Background: Referred pain often complicates and delays the diagnosis of temporomandibular disorders (TMD). Elaborating the prevalence and characteristics of TMD-associated referred pain as well as the distribution of referred pain in different TMD classes will significantly improve the diagnostic process. The objectives of the present study were to assess the prevalence and to evaluate the characteristics of referred pain associated with TMD diagnosed according to the DC/TMD. Methods: A total of 252 patients were evaluated using the DC/TMD Axes-I and –II assessment tools. Different modalities were used to treat the diagnosed TMD. Referred pain was diagnosed when the location of the perceived pain in response to palpation extended beyond the boundary of the structure that was examined. For pain locations that were perceived as deep, patients were asked to locate the surface of the area of pain. The result of the assessment was identified as positive if the patient described his perceived pain during the clinical examination as being familiar pain that was experienced in the same location in the last 30 days.  Results: TMD-associated referred pain was recorded in 153 patients (60.7%). The most common referred pain location was the temporal area (45.2%), followed by the ear (42.1%). The referred pain was recorded in disc displacement with reduction with intermittent locking and myofascial pain with referral in all patients (100%). The proportion of patients with referred pain was significantly different between the different TMD diagnostic subgroups (P < 0.001).  The recorded percentage of improvement in the referred pain following the treatment was 50.41% after 3 months and 56.65% after 6 months. Conclusions: Referred pain is a prominent feature of TMD. The prevalence of referred pain associated with TMD was 60.7%.  A strong strength association between the different diagnostic subgroups and the presence of referred pain existed. The pain associated with TMD is often a concatenation of diverse entangled pain sources. Microtrauma due to bruxism, joint laxity, and functional overloading are reported as the main causes of TMD, whereas TMD have been described as the most prevalent cause of non-odontogenic orofacial pain. The reported prevalence of TMD was contradicting among studies, mainly due to the different evaluation techniques, diagnostic criteria and different TMD taxonomy used in different studies.– Patients tend to ignore their TMD symptoms which can lead to more advanced forms of these disorders. The prevalence of incidentally discovered TMD was 10.8% in one study, among whom osteoarthritis was diagnosed in 11.69%.Temporomandibular disorders are a combination of muscular, skeletal, and neuromuscular pathologic conditions that influence the temporomandibular joint (TMJ), the muscles of mastication, and the related tissues. The common symptoms of TMD are headache , pain during chewing food, pain on opening or closing the jaws, TMJ pain, pain in the back of the neck, joint sounds, deviation upon opening the mouth, and limitation of mouth opening. An updated diagnostic protocol that relied on strong evidence was published in 2014 to enhance the sensitivity and specificity of the original RDC/TMD. The modified protocol was identified as the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), and included new Axis-I assessment algorithms, and new Axis-II evaluation methods. The Axis-I assessment algorithms are combinations of different assessment tools like pain screeners, symptom questionnaires, clinical examination criteria using specific examiner’s commands and radiographic criteria. The results of the assessment tools are used to interpret a decision tree that leads to the diagnosis of a specific TMD class. The DC/TMD instruments proposed new nomenclature for different TMD classes, as it expanded to evolve new instruments on evaluating pain perspective, psychological standing and psychosocial bahavior.The diagnosis of TMD is challenging even to the most experienced practitioner mainly due to the concurrence of symptoms among different disorders. TMD diagnosis is usually achieved through history, physical examination and different imaging modalities. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) is a reliable instrument for TMD diagnosis, and it incorporates two axes; Axis-I involves the clinical and the radiographical diagnostic criteria, whereas Axis-II focuses on the evaluation of the psychosocial status and pain-related disabilities. It is often challenging to the patient to identify the location of referred pain that spreads to deeper structures. Referred pain often complicates the diagnosis of TMD, as pain appears to originate from areas outside the anatomical boundaries of the joint and the associated muscles. In one study that compared the prevalences of comorbid headache, back, neck and joint pains in patients diagnosed with TMD in the United States, it has been reported that 0.77% of the studied population reported no comorbid pain, whereas 53% reported severe headache and migraine, 54% reported neck pain, 64% reported back pain and 62% reported joint pain. The close relationship between TMD, headache and neck pain was conformed in another study that suggested that headache intensifies TMD pain. The information about the TMD referred pain is still however limited in the literature. Elaborating the prevalence and characteristics of referred pain associated with TMD will benefit the patients’ community as well as the medical professionals by facilitating the complex diagnostic process of these disorders.TMD referred pain has been described as a familiar pain that spreads to an anatomically distant location away from the boundaries of the muscle or joint being examined. Familiar pain is the pain that can be reproduced in response to clinical provocation and has been experienced by the patient in the same anatomical location for 30 days prior to the clinical setting.The aim of this study was to assess the prevalence of referred pain associated with TMD diagnosed according to the DC/TMD in Sharjah, United Arab Emirates, to evaluate the characteristics of TMD referred pain, and investigate the correlations between the distribution of referred pain and the different TMD classes.2 p (1 – p)/d2, where z = level of confidence according to the standard normal distribution, p = estimated proportion of the population and d = tolerated margin of error. Comprehensive TMJ clinical examination was performed for all patients during their preliminary screening procedures. All patients who were initially diagnosed as having signs and symptom of TMD were enlightened about the objectives of the study and were asked to sign consent forms before participation.The study was performed at the College of Dental Medicine, University of Sharjah, United Arab Emirates, between February 2020 to June 2021. Ethical approval was granted by the Institutional Review Board at the University of Sharjah (REC-20-11-02-01-S). The ethical principles for medical research involving human subjects as mentioned in the Declaration of Helsinki were applied in this study. Sample size was calculated based on the formula n = (z) Helkimos clinical dysfunction index (Di) was utilized to identify patients with severe dysfunction symptoms (group Di III) and refer them for cone beam computed tomography (CBCT) examination. The diagnosis of disc displacement was endorsed by the use of magnetic resonance imaging.All subjects aged 18 to 60 years with signs and symptoms of TMD that were diagnosed during the initial examination were invited to participate in this study. The inclusion criteria involved all the signs and symptoms of TMD as clicking or crepitus sounds, TMJ pain, deviation in the path of mouth opening, catching sensation on opening or closure, limitation in mouth opening, headaches, ear pain and tenderness in the muscles of mastication. Patients were excluded from the study if they have been previously treated from TMD or if they had any systemic disease or used any medications that interfered with the perception of pain. Pregnant women were not enrolled in the study to prevent any detrimental effects from radiation. Patients were further evaluated using the DC/TMD validated assessment tools that included questionnaires, clinical examination, and radiographic examination., Symptom Questionnaire and Demographic Questionnaire.The Axis-I assessment instruments used to evaluate all patients were the TMD Pain Screener, The TMJ clinical evaluation was carried out by an oral and maxillofacial surgeon, who had over 15 years specialization in the management of TMDs. This examiner was blinded to the outcome of the initial screening procedure  as well as to any related outcomes that were evaluated in all questionnaires. Calibration of the examiners based on the DC/TMD protocol was accomplished before the start of the study by asking each examiner to assess the same 20 subjects independently. The results were then analyzed, and any disagreements were resolved through group discussion. Inter-rater reliability was measured using the intraclass correlation coefficients (ICCs). Radiographic evaluation was done by using CBCT for any suspected degenerative joint diseases, whereas MRI was conducted to evaluate suspected internal derangement. All CBCT assessments were performed using GALILEOS 3-D X-ray systems , whereas MRI examinations were performed using a 1.5 Tesla machine  with a TMJ surface coil. The joints were evaluated observing any disc displacement with any indication of recapture. MRI and CBCT records were analyzed twice, with a 1-week interval, by a specialist in oral radiology with 32 years of experience. The radiologist was blinded to the clinical evaluation outcomes. Intra-rater reliability was measured using the intraclass correlation coefficients (ICCs). TMD were then diagnosed and classified according to the DC/TMD Axis I criteria.Axis I-based clinical and radiographic examinations and structured diagnosis were carried out and included palpating the muscles of mastication and cervical muscles to diagnose the sites of tenderness or sustained contraction, auscultating, and palpating the joints during mandibular motion, observing the pattern of opening, and measuring the maximal mouth opening . Lateral excursions and the range of mandibular protrusion were also recorded. Pain level was assessed using the 10-point visual analogue scale (VAS) (0 indicating no pain and 10 indicating the most severe pain). disability score, muscle tenderness score and Jaw Functional Limitations Scale were used as assessment tools for DC/TMD Axis II evaluation. A diagram was given for the patients to illustrate and shade the area of pain and referred pain. GCPG was measured with a time frame of 30 days and classified by using the 10-point VAS. The disability scale assessed the pain related dysfunction while opening the mouth, while eating and after waking up, and was graded as no disability = 0 points, mild disability = 1 point, moderate disability = 2 points and severe disability = 3 points. The muscle tenderness assessments was graded as no tenderness = 0 points, mild tenderness = 1 point, moderate tenderness = 2 points and severe tenderness = 3 points. Functional Limitations Scale was measured by asking the patients if they develop any limitation during chewing hard food, wide opening, eating, yawning and talking. Back pain, neck pain, ear pain, dizziness and trouble sleeping were also evaluated. All patients were asked about their oral behavior in regard to clenching or grinding teeth while sleeping or when awake.Pain drawings, Graded Chronic Pain Scale (GCPG),Conservative therapyConservative therapy involved the use of stabilizing occlusal splints, soft diet, hot fomentation, limitation of mouth opening and non-steroidal anti-inflammatory drugs when needed. All patients were reevaluated postoperatively at 1, 3, and 6 months later to decide if any further treatment was required.ProlotherapyProlotherapy was used for the treatment of patients with subluxation. The auriculo-temporal nerve was anaesthetized then 10% dextrose solution was injected at four locations. The first injection point was employed for the upper joint compartment, and the pericapsular tissues where the needle was inserted 10 mm anterior to the tragus and 2 mm below the canthal-tragus line. The needle was then directed anteromedially and 0.8 ml of the solution was injected intraarticularly. The needle was then withdrawn and 0.4 ml solution was injected into the pericapsular tissues. The second injection point was marked 2 mm below the canthal-tragus line and 1 cm in front of the mid-tragus and the needle was inserted at a depth of 3 mm from the skin surface targeting the superior capsular attachment and 0.4 mL of solution was deposited. Then the inferior capsular attachment was injected at the third injection point; 1 cm below the first one, and 0.4 mL of solution was applied. The forth injection point was placed anterior to the tragus and the needle was inserted to a depth of 20 mm to reach the posterior disc attachment and 0.4 mL of the solution was then applied.Arthrocentesis The condyle was located and distracted downward and forward to widen the joint compartment and two 18-gage needles were inserted into each entry point. Single-needle arthrocentesis was done using a Y-shaped double-port cannula . The location for insertion was identical to the first needle in the double-needle technique. The joints were irrigated with 300 mL normal saline followed by the articular injection of 1 mL of low-molecular-weight Hyaluronic Acid (HA) . TMJ physical exercise regimen started after the procedure and continued for one month. Splint therapy was provided, and all patients were reevaluated at 1 week, 1 month, 3 months, and 6 months.The skin was prepared with povidone iodine then local anesthetic solution was injected to block the auriculo-temporal nerve. For the double-needle arthrocentesis technique; the location for the first needle puncture point was decided by marking the canthal-tragus line and marking the puncture point at either 10 mm or 7 mm anterior to the tragus depending on the canthal-tragus distance, and 2 mm under the canthal-tragus line. The second needle was inserted at a point 10 mm anterior to the first point and 10 mm under the line.Botulinum toxin (Botox) injection®, Allergan Inc., Dublin, Ireland) combined with conservative treatment. Trigger points in the masseter muscle were injected by a maximum of 35 units, whereas the trigger points in the temporalis muscle were injected by a maximum of 25 units. The patients were recalled for follow up after one week and then at 1 month, 3 months and 6 months. The injections were repeated after 3 months if needed.Patients diagnosed with local myalgia and local myalgia with referral were treated by the injection of OnabotulinumtoxinA .2 test of independence was used to determine the association between the 2 categorical variables. Various measures of correlation were applied as appropriate including; Cramer’s V measure of association, Point-biserial correlation coefficient, Rank biserial correlation coefficient and Phi correlation coefficient. Pareto Analysis was applied followed by the application of a z-test of 2 proportions to detect any statistically significant differences between the proportions of two groups. Reliability was measured using the Bland-Altman analysis. The significance level was set at P ˂0.05. Two-Tailed tests were assumed throughout the analysis for all statistical tests.Statistical analysis was performed using SPSS (version 20). Quantitative variables were described by the Mean, Standard Deviation (SD), Range (Minimum-Maximum), Standard Error (SE), and 95% confidence interval of the mean. Shapiro-Wilk test of normality was used to test the normality hypothesis of quantitative variables for further choice of appropriate parametric and non-parametric tests. Paired sample t-test was used for comparing pain levels at two-time points. Mann-Whitney U test was used for comparing mouth opening and duration between two groups. Qualitative categorical variables were described by proportions and Percentages. The χIn the present study, 252 patients  with a mean age of 34.19 ± 10.85 were enrolled. Patients were mainly Asian (53.2%), followed by Whites (39.7%) and Others (7.1%). TMD were diagnosed in the left TMJ in 180 patients (71.4%), whereas the right TMJ was involved in 167 patients (66.3%). TMJ pain on one side was reported in 141 patients (56.0%), whereas bilateral TMJ pain was reported in 103 patients (40.9%). Anterior disc displacement with reduction was the most prevalent diagnosis (40.5%), followed by local myalgia (13.9%), anterior disc displacement without reduction with limited mouth opening (13.5%), myofascial pain with referral (11.5%), osteoarthritis (8.3%), hypermobility (6.0%), anterior disc displacement without reduction without limited mouth opening (5.2%) and disc displacement with reduction with intermittent locking (1.2%). Muscle tenderness was recorded on the masseter muscle in 76 patients (30.2%), in the temporalis muscle in 62 patients (24.6%) and in the lateral pterygoid muscle in 23 patients (9.1%). Excellent inter-rater and intra-rater reliability was achieved for the clinical and radiographic diagnosis respectively (ICC = 0.95-0.96). Axis II evaluation showed that 83.7% of patients had moderate to severe GCPG that interfered with their ability to work and with social activities, whereas 71.8% of patients had severe limitation according to the Jaw Functional Limitations Scale.Referred pain was recorded in 153 patients (60.7%). The highest prevalence of referred pain was seen in the temporal area (45.2%), followed by the ear (42.1%), neck (19.0%) and forehead (17.5%) . The preThe referred pain was recorded in disc displacement with reduction with intermittent locking and myofascial pain with referral in all patients (100%), in osteoarthritis in 19 patients (90.48%) and in hypermobility in 11 patients (73.33%) . The proIn anterior disc displacement with reduction, dull referred pain was reported in 41 patients (40.2%), sharp and throbbing referred pain was reported in 24 patients (23.5%) and heterogeneous referred pain was reported in 2 patients (1%). In anterior disc displacement with reduction with intermittent locking, dull referred pain was reported in 2 patients (66.7%) and sharp and throbbing referred pain was reported in 1 patient (33.3%) . The CraIn the present study, 198 patients (78.6%) received the required treatment for their TMD. Following treatment, 83 patients (62.4%) reported improvement of their referred pain . The ref The central sensitization theory also explains the referred pain mechanism through the continuous painful stimulus that can lead to the activation of distinct receptors that expand the sensitivity of neurons, thus widening the receptive field area. This changes the normal processing at the higher centers and causes nonpainful information to be perceived as painful. The studies concerned with the TMD-associated referred pain are limited in the literature.The referred pain often complicates the diagnosis of TMD and may lead to progression to advanced forms of the disorders before the proper diagnosis is reached. Referred pain is mainly due to the visceral and somatic senses that have been carried to the brain through the same neurons, accordingly patients are not capable to localize the origin of the pain. The convergence projection theory stated that the sensory information travel to the central nervous system (CNS) through nerves that converge to neurons. The number of neurons is less than the number of nerves so the information from multiple nerves has to converge to a less number of neurons to be carried to the CNS. The convergence appears at the level of the neurons that transmit impulses from deep structures like teeth pulp, joints, and muscles rather than from superficial structures. The neurons that originate from the TMJ and the masseter muscle appear mainly to converge in the trigeminal subnucleus caudalis. This theory elucidates the difficulty in localizing the pain which originates from the TMJ and the associated muscles and leads to referred pain away from the pain origin site. The study was based on the RDC/TMD Validation and TMD Impact studies, whereas the present study was based on the modified DC/TMD classification that imposed new pain definitions and localization protocols. In the present study, the referred pain was recorded most commonly in the temporal area (45.2%) followed by the ear (42.1%) then the neck (19.0%). In another study, the TMD referred pain was reported most commonly in the cheek region followed by the ear and the forehead. The author of the study concluded that the pattern of TMD referred pain was consistent and predictable, which agrees to our study. Another study reported the prevalence of referred TMD pain in the ear as 51.3%, which is in accordance with our results.,In the present study, the prevalence of referred pain in patients diagnosed with TMD was 60.7%. Another study showed a lower prevalence of referred pain (26.4%), where the locations of referred pain were classified into extraoral, intraoral, and joint sites. According to this study, the TMD referred pain was diagnosed at the temporalis muscle (9.6%), masseter muscle (14.3%) and at the mandibular area (8.6%) whereas the joint area was involved in 7.5%.The evaluation of the prevalence of referred pain in different DC/TMD classes has shown that the most common location for referred pain in anterior disc displacement with reduction was in the temporal area (36.8%), in anterior disc displacement with reduction with intermittent locking was in the ear (37.5%), in anterior disc displacement without reduction with limited mouth opening was in the temporal area and the ear equally (36.4%) and in anterior disc displacement without reduction without limited mouth opening was in the temporal area and in the ear equally (29.4%). Referred pain was recorded in the ear and in the temporal area equally in hypermobility (26.1%), and in myofascial pain with referral (29.0%). These results are expected to facilitate the complex diagnostic processes of TMD by elaborating the possible pathways of referred pain related to each DC/TMD class. There was a weak association in our study between temporalis muscle and masseter muscle tenderness and referred pain, and there was no association between lateral pterygoid muscle tenderness and referred pain. It has been shown that the presence of TMD-associated headaches in patients with myofascial pain does not negatively affect the treatment of pain; however it might change the pattern of pain improvement after the proper management.In the present study, the association between referred pain and mouth opening was found to be weak. This result was not in accordance with another study that showed strong association between the mouth opening and referred pain in patients with TMD-related migraine.The significant reduction in referred pain levels following different forms of treatment confirms that TMD was the cause of referred pain. Similar results were reported in another study that showed a reduction in the disability scores and referred pain levels following TMD treatment. The inconsistency in describing orofacial pain characteristics among various studies may negatively affect the scientific value of these studies. The authors of the present study recommend the unifying of the pain descriptive terms in different studies to maximize the benefit to the scientific community when comparing the results of these studies.In the present study, the TMD referred pain characteristics were reported as dull pain in 42.5% of patients and as sharp and throbbing pain in 36.2% of patients. In another study, the TMD-related referred pain in the ear was described as severe and unbearable pain in 31.03% of patients, and as mild and bearable pain in 68.97% of patients.The main limitation of this study was the small sample size. Therefore, the presented data should be interpreted with caution. However, considering the high prevalence of TMD, the findings of this study might encourage the pursuing of future studies with larger sample sizes.In conclusion, referred pain is a prominent feature of TMD. The prevalence of referred pain associated with TMD was 60.7%. The most common referred pain location was the temporal area, followed by the ear. Anterior disc displacement with reduction with intermittent locking and myofascial pain with referral were the most common diagnoses associated with referred pain. There was a strong strength association between the different diagnostic subgroups and the presence of referred pain, a moderate strength association between the pain character and the diagnostic subgroups, whereas a weak association was found between the diagnostic subgroups and the referred pain locations. Following treatment, 62.4% of patients reported improvement of their referred pain levels. More studies are required with longer follow-up periods and bigger sample sizes to support the findings of the present study that are expected to significantly improve the diagnostic processes of TMD.This study is a part of a thesis submitted for partial fulfillment of the requirements of the Masters of Science Degree in Oral Surgery.Research Ethics Committee, University of Sharjah.Written informed consent for publication of the participants/patients’ details and/or their images was obtained from the participants/patients/parents/guardian/relative of the participant/patient.https://doi.org/10.7910/DVN/GXTCDRRepository: Harvard Dataverse: “Replication Data for: Prevalence and characteristics of referred pain in patients diagnosed with temporomandibular disorders according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)”,•Data file 1. This project contains the following underlying data:Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).Data are available under the terms of the All comments were addressed.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Dental Public HealthI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The submitted manuscript wishes to report the “Prevalence and characteristics of referred pain in patients diagnosed with temporomandibular disorders according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)”. The topic is of interest however at first reading some modifications maybe required to improve the quality of the manuscript. A proper rationale for the outlined hypothesis is not feasible without providing details of the demographic information of the included sample. In addition, authors should mention details of their inclusion and exclusion criteria. It will be surprising if the sample included for examples medically compromised patients who suffer from systematic diseases, on medications, previous surgery or TMJ problems, or diagnosed with bone diseases or osteoporosis.  The reviewer is also wondering whether the case diagnosis, evaluation, and data recording were done by only one investigator and whether the investigators had checked for intra- or inter-rater reliability.  It will also be very useful to the readers if the authors included the power of study analysis or sample size calculation.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Orthodontics, 3D imaging, Airway Analysis, Obstructive Sleep Apnea (OSA), Virtual Reality (VR), Augmented Reality (AR), and Artificial Intelligence (AI)I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Response to Reviewer 2: Ahmed Ghoneima The authors would like to express their gratitude for the reviewer for his constructive comments. We are hereby providing a point by point response. Comment 1: A proper rationale for the outlined hypothesis is not feasible without providing details of the demographic information of the included sample. Response: More demographic details were added in the results section. Comment 2: Authors should mention details of their inclusion and exclusion criteria. Response: The inclusion and exclusion criteria were elaborated in the Methods Section. Comment 3: The reviewer is also wondering whether the case diagnosis, evaluation, and data recording were done by only one investigator and whether the investigators had checked for intra- or inter-rater reliability.  Response: The TMJ clinical evaluation was carried out by two examiners; an oral and maxillofacial surgeon and a general dental practitioner who did the initial screening. The surgeon was blinded to the outcome of the initial screening procedure as well as to any related outcomes that were evaluated in all questionnaires. Calibration of the examiners based on the DC/TMD protocol was accomplished before the start of the study by asking each examiner to assess the same 20 subjects independently. The results were then analyzed, and any disagreements were resolved through group discussion. Inter-rater reliability was measured using the intraclass correlation coefficients (ICCs). The radiographic evaluations were analyzed twice, with a 1-week interval, by one specialist in oral radiology. The radiologist was blinded to the clinical evaluation outcomes. Intra-rater reliability was measured using the intraclass correlation coefficients (ICCs). Excellent inter-rater and intra-rater reliability was achieved for the clinical and radiographic diagnosis respectively (ICC=0.95-0.96). Comment 4: It will also be very useful to the readers if the authors included the power of study analysis or sample size calculation. Response: The formula used for the sample size calculation was added to the Methods Section. TitleThe study was conducted in Sharja, UAE - this needs to be reflected in the title and aim of your study.IntroductionNo prevalence studies in the introduction.Explain Axis-I assessment algorithms for the reader.MethodsWhere is the reference for Helkimos clinical dysfunction index?All instruments used - you need to use references. The author needs to cite all instruments used in the study.Are the tools used in the study validated?What is the gold standard for TMD?Spelling mistakes e.g., month vs mouth.Please arrange the diagnosis to be the same for figures and tables. TablesTable 1 - mention n(%) in one cell instead of two.Figure 3 is not clear, it would be better to remove the figure to avoid confusion.Combine table 1 and 2.Discussion & ConclusionFirst part of the discussion should be in the introduction.You need to cite more papers in the discussion unless the information provided is new and has not been conducted in this case state that this clearly. Limitations of the study should be stated before conclusion.Please re-write your conclusion based on your results.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Dental Public HealthI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Response to Reviewer 1: Khalifa Sulaiman Al-Khalifa The authors would like to express their gratitude for the reviewer for his constructive comments. We are hereby providing a point by point response. Comment 1: Title: The study was conducted in Sharjah, UAE - this needs to be reflected in the title and aim of your study. Response: It has been indicated in the title and aim that the study was conducted in Sharjah, United Arab Emirates. Comment 2: Introduction: No prevalence studies in the introduction. Response: The related prevalence studies were added in the introduction. Comment 3: Explain Axis-I assessment algorithms for the reader. Response: Axis-I assessment algorithms have been explained in the Introduction Section. Comment 4: Where is the reference for Helkimos clinical dysfunction index? Response: The reference was added in the Methods Section. Comment 5: All instruments used - you need to use references. The author needs to cite all instruments used in the study. Response: The missing citations were added in the Methods Section. Comment 6: Are the tools used in the study validated? Response: Yes, only validated tools were used in this study. An indication was added in the Methods Section. Comment 7: What is the gold standard for TMD? Response: The DC/TMD  is an objective and reliable diagnostic protocol that uses several validated assessment tools with high sensitivity and specificity. Magnetic resonance imaging is usually required to diagnose soft tissue disorders whereas cone beam computed tomography is needed to evaluate the bony changes. Comment 8: Spelling mistakes e.g., month vs mouth. Response: The spelling mistakes were corrected. Comment 9: Please arrange the diagnosis to be the same for figures and tables. Response: The diagnosis was arranged to be the same for figures and tables. Comment 10: Table 1 - mention n(%) in one cell instead of two. Response: Table 1 was modified and n(%) was mentioned in the same cell. Comment 11: Figure 3 is not clear, it would be better to remove the figure to avoid confusion. Response: Figure 3 was modified so that it is clearer to the reader. Comment 12: Combine table 1 and 2. Response: Tables 1 and 2 were combined in one table (table 1). Comment 13: First part of the discussion should be in the introduction. Response: The authors totally understand and value the comment of the reviewer. In the Introduction Section, the authors define the TMD referred pain as described by the DC/TMD and explain the reason why this type of pain often complicates the diagnosis of TMD. In the discussion section, the authors explain the neuroanatomic and physiologic theories of the referred pain. Comment 14: You need to cite more papers in the discussion unless the information provided is new and has not been conducted in this case state that this clearly.  Response: Although many studies evaluated the pain associated with the different classes of TMD, a limited number of studies were concerned with the TMD-associated referred pain. This was elaborated in the first paragraph in the Discussion Section. Comment 15: Limitations of the study should be stated before conclusion. Response: The limitations of the study were added before the conclusions. Comment 16: Please re-write your conclusion based on your results. Response: The conclusions were re-written based on the results.


I had been practising acupuncture for 30 years and noticed while working in the rheumatology clinic that costochondritis had a particular response to acupuncture. As this condition is extremely debilitating and often misdiagnosed, a case series of 8 cases is presented, the majority of whom were seen in primary care.Costochondritis is characterised by anterior chest pain associated with painful tender costochondral (CC) joints felt on palpation. These mainly affect the 2nd to 5th costochondral junctions, either unilateral or bilateral. Other areas of the anterior and lateral chest wall can also be affected. The pain is often severe and nocturnal, of sudden onset and can be associated with shock, nausea and dyspnoea, causing patients to call for an ambulance. Tietze's syndrome is a rare variant of this, usually affecting younger patients.Patients with persistent chest wall pain were offered acupuncture. Details of age, duration of symptoms, number of treatments and VAS pain scores were recorded day and night,  pre and 0.25*25mm and 0.25*30mm needles were used with silicon tips and a guide tube, to help prevent painful insertion. An infra-red lamp (Bio-lamp) was used + electro-acupuncture (EA) if insufficient improvement after two close treatments, sessions were continued weekly.Acupuncture points used were local tender/trigger points + distal Chinese points P6 and LI4. Other points used were CV 17, GB 34, SI6, GB39 or Sp 6 and St36. An average of 4.7 sessions were needed.Audit of Acupuncture Treatment Table 1Six patients took daily analgesia which was rapidly reduced to nil. All completed their treatment until their pain stabilised. There were no adverse events.Average improvement in the day was 89% and night 85%. Recurrences of pain improved by 11% in the day and 72% at night. The attacks of severe chest pain and dyspnoea stopped, abating anxiety.Costochondritis is a highly debilitating condition and I had noticed that acupuncture could be a dramatic treatment for this[i]. It can affect up to a third of patients attending emergency departments with atypical chest pain[ii] and 1-3% of patients in primary care[iii].It seems to be a missed diagnosis by Accident and Emergency (A&E) doctors and GPs, perhaps because the chest wall was not carefully palpated. One patient had ankylosing spondylitis (AS) and another had systemic lupus erythematosus but attributed her pain to prolonged laughter. Five patients attended cardiology clinics including one who had a coronary angiogram. Another had tests for upper abdominal pain which also were normal.All the patients were female although quoted F:M ratio is 7:3Differential diagnoses include: acute coronary syndromes, lung problems, trauma, upper gastroenterology pathology or neoplasiaPathogenesis is unclear but the onset can be acute and follow:Respiratory tract infection  Extreme sneezing, coughing or laughterChest wall trauma        Micro trauma from costovertebral dysfunctionFibromyalgia          Inflammation from inflammatory joint disease.[i] Alexander R; White A. Acupuncture in a Rheumatology Clinic. Acupuncture in Medicine; Dec 2000 vol.18 (no.2): 100-103[ii] Disla E; Rhim HR; Reddy A; Karten I; Taranta A. A prospective analysis in an emergency department setting. Arch Intern Med. 1994; 154(21):2466-2469[iii] Ayloo A; Cvengros T; Marella S. Evaluation and treatment of musculoskeletal chest pain. Prim Care (Review) Dec 2013 40(4): 863-87Normal management of costochondritis includes analgesia, physiotherapy, steroid injections and occasionally surgery[i]. 30% can have protracted pain. There are isolated reports of acupuncture for this condition, integrated with conventional medicine[ii] [iii]. Acupuncture also has been used for myofascial trigger points including costochondritis[iv].Acupuncture is now an accepted modality of pain management and in 2021 was recommended in NICE guidelines for the treatment of Chronic Primary Pain alongside exercise programmes and CBT ahead of analgesic medication[v]. It has also been recommended in the management of low back pain in patients aged 60 years and over as a non-drug treatment[vi].This paper highlights the fact that acupuncture appears to be a safe effective treatment for costochondritis, with further research and more access needed for this therapeutic modality.Increased awareness of this condition would make complex invasive investigations less necessary.[i] Gologorsky R; Hornik B; Velotta J. Surgical Management of Medically Refractory Tietze's Syndrome. Annals of Thoracic Surgery; Dec 2017; vol. 104 (no. 6)[ii] Jonkman FAM.; Jonkman-Buidin M.L; Stolwijk P.W.J. Surprise after successful treatment of a patient with noncardiac chest pain using acupuncture. Medical Acupuncture; Feb 2015; vol.27(no 1):83-90[iii] Lin, Katerina; Tung, Cynthia. Integrating Acupuncture for the Management of Costochondritis in Adolescents. Medical Acupuncture; Oct 2017; vol.29(no 5): 327-330[iv] Baldry P. Cardiac and non-cardiac chest wall pain. Acupuncture in Medicine;1997; vol.15(no.2): 42-45[v] NICE guideline; Chronic Pain (primary and secondary) in over 16s (NG 193 April 2021)[vi] Traeger A; Underwood M;Ivers R; Buchbinder R. Low back pain in people aged 60 years and over. BMJ 2022 vol. 376: e066928


N = 216, 90 implanted) and 2 others that examined LF-SCS . Our analysis of 6-month data found clinically meaningful pain relief with each SCS modality. However, significantly greater pain reduction was identified for 10 kHz SCS over LF-SCS: average pain reduction in the 10 kHz SCS cohort was 73.7% compared with 47.5% in the pooled LF-SCS group (p < 0.0001). In the permanent implant subset, the 50% pain reduction responder rate was 83.3% in the 10 kHz SCS cohort versus 63.0% in the pooled LF-SCS group (p = 0.0072). The overall risk of bias of each included RCT was deemed high, mainly due to the absence of patient blinding. Our analysis indicates that paresthesia-free 10 kHz SCS can provide superior pain relief and responder rate over LF-SCS for managing PDN patients refractory to conventional medical management.Spinal cord stimulation (SCS) is increasingly used to treat painful diabetic neuropathy (PDN). At the time of a recent meta-analysis in this field, data were only available from randomized controlled trials (RCTs) of traditional low-frequency SCS (LF-SCS). However, outcomes from high-frequency 10 kHz SCS treatment are now available. Our study aimed to systematically review the contemporary evidence for SCS in patients with lower limb pain due to PDN and include an indirect comparison of the high- and low-frequency modalities. We searched the PubMed/CENTRAL databases up to 18 August 2022, for peer-reviewed RCTs of SCS that enrolled PDN patients with lower limb pain symptoms. The quality of the evidence was assessed with the Cochrane Risk of Bias tool. Using SCS treatment arm data from the RCTs, we indirectly compared the absolute treatment effect of 10 kHz SCS and LF-SCS. Results are presented in tables and forest plots. This systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Three RCTs met our eligibility criteria, including the recent 10 kHz SCS RCT ( Diabetic neuropathy (DN) is the most common complication of diabetes, affecting approximately half of all patients ,2. The cPharmacotherapy is the mainstay of analgesic treatment for PDN, with clinical guidelines recommending pregabalin and duloxetine as first-line treatment options . Other rSince the late 1960s, traditional low-frequency spinal cord stimulation (LF-SCS) has been a recognized treatment for chronic neuropathic pain. During LF-SCS, therapeutic paresthesia is elicited in the painful dermatomes by applying electrical pulses to the spinal cord at frequencies ranging from 40 to 60 Hz. Successful masking of pain relies on concordance of the induced paresthesia with the painful area. The therapy is a common treatment option for postlaminectomy syndrome and complex regional pain syndrome . Howeverp < 0.001) [Over the last decade, novel SCS waveforms have emerged that provide pain relief at subsensory levels, which may be a more comfortable and desirable option for patients. One such stimulation paradigm is high-frequency SCS at 10 kHz (10 kHz SCS), a paresthesia-free therapy whose mechanism of action is independent of paresthesia . Compare< 0.001) ,16. In a< 0.001) ,23,24,25Several pilot studies have also explored SCS as a treatment for PDN refractory to conventional medical management (CMM), with encouraging outcomes across all modalities ,35,36,37A recent systematic review and meta-analysis assessed the effectiveness of SCS for the management of PDN . At the Articles were eligible for inclusion if they reported pain-related outcomes from an RCT of SCS that enrolled PDN patients with lower limb pain symptoms. Publications were excluded if (1) they were not peer-reviewed or had no full-text manuscript available , (2) no original data were presented , or (3) data could not be extracted for the population of interest .We searched the PubMed and CENTRAL electronic databases from inception to 18 August 2022, using a combination of MESH terms and free-text words. Additional published filters were used to identify RCTs during the PubMed search ,57. The A single reviewer (D.E.) screened titles and abstracts to identify articles eligible for further review. Full-text manuscripts were subsequently obtained and assessed for compliance with eligibility criteria.Two reviewers (S.L. and D.E.) extracted the following data from the eligible RCT publications: study design variables, patient demographics, sample size, interventions, mean pain intensity scores measured using either the visual analog scale  or a numerical rating scale , number of subjects with at least a 50% reduction in pain intensity from baseline , and treatment-related adverse events (AEs). In addition, SL extracted patient-level pain intensity scores if the individual patient data (IPD) were available.Two standard SCS efficacy outcomes were used in our analysis: (1) mean pain intensity reduction from baseline and (2) responder rate, i.e., defined as the proportion of subjects with at least a 50% reduction in pain intensity from baseline.Cochrane Handbook for Systematic Reviews of Interventions [A single reviewer (D.E.) assessed the risk of bias for each eligible RCT using the Cochrane Risk of Bias 2 (RoB 2) tool, according to the criteria outlined in the ventions . The RoBWe used the mean difference (MD) with a 95% confidence interval (CI) for the continuous outcome of pain intensity reduction from baseline. Relative risk (RR) with a 95% CI was chosen for the dichotomous responder rate outcome.We conducted an indirect comparison of the absolute treatment effect of 10 kHz SCS and LF-SCS using SCS treatment arm data from the included RCTs  10 kHz SCS , (2) SlaTwo analysis populations were defined for each group that allowed the comparison of equivalent patient cohorts: (1) a modified intention-to-treat (mITT) population consisting of randomized individuals who entered the SCS trial phase and (2) a permanent implant population with subjects who completed the SCS trial phase and received a permanent system.Next, we determined the mITT mean pain intensity reductions with 95% CI at 6 months for each of the 4 groups, including data conversion as needed to allow consistent comparison between studies . The mehttps://automeris.io/WebPlotDigitizer, accessed 25 August 2022). For the de Vos LF-SCS group, we extracted mean pain scores directly from the study publication. Since the investigators assessed pain using a 0-100 VAS, we divided the mean pain scores by 10. Data from the Slangen and de Vos studies were combined for the pooled LF-SCS group, with the pooled mean pain reduction and variance determined via the inverse variance method.Data for the Slangen LF-SCS group were sourced directly from the study publication. The investigators assessed day- and night-time pain separately and presented outcomes at the aggregated subject level. From these data, we calculated an average (with pooled variance) of the 0–10 NRS daytime and night-time pain scores . We averaged the day- and night-time responder rates from the Slangen study. For the pooled LF-SCS group, we combined the responder data from the Slangen and de Vos study publications. The pooled relative risk for the responder rates and associated confidence intervals were calculated using the Mantel-Haenszel method.We subsequently compared the population-level responder rates between the 10 kHz SCS cohort and each LF-SCS group. These comparisons used the Wald Chi-square statistic under the null hypothesis of RR = 1, i.e., no difference between groups.Given the varied presentation methods used in the included studies, formal numeric synthesis of study-related AEs was not applicable. Instead, we tabulated and narratively summarized the AE findings across the included trials.The search strategy retrieved 194 unique citations . Of thesStudy characteristics are summarized in Among the studies, all subjects had PDN with predominant lower limb or lower extremity pain  refractory to previous treatments; however, the definition of refractory varied. In addition, significant upper limb or upper extremity pain symptoms were an exclusion criterion in all studies.All 3 RCTs had an open-label, parallel-group design with a total of 312 participants (range 36 to 216) randomized in differing ratios  [All studies reported adverse events (AEs). However, the level of detail varied. For example, the Slangen RCT presented only serious adverse events (SAEs) during their 6-month randomized phase . In contmplants) .We judged all RCTs to have a low risk of bias for the randomization process (D1) and deviations from the intended interventions (D2).In the missing outcome data assessment (D3), we judged all 3 RCTs to have a low risk of bias at 6 months for different reasons. For example, despite an imbalance in the levels of missing data between the groups in the Slangen RCT, the levels of missing data were low, and the analysis designated all missing subjects as nonresponders . At the We deemed all 3 studies to have a high risk of bias in the fourth domain (D4) due to the use of a patient-reported outcome (PRO) in an unblinded study, i.e., the assessor was aware of the treatment allocation. Open-label study designs, such as those used in all 3 RCTs, are standard in the SCS field due to the need for an implanted device and perceptible paresthesia during LF-SCS. Using validated pain PROs, such as VAS and NRS, is also typical. Considering the design of the included RCTs, the pain PRO could have been influenced by an expected benefit from permanent stimulation or CMM not perceived as proper treatment. Furthermore, participants in all 3 studies knew they could cross to the other treatment arm after 6 months if their treatment was inadequate.While there were no apparent indications of selective data reporting in the Slangen or de Vos studies, neither had a published protocol or statistical analysis plan (SAP) ,40, leadThe overall risk of bias was deemed high for each RCT due to the high risk of bias rating in D4, primarily due to the studies using a PRO in the absence of patient blinding.p < 0.0001 vs. Slangen LF-SCS; p = 0.0060 vs. de Vos LF-SCS; p < 0.0001 vs. pooled LF-SCS; p = 0.016) and the pooled LF-SCS group (p = 0.018), respectively (p = 0.1478).ectively . While fp = 0.026), de Vos LF-SCS group (p = 0.044), and pooled LF-SCS group (p = 0.0072), respectively.The corresponding outcomes and RRs for the permanent implant populations are shown in n = 3), wound dehiscence (n = 2), impaired wound healing (n = 1), device extrusion (n = 1), incision site pain (n = 1), implantable pulse generator (IPG) site pain (n = 1), lead migration (n = 1), and uncomfortable stimulation (n = 1) [ (n = 1) . The inv (n = 1) . In addiSlangen and colleagues documented 2 SAEs during their 6-month randomization phase, including 1 death from a subdural hematoma following a dural puncture and 1 postimplant infection leading to explant . No IPG The investigators in the de Vos study reported several treatment-related AEs during their 6-month RCT. These included the repositioning of 1 lead due to migration and 2 leads due to poor paresthesia overlap, the revision of 2 IPGs due to pain around the implant site, 1 infection during the trial phase, and 1 coagulopathy during the permanent implantation procedure .Our literature search identified 3 RCTs that assessed the impact of SCS in patients with lower limb pain due to PDN. One study reported outcomes from 10 kHz SCS treatment, a modality that provides pain relief without paresthesia . The rep < 0.0001).Overall, our analysis found a mean reduction in pain intensity from baseline that exceeded the minimal clinically important difference (MCID) of 2 points or a 30% reduction, regardless of SCS modality . HoweverIn all but one scenario of analysis population, individuals treated with 10 kHz SCS were also significantly more likely to respond to therapy at 6 months postimplantation than subjects who received LF-SCS.In summary, patients with refractory PDN who received 10 kHz SCS had a significantly higher reduction in pain and a greater likelihood of response to therapy at 6 months than those who received LF-SCS. In addition, 12-month results from the SENZA-PDN study showed sustained pain relief and replication of outcomes in crossover patients , with 24p < 0.001). While the patient populations in the SENZA-RCT and the SENZA-PDN studies differed, the higher level of pain relief provided by 10 kHz SCS in both patient groups suggests that the high-frequency modality may be a more robust pain therapy than LF-SCS.Our findings support previous research that showed the superiority of 10 kHz SCS over LF-SCS in chronic back and leg pain ,16. In tIn general, SCS is a well-recognized treatment option for patients with neuropathic pain symptoms, with the therapy increasingly used in the PDN indication. Our results suggest that 10 kHz SCS may improve clinical outcomes over LF-SCS in this patient group, an important finding in a difficult-to-treat cohort. Furthermore, the need for effective nonpharmacological treatments for this indication will only increase, given the rising prevalence of diabetes worldwide .The difference in outcomes between the high- and low-frequency stimulation modalities may be due to differing mechanisms of action (MOA). The analgesic effect of LF-SCS is premised on the gate control theory of pain, which postulates that the transmission of pain signals can be modulated by inhibitory interneurons in the spinal dorsal horn activated by antidromic stimulation of Aβ fibers in the dorsal column ,64,65. TThe absence of paresthesia during 10 kHz SCS suggests that its pain-relieving effect is not dependent on the activation of dorsal column Aβ fibers. This theory is supported by preclinical research that suggests low-intensity 10 kHz stimulation activates inhibitory interneurons in the dorsal horn without activating the dorsal column fibers that cause paresthesia . High-frp < 0.001) [In support of a different MOA, in a head-to-head clinical trial (SENZA-RCT), 10 kHz SCS provided superior relief of back and leg pain over LF-SCS, with a significantly higher proportion of 10 kHz SCS individuals with chronic back pain reporting response to therapy at long-term follow-up  ,16. AccoThe absence of paresthesia during 10 kHz SCS may improve patient comfort and therapy acceptability in general, and may be especially beneficial in PDN patients who often have underlying disease-related paresthesia symptoms. Moreover, 10 kHz SCS may improve neurological deficits associated with PDN, an outcome that does not appear to have been assessed in the LF-SCS studies. Petersen et al., reported that 62% of patients experienced a clinician-assessed neurological improvement after 6 months of 10 kHz SCS treatment, with most improvements observed in sensory function . Taken tComplications arising from lead displacement, lead breakage, and pain around the implant site are well described during SCS, with respective incidence rate ranges of 2% to 27%, 6% to 10%, 1% to 12% (excluding PDN studies) . HoweverAlthough all studies included in our review reported AE data, the number of studies was small, and the level of detail varied. Overall, the reported complication rates associated with leads and IPGs were broadly comparable to the SCS literature. Importantly, this was also true for the incidence of infection, which is of particular interest in PDN patients, given the susceptibility of diabetic patients to infection . The genThis review is the first to compare 10 kHz SCS with LF-SCS for the treatment of PDN. While we did not prepare a predefined protocol or register the systematic review, we conducted structured searches and analyses. In addition, we provided a detailed and transparent presentation of methods and data to allow reproducibility. We also reported the study in line with the PRISMA 2020 guidelines for systematic reviews .The small number of RCTs included in our review should be borne in mind when interpreting our results. In addition, the control arm in each included study was CMM, which prevented a direct comparison of 10 kHz SCS and LF-SCS. However, as the individual RCTs were broadly similar concerning interventions, patient populations, and pain intensity outcome measures, an indirect comparison method was deemed reasonable.Limitations arising from our analysis approach should also be considered. For example, we defined and calculated a responder rate endpoint of 50% pain relief from the included datasets. While we selected this outcome to allow consistent comparison across studies, the Slangen and Petersen RCTs had study-defined primary endpoints that combined ≥ 50% pain relief with another measure. The Slangen study defined treatment success as meeting any 1 of 4 criteria . In the Petersen study, the criteria were narrower, with only a single pain threshold measure (≥50% pain relief) combined with no observed neurological deterioration. Our use of a different endpoint to the original study analyses may have introduced bias.In addition, the necessity for data conversion in the LF-SCS studies may have impacted the fidelity of data pooling and between-study comparisons. Notably, Slangen et al., did not measure overall pain but instead assessed separate day and night pain in anticipation of a potential diurnal effect ; thus, wThe studies included in our review also had important shortcomings. Principally, none of the RCTs included a sham stimulation control arm. While this type of open-label study design is standard in the SCS field for practical reasons, it introduces a risk of bias and placebo effect. That said, the longer-term follow-up durations in the Petersen (12 months) and Slangen (60 months) RCTs should mitigate the placebo effect to a great extent. However, this mitigation may be weakened in the 60-month Slangen analysis due to the inclusion of an additional cohort and a high attrition rate  .We also noted that the LF-SCS sample sizes in the Slangen and de Vos studies were small compared with the Petersen study; this may have resulted in the individual study comparisons between the modalities being underpowered. In addition, the de Vos study had nearly 4-fold the percentage of type 1 diabetes at baseline compared with the Petersen RCT. This large difference in type 1 diabetes prevalence may have contributed to the nonsignificant difference in responder rate between these 2 studies, the only comparison between 10 kHz SCS and LF-SCS that did not show a statistically significant difference.Other considerations include a large number of centers in the 10 kHz SCS study compared with the LF-SCS trials and the time frame of study enrollment  overall health score (VAS) measured during the 6-month randomized phase. However, our analysis was focused on pain relief and did not include this outcome. Future systematic reviews should examine these results and the long-term HRQoL outcomes available from the Petersen  and SlanSpinal cord stimulation is increasingly used to address the debilitating symptoms of neuropathic pain in PDN patients. We identified RCT evidence supporting both 10 kHz SCS and LF-SCS as beneficial treatments for patients with PDN who fail conventional medical management. Our analysis indicates that 10 kHz SCS can provide superior pain relief and pain responder rate over LF-SCS for managing PDN patients. An RCT that randomizes PDN patients to either 10 kHz SCS or LF-SCS would be valuable for confirming these results.


Effective symptom control is a stated goal of palliative care (PC) to improve quality of life for terminally ill patients. Virtual reality (VR) provides temporary escapes from pharmacologically resistant pain and allows for experiences and journeys patients may not access in any other way. Enabling wishes through virtual worlds may also offer additional benefits such as controlling psychological and physical symptoms.We investigated the feasibility of a single VR experience as a viable, satisfying, and effective tool for end-of-life pain relief for inpatients presenting palliative needs.This is an observational, single-arm and national single-center feasibility trial.A one-time VR experience with a selection of several videos and games was offered to 45 inpatients receiving PC at Muenster University Hospital. Patients with brain tumors, brain metastases, seizures, motion sickness, claustrophobia, vertigo, hearing or visual impairment, or unable to consent were excluded. Primary outcome measured patient reported pain on a visual analogue scale (VAS). We also measured Karnofsky performance status, health-related quality of life (HRQOL) using the EQ-5D-5 L questionnaire, and the Pain Out Questionnaire for postoperative pain.We analyzed data from 21 women (52.5%) and 19 men (47.5%) at an average age of 51.9 (SD: 15.81) years. The mean Karnofsky score among the sample was 45.5 (SD: 14.97) and the HRQOL was 41.9 (SD: 23.08). While no serious side effects were reported during the intervention, three patients experienced nausea (7%), two headaches (5%), and three reported dry eyes (7%) afterwards. Significant pain reduction (baseline VAS 2.25 (SD: 0.4399)) was demonstrated during ), immediately after ) and one hour after the intervention ). More than 80% rated the VR experience as very good or good  and intended to make use of the device again . However, two participants (5%) also expressed sadness by becoming aware of old memories and previous opportunities that are gone.The present pilot study suggests that VR seems to be a feasible and effective tool for pain relief in PC. Its use encompasses the approach of a total pain and symptom therapy and enhances patients’ dignity and autonomy. Future research ought to include if and to what extent VR could reduce the necessity of pharmacological pain relief. The World Health Organization defines palliative care (PC) as an interdisciplinary specialty that aims to improve the lives of patients suffering from life-threatening disease and is most commonly provided by PC consultation teams or PC units in inpatient healthcare services. There is evidence that PC is associated with lower symptom burden, improved quality of life, and prolonged survival –4.A comprehensive concept is required whenever seriously ill and dying people are accompanied, treated and counselled, in order to cope with life-limiting diseases, usually associated with various ailments and high symptom burden during their progression , 6. BesiPatients with advanced malignancies represent the largest group of people receiving hospice and palliative care. Hess et al. determined that only 8.1% of their sample had non-cancer diagnoses . Most frIncreasing attention has been paid to non-pharmacological methods in the treatment of both acute and chronic pain in recent years. In fact, pain perception can be reduced by stimuli that attract attention . AccordiVR is a three-dimensional computer-generated 360° immersion provided by head-mounted displays or stereoscopic glasses. Paired with headphones and optional haptic feedback, the system creates a multi-sensory experience. As a result, perfect distraction and immersion in the “virtual world” can be created. Besides animated clips, 360° cameras also offer the technology for generating virtual impressions of any existing places. Other characteristics include real-time vision transmission, 3D interactions, and changes in the virtual environment following head movements.Pain reduction through VR was already demonstrated in several studies –22. It iAim of this pilot study was to investigate the feasibility of VR for symptom control, in particular for the relief of pain in PC. We were also interested in the acceptability of a VR intervention for patients receiving PC and any adverse side effects.This study is an observational, single-arm and national single-center pilot study, performed at the University Hospital Muenster, Germany.Each participant received a single VR intervention and was followed up for one hour regarding pain and further related parameters.The study was conducted at Muenster University Hospital, which is an urban tertiary care hospital providing healthcare services to a large catchment area. Our sample included inpatients suffering pain who were treated by the PCCS or received usual PC. Screening was performed by PCCS physicians, assisted by nurses specialized in PC. General information, informed consent, and the VR intervention as well as all questionnaires were given and answered in the patient’s rooms. Any patients unable to complete the documents unassisted received help from the medical student. Depending on their individual preferences and physical conditions, patients either were lying in bed or were sitting in a chair throughout their VR session. Patients were observed by a medical student both during the intervention and, as a safety precaution, for half an hour following the intervention to provide immediate medical action for any side effects. A PCCS team member collected the VR questionnaire within the same day or the day after intervention. Each patient was kept under the care of the PCCS until being discharged from hospital.Due to our study design, no further follow-up was performed, even though we were able to exclude any negative long-term effects by continuing PC treatment.Recruitment period started in September 2018 and was completed in May 2019.Informed consent was obtained from all patients. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was a priori approved by the local ethics committee of the University of Muenster (2018-168-f-s). In addition, the study was registered .The feasibility trial includes data from 45 patients with advanced life-limiting and progressive diseases. Biostatistical consultation with case number planning prior to the study indicated at least 39–40 patients for an 80% power with a 5% drop-out rate. We solely included patients with the main problem pain. Except one patient, all participants were treated as inpatients at Muenster University Hospital with co-care by the PCCS or received usual PC. No threshold was set for pain level since our main goal was to evaluate an overall reduction. Thus, all patients suffering from pain were offered the opportunity to participate in the VR experience. Main complexity was coordinating screening by the outpatient PC service and visiting patients due to scheduling conflicts.Inclusion criteria were: a minimum age of 18 years, progressive life-limiting disease in need of PC, and capacity to adequately understand the information and to give written consent in case of agreement. We excluded patients lacking the capacity to consent and those with hearing or visual impairments. Considering that there is a small presumed risk of VR induced seizures, patientshttps://www.appliedvr.io/). These devices were explicitly developed for medical use and suitable in clinical settings . Sa. SahttpsFor sanitary cleanliness, the devices were disinfected both before and after any use, including headsets and cell phones. In case of isolated patients, the foam cushioning has been changed.As primary outcome, patients’ self-reported pain intensity was measured using a visual analog scale (VAS). The patients marked their pain intensity on a horizontal line of 100 mm length, ranging from “no pain” (0 mm) to “very severe pain” (100 mm).Based on our hypothesis that VR leads to significant pain reduction, we evaluated pain levels across multiple time points . In addition, we collected a number of patient characteristics and procedural data prior to and after the VR experience.The questionnaire used immediately after the intervention was particularly related to the pain during their VR experience. All of the following questions focused on the intensity of pain after the VR intervention. To analyze the VAS scores, each marked value was measured in millimeters and then converted into centimeters with one decimal place .Characterization of symptom-related disability at the day of the intervention was based on Karnofsky performance status scale. For the assessment of health-related quality of life (HRQOL), patients completed EQ-5D-5 L health questionnaire . Both scTo detect any differences between the perception of pain pre and post VR intervention, participants completed the Pain Out questionnaire at both times. Although this questionnaire is regularly used to measure patients’ satisfaction with postoperative pain management, we utilDescriptive statistics were used to analyze demographic data. We summarized continuous variables mainly by the mean and standard deviation (SD) or in some cases by median if specified. Categorical variables are presented as absolute and relative frequencies. Tests for normal distribution of pain scores measured by VAS were performed with Kolmogorov-Smirnov and Shapiro-Wilk tests. Continuous parameters were analyzed using the Wilcoxon-Mann-Whitney-Test. Two-sided p-values of ≤ 0.05 were considered statistically significant. Spearman’s Correlation was used to identify any correlation between parameters. This takes on values ranging from − 1 in the case of a negative to + 1 in the case of a positive correlation.SAS Software .Statistical analyses were performed using SPSS Software  and Our cohort included 45 patients (n = 45). We excluded four participants. Either they met exclusion criteria, or their exclusion was due to acute health problems or health deterioration that inhibited participation. We also excluded a patient who was receiving hospice care. Of the remaining 40 patients (89%) included, 37 (92.5%) received specialized PC provided by the PCCS, compared to 3 patients (7.5%) receiving usual PC. Gender balance was fairly equal, as 21 patients  were female and 19 male . Mean age was 51.9 ± 15.81 years, with the youngest patient being 19 years and the oldest 80 years old.Albeit pain was the main problem for all patients when VR intervention was performed, initial contact with specialized PC resulted due to pain , organization of outpatient care 35%, n = 14), and complexity of care in ICU/isolation . Patients were treated by the PCCS according to their actual needs and under the consideration of our treatment algorithm . Variati4, and coWhile there were only three patients with previous experience of VR (7.5%), there were five (12.5%) with general knowledge of its use in healthcare and the treatment of patients.On average, each session lasted 31.3 ± 11.16 min. There were several video experiences patients could choose from; one person watched a single video (2.4%), five of them watched two videos (14.6%), eight watched a number of three videos (19.5%), and there were 26 participants who watched more than three videos (63.4%). Among all videos, the most viewed ones were Iceland ), London , Dolphins ), Dream Beach , and Wild West . In addition, games were played by 20% (n = 8) of the patients. The supervising medical student observed signs of physical relaxation during most of the interventions , as well as numerous head movements. No withdrawals were seen within the study and no participant requested discontinuation of the VR intervention.On average, isolated patients reported less pain compared to non-isolated patients prior to their VR intervention . Pain reduction was fairly similar across both groups. Significant pain reduction  was observed for all three measuring points  as compared to the baseline values . In total, there were seven patients  who reported lower values than before. All other values had no significant variation.Most participants described a feeling of joy or happiness following the VR intervention . Nevertheless, there were two participants reporting sadness (5%) due to reminiscences and wishes to be healthy again so they are able to experience the seen things on a more realistic basis.No serious side effects occurred. However, after the intervention, three patients reported either nausea or dry eyes (7%), two reported headache (5%), while no one reported dizziness.Following the intervention, all patients were asked to rate their VR experience as very good, good, fair, or poor. The responses are shown in Table A total of 82.5% (n = 33) would like to experience a VR session once again. A significant correlation  was found regarding the evaluation of their VR experience and a request for further sessions, which means that the better the VR experience was evaluated, the greater was the request for further VR interventions.We aimed to investigate whether VR might offer to be a beneficial supplementary and feasible tool for pain relief among patients receiving PC. To our knowledge, this study is one of the first to investigate the feasibility of VR for palliative care in Europe and the very first study on this topic conducted in Germany. As we live in pandemic times with restricted person-to-person contacts in many places, VR provides an opportunity for escaping isolation through distraction.Highlight of this study lies in the application of VR technology, which has already been successfully used in several studies , 35–37. Except rare reports of nausea, headache and dry eyes, there were no serious side effects. However, similar to Mosadeghi et al.‘s study, some participants requested improvements regarding weight reduction and a more comfortable fit of the VR devices. In addition, some participants reported intermittent difficulties to maintain concentration .When comparing the Pain Out questionnaires, only one significant improvement (sleep impairment) was found. There were no significant deviations in any of the other values. A limiting factor in this context could be that this questionnaire was not originally developed for PC. Perhaps this questionnaire simply lacks relevant elements that would be appropriate for our study.Recently, an Australian study demonstrated the feasibility and high acceptance of VR (Oculus Rift® with the non-interactive video Nature Trek®) for patients with pain caused by cancer in PC . The samAnother study showed the efficacy of a single VR intervention (HMD VR with Ocean Rift® or sitting on the beach with the “Happy Track”) when combined with morphine versus treatments with solely morphine for the reduction of pain and anxiety among patients with breast cancer using a randomized control design . Just a Even one hour after ending their VR intervention, a significant pain reduction was shown according to our results on the analgesic effects of VR. Short-term effects of VR seen in this study are most likely due to distraction. Presumably, attention is directed to the virtual world and less perception of pain occurs. Besides this, also longer-lasting effects are discussed as a result of neuromodulation. Thus, a functional magnetic resonance imaging (fMRI) study by Álvarez-Pérez et al. revealed decreased activity in brain areas associated with anxiety and pain after VR interventions . In addiAs a potential limitation, in view that the investigators monitored all interventions, we cannot exclude investigator bias. This may have confounded the study outcome, for instance by affecting well-being and the perception of subjective pain. However, this is most likely a systemic bias, since all participants received increased attention throughout the study. Also, the “VAS questionnaire” was self-constructed and is not standardized, although visual analog scales are proven and validated instruments for the measurement of individual pain over several years .Each participant was invited to choose the number and type of videos or games independently, as well as duration of the intervention was arbitrary, according to patients’ preferences and capabilities. There is need for further randomized clinical trials to investigate correlations between the duration of VR use and its benefits. Since there are many outpatients requiring PC, further studies should also evaluate the use of VR across these settings. We assume a wide range of different usages, considering that mobility of the cervical spine is necessary for the complete experience of using and viewing VR. While patients with high mobility of the head and cervical spine are able to fully utilize the device, those patients who are immobile may potentially strongly benefit from VR technology as a result of newfound freedom of movement in virtual worlds. Yet, it is important to consider that head and neck cancer with large tumor mass could limit the use of VR technology particularly in lower middle-income countries. In this context, it is important to be aware that using VR equipment could even cause pain instead of relieving it.Currently, VR technology and its use in PC is quite unfamiliar. Nevertheless, presented data indicate an enormous potential for PC and suggests further studies to optimize this technology for individual needs. For example, personalized film recordings to support autobiographical work involving patients might offer an address for research. Among other imaginable aspects, it would be also useful in the context of patients’ desire to revisit certain places.Based on the benefits of dignity therapy in PC , 45, VR We launched our study in 2018, and even then, VR devices were affordable (usable models started around $100–200). Increasing availability and decreasing costs will enable researchers and clinicians to conduct further studies more easily. Indeed, there is a realistic opportunity for patients to independently incorporate VR into pain management even now, based on manageable costs as well as it’s not pharmacy-only. Thus, in certain cases, physicians may recommend its use to patients even at this early state of research.Overall, we demonstrated that a single VR experience is an effective non-pharmacological treatment for the relief of pain in PC. There is broad acceptance and high potential for its future use in PC. Notably, its use is appropriate for PC due to its ability to encompass the approach of a total pain and symptom therapy, to enhance patients’ dignity and autonomy, and to open up conversations and foster optimism by providing content that differs from daily reality. Future research ought to include if and to what extent VR could reduce the necessity of pharmacological pain relief and potentially be applied to larger cohorts within the health care system. Since there is a solid foundation of positively evaluated evidence-our study also reinforces its benefits-available, including VR in guidelines for pain management and PC merits consideration.


Chronic low-back pain (CLBP) is a common disease with several negative consequences on the quality of life, work and activity ability and increased costs to the health-care system. When pharmacological, psychological, physical and occupational therapies or surgery fail to reduce CLBP, patients may be a candidate for Spinal Cord Stimulation (SCS). SCS consists of the transcutaneous or surgical implantation of different types of electrodes in the epidural space; electrodes are then connected to an Implanted Pulse Generator (IPG) that generates stimulating currents. Through spinal and supraspinal mechanisms based on the “gate control theory for pain transmission”, SCS reduces symptoms of CLBP in the almost totality of well-selected patients and its effect lasts up to eight years in around 75% of patients. However, the evidence in favor of SCS still remains weak, mainly due to poor trial methodology and design. This narrative review is mainly addressed to those professionals that may encounter patients with CLBP failing conventional treatments. For this reason, we report the mechanisms of pain relief during SCS, the technical features and some clinical considerations about the application of SCS in patients with CLBP.  Pain is a subjective unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage . Pain isChronic low-back pain (CLBP) is very common. CLBP prevalence has been reported by several studies and it increases with the age of the population. In particular, CLBP affects up to 4.2% of patients aged between 24 and 39 years old, and its prevalence increased up to 20% in the more aged population . In addiThe presence of CLBP causes activity limitation, with negative consequences on the daily quality of life, the ability to work, and increased and costly demand on the health-care system . StrategSCS is a modern neuromodulation technique to treat and reduce CLBP. It consists of an implanted generator of pulsed electrical signals conveyed to a precise region of the spinal cord through electrodes . SCS is Although several authors have recently published reviews about the use of neuromodulation in chronic pain relief ,11,12,13SCS relies on neurophysiological and neurochemical mechanisms of action, based on the “gate control theory for pain transmission” . Two neuPainful stimulations are transmitted through the nociceptive afferent neurons to the dorsal root ganglia, and, at the end, to the superficial (I/II) and deep (V) laminae, where they are modulated before being dispatched to the supraspinal centers. The dorsal column of the spinal cord contains large diameter fibers, carrying highly specific and detailed cutaneous and proprioceptive afferences, which do participate to the gate control of pain. Small diameter fibers (Aδ and C) ascend as a spinothalamic tract in the antero-lateral column and they carry the nociceptive stimuli to the supraspinal centers. In addition, the dorsal horn works as a relay station and integration site for nociceptive signals before ascending the pain control pathways ,17. SCS also interferes with the processing of the nociceptive signal through the lateral spinothalamic tract, modulating supraspinal brain centers such as the ventral posterior nucleus of the thalamus, somatosensory cortex, cingulate cortex, and insula ,19. OrthConcerning neurochemical mechanisms of action, SCS modulates neurochemicals such as gamma-aminobutyric acid (GABA) , serotonSCS also increases the release of serotonin and substance P  and the Finally, SCS analgesia is also promoted by modulation of the cholinergic and adrenergic neurotransmission, by releasing acetylcholine and noradrenaline in the dorsal horn of the spinal cord ,26.The first application of SCS has been described in 1967 by Shealy et al. , now knoThereafter, the type of stimulation has evolved to a “burst-SCS”. This approach consists of intermittent bursts of electrical pulses  to mimic thalamic bursting within the nervous system. Compared to the conventional SCS, burst-SCS activates also the dorsal anterior cingulate and the dorsolateral prefrontal cortex , which mMore recently, kilohertz-frequency SCS has been introduced in clinical practice. This latter is a tonic stimulation with a rate > 1kHz, up to 10Khz. This type of stimulation guarantees optimal (around 80%) pain relief without paresthesia . In factIn addition to the type of electrical stimulation, the design of the lead is fundamental to optimizing pain relief. In principle, the electrical field should be shaped in order to optimize the stimulation. Increasing the number of electrodes improves the pain-to-paresthesia overlap and ameliorates pain relief ,48. At tWith the continuous implementation of the SCS technique, the epidural stimulation has been preferred over the intrathecal or subdural one, due to reduced incidence of complications such as cerebrospinal fluid leakage and acute neurological deficit . More reThe choice of the type of electrode  is an important issue in SCS implantation . The choImplanted pulse generators (IPG) stimulate the spinal cord through precise extracellular voltages. However, the heterogeneity of impedance of electrodes may impair the ability to provide an optimal stimulation . This drAnother important technical advance in IPG are the multi-source systems. Most of the available IPG uses a single-source system, allowing the user to select the configuration for every single catheter as cathodes, anodes, or inactive . In an aThe innovations in rechargeable and longevity (up to 25 years) batteries also reduces the invasiveness and sizes of IPG ,66. WireAnother limitation for patients with SCS was the lack of possibility to perform magnetic resonance imaging (MRI), a fundamental exam in patients with CLBP. Of note, up to 84% of SCS-implanted patients could require at least one MRI exam within 5 years from the implantation . The devFinally, SCS systems are generally implemented as “open-loop”. Although easier in their concept, they may be ineffective during body position changes. Indeed, when a patient changes his/her body position, the thoraco-lumbar spinal cord moves up to 3 mm in the anterior-posterior direction . Since tThe procedure of SCS implantation typically implicates two consecutive stages . The first one is a trial phase lasting between 3 to 10 days. As shown in The kit for SCS transcutaneous implantation is shown in panel A. The kit is constituted by a Tuohy needle (*), a wire guide (^) and the electrode (§). In panel B, the setting in the operating room is depicted. After the identification of the correct vertebral space (panel B), the Tuohy needle is inserted (panel C) and the electrode is positioned (panel D).The figure shows the radiological check for the correct positioning of the electrode at L1 and of an external and temporary pulse generator for the trial phase.Noteworthy, SCS electrode arrays could be also surgically implanted. This is the case of paddle- or plate-style electrode arrays, where laminotomy is required for their implantation ,74,77. AThe etiology of CLBP can be referred to as specific spinal cord lesions  or not related to a spinal source. In the case of CLBP, physicians have to collect the clinical history and perform a detailed physical examination in order to understand the possible etiologies. If symptoms may be attributable to any spinal cause, magnetic resonance imaging or computed tomography of the spine is required to identify possible indications for pharmacological therapies, surgical treatments or physiotherapy. Noteworthy, the vast majority of patients with CLBP will not benefit from surgery, which remains indicated only in selected patients with functional disabilities or with refractory pain despite multiple nonsurgical attempted treatments . If CLBPThe selection of patients is fundamental for the success of SCS treatment . First oAs mentioned above, when a patient is a good candidate for SCS, an external and temporary stimulator is used to optimize the settings of the treatment to control the pain (first phase). If the patient achieves good pain relief (at least 50%), an IPG can be implanted after around 10 days (second phase). Noteworthy, a center for SCS implantations requires specific characteristics, such as trained personnel for diagnosis, indications, implantation and follow-up . Of noteOnce SCS is implanted, nearly half to 80% of the patients report immediate good pain relief with an indication of definitive implantation ,90,91. IAlthough the interest in SCS application to chronic pain is growing, to date large studies providing strong scientifically sound evidence are few ,102. FroAmong different techniques of neuromodulation, SCS is increasingly used to treat selected patients with CLBP resistant to other therapies (including drugs and physiotherapy). Technical advances in this field have improved the efficacy of pain relief and the treatment duration lasts up to eight years in around 75% of patients. More studies are however required to reinforce and to better define the current evidence in favor of SCS.