not only different study settings and population characteristics, but also program settings, number of leads, and electrode contacts, or how sham stimulation was enabled may all contribute to the discrepancy in the results reported. Methodological and reporting deficiencies in trials of SCS have been previously highlighted.50 Development of SPIRIT and CONSORT extensions specific to implantable neurostimulation devices may potentially lead to improved reporting and transparency of clinical trial protocols and reports while facilitating identification of possible reasons for discrepant findings.51Parallel and crossover RCTs have previously reported no differences in effectiveness when comparing different paresthesia-free frequencies,We provide a long-term follow-up of the only RCT to date that evaluated the clinical utility of SCS screening trials. Similar to the TRIAL-STIM RCT, the follow-up assessment was independent from industry funding. Few RCTs of SCS are fully independent of industry and none report results to 36 months. We observed some loss to follow-up; however, this was not substantial, considering that 77% of the participants that completed the primary end point at 6 months completed the follow-up at 36 months.Supplementary Material 2, http://links.lww.com/NEU/D381). Previously, it had been suggested that the use of screening trials could be cost-saving if at least 20% of patients had an unsuccessful trial.52 Recent evidence from a budget impact analysis evaluating the costs or savings of conducting screening trials suggests that this figure may be closer to 14.4%,53 an unsuccessful trial failure rate approximately two-fold of previous rates observed in UK clinical practice.54Analysis of cost-effectiveness at 36 months was not conducted as the length of recall required between assessments  would limit interpretation of the results (see 55 Our findings suggest that the utility of screening trials in identifying long-term responders to SCS may be limited. We consider that patient selection with support from a multidisciplinary team may identify suitable patients who will obtain satisfactory pain relief with SCS in the long term based on pain reduction and limited number of device explants in the NTG group. An e-health tool has been recently developed to assist the assessment of the appropriateness of a patient for referral and selection for SCS, considering clinical and psychosocial factors.56 A study of 483 consecutive patients in 12 experienced European centers showed a strong correlation between the retrospective application of the e-tool panel recommendations and SCS trial and treatment outcome.57 Further prospective research is ongoing to evaluate the predictive value in e-tool-naive centers that are blinded to the e-tool panel recommendations.Screening trials continue to be recommended by clinical guidelines and required by regulators. The FDA recently issued a letter to healthcare providers reminding of the importance of conducting a screening trial to confirm satisfactory pain relief before implanting a SCS device.We do not suggest that screening trials should be eradicated, but they should not be made mandatory. An informed decision on whether to perform a screening trial should be based on professional judgment and patient preferences, considering the advantages and disadvantages of screening trials.The results of this long-term follow-up demonstrate that there is no patient outcome benefit in undertaking a SCS screening trial.