In conclusion, a single session of ICT can shift the autonomic balance towards increase parasympathetic dominance and decrease the sympathetic dominance and intensity of pain perceived by patients with NSCLBP.Interferential current therapy (ICT) is an electrotherapeutic intervention that combines the advantages of high permeability from middle frequency currents and efficient tissue stimulation from low frequency currents, delivering the maximum current with high tissue permeability. The aim was to evaluate the effects of ICT on heart rate variability (HRV) and on pain perception in patients with non-specific chronic low back pain (NSCLBP). In the study, 49 patients with NSCLBP were randomly divided into an experimental (EG) and a sham group (SG). All participants received a single intervention, ICT, or simulated intervention. Outcome measures including baseline (sit-down position) and postintervention (prone position) pain, heart rate (HR), time domain parameter (rMSSD), diameters of the Poincaré plot , stress score (SS), and sympathetic/parasympathetic (S/PS) ratio were investigated. In both groups, significant statistical differences were found in perceived pain and in all HRV parameters except in HRmax. Between-group comparisons showed statistically significant differences in all variables except for HRmin and HRmean in favor of the experimental group. These changes reported an increase in parasympathetic activity (rMSSD) ( Back pain is one of the most common health problems among the population. Specifically, non-specific chronic low back pain (NSCLBP) is the most prevalent among adults, and it often leads to functional limitations, psychological problems, low quality of life and low productivity in the workplace ,2. NSCLBSeveral studies suggested that non-organic signs (NOS) should be part of routine screening in chronic pain rehabilitation, to help identify patients who require thorough psychosocial evaluation and to distinguish pain from conditions mainly determined by biological factors ,6.In this sense, there are NOS that have been related to back pain, such as aerobic functional capacity or somatosensory and/or autonomic function. Among the latter, heart rate variability (HRV) has been considered as a noninvasive, feasible diagnostic tool that evaluates different symptoms and clinical reference signs indicative of persistent pain ,8,9.Specifically, detection of changes in HRV have been considered an important diagnostic measure of neurogenic homeostatic regulatory capacity in subjects with low back pain . SimilarAlthough there is still a knowledge gap concerning the relationship between autonomic balance functioning and NSCLBP, it can be assumed that stress and pain in patients with NSCLBP cause them to be less physically active and, consequently, deconditioned. Research into stress of patients with NSCLBP has primarily been performed with HRV parameters ,10. The Evidence-based guidelines about the management of chronic low back pain highlight the importance of recognizing that chronic pain can alter the autonomic balance, with increased sympathetic activity reflected in altered HRV ,11,12,13In recent years, the benefits of electrical stimulation in the symptomatic management of chronic pain have been researched. Even though this approach can expand the size of the cortical receptor area and improve the sensitivity of the somatosensory system, there is no clear consensus about which is the most effective type of electric current . This coHowever, despite electrotherapy treatments (including ICT) being effective for NSCLBP, they are controversial, and their evidence is uncertain. This may be due to two main reasons: First, ICT has been used together with other interventions, which has limited the studies that examine its effects in isolated conditions . Second,Although these mechanisms of pain processing have been related to demographic variables  and to thttps://clinicaltrials.gov/ct2/show/results/NCT04483128?term=04483128&draw=2&rank=1 (23 July 2020) and it was completed in accordance with the Declaration of Helsinki. We followed CONSORT statements for conducting and reporting this randomized controlled trial.The present study is a randomized, single-blind, controlled trial. This study was supervised by the Institutional Ethics Committee of CEI University Hospital Virgen Macarena and Virgen del Rocio, with ethics approval number 1591-N-16, registered in ClinicalTrials.gov: NCT04483128, available at Fifty-six male patients with NSCLBP, age between 19 and 65 years  participated voluntarily in the study. The recruitment period went from 1 to 31 November 2020. The inclusion criteria were the following: (i) male subjects aged 18–65 ; (ii) dihttp://www.randomization.com) (accessed on 27 May 2020) was used to complete the group allocation. Participants were randomly  allocated into 1 of the 2 groups created: the experimental group (ICT) and the sham group. The randomization was performed by an external assistant. The participant had to pick up a number out of a hat. Two researchers were in charge of the study procedure. A blinded researcher collected the measurements at baseline and immediately after the treatment. The other researcher was in charge of implementing the intervention in both groups. Both were physiotherapists with more than 15 years of experience.An external website (n = 25) received an intervention protocol using ICT  . The self-adhesive electrodes  were placed using a crossed pattern at the level of the first and fifth lumbar vertebrae, as indicated by Hurley et al. [n = 24) received the sham intervention. Likewise, the subject was unaware of which group he belonged to in the study.To avoid being influenced, the participants of both groups were evaluated in separate rooms, at the same temperature, in order to maintain the environmental conditions between subjects. Group 1  of 2 points [All instruments were applied in a single day and baseline and post-treatment testing times were the same for all participants. The data were collected in the same room in which the procedure was performed. The rater, who was blinded to group allocation, collected the baseline clinical data. Demographic, anthropometric, and clinical data were collected using a self-assessment questionnaire created for this study. The primary outcome was pain intensity perceived, measured according to the Numeric Pain Rating Scale (NPRS), which exhibited a standard error of measurement (SEM) of 1.02 points, corresponding to a minimum variation in the 95% confidence level  (® HRV software (v.2.1.)  [The HRV R-R heartbeat interval was used as measure of autonomic modulation, which was estimated with a Firstbeat BodyguardFinland) . This deFinland) .The HRV method is commonly used to calculate the autonomic balance is based on the Poincaré plot . It has We also considered a checklist regarding the use of HRV collection and analysis methodology to improve the reporting of evaluation and intervention results using HRV . PhysiolThe sample size was estimated using GPower 3.1.3. software . At the beginning of the study, the sample size was of 50 patients with NSCLBP. For ANOVA F-test, a total sample size of 46 participants was estimated, bearing in mind repeated measures, within-between interaction, and assuming an effect size (f) of 0.25, an alpha level of 0.05, and 90% power. The sample was inflated by 10% to account for potential dropouts, resulting in a sample size of 49 participants.t-test for continuous data and Chi-square test for categorical data. The interclass correlation coefficient (ICC) and SEM values were used to determine the reliability of the measurements. Differences in the outcome measures were detected using a repeated measures analysis of variance (ANOVA), with the group  as the between-subjects factor, and time effects (baseline vs. intervention) as the within-subjects factor. Eta square (η2) was used to calculate the effect size  [p-value < 0.05 was considered statistically significant.Statistical analyses were carried out by an assessor blinded to the treatment allocation, using SPSS statistical software , in its 21.0 version. Firstly, the normal distribution of variables was verified by the Kolmogorov–Smirnov test, after a descriptive analysis. The homogeneity of variances was observed by Levene’s test. Linearity was evaluated by bivariate scatter plots of observed residual values against the expected values. Comparisons between groups were conducted for baseline demographic and clinical data using Student’s  > 0.14) . A p-valp > 0.05) were found  were calculated in the EG for NPRS = 0.58 (0.18–0.82), SEM: 1.35; min heart rate = 0.93 (0.83–0.97), SEM: 0.33; max heart rate = 0.70 (0.31–0.87), SEM: 0.79; mean heart rate = 0.91 (0.8–0.96), SEM: 0.38; rMSSD = 0.96 (0.9–0.98), SEM: 0.32; SD1 = 0.82 (0.59–0.92), SEM: 2.29; SD2 = 0.36 (−0.44–0.72), SEM: 15.96; SS = 0.23 (−0.77–0.67), SEM: 3.03; and S/PS ratio = 0.67 (0.1–0.79), SEM: 0.12.p = 0.007, d = 0.34) and in SS  and a decrease in SD2  and S/PS ratio  after intervention. In comparison with baseline values, the EG exhibited statistically significant increase in rMSSD , SD1  and SD2 , whereas it showed a significant decrease in SS  and S/PS ratio  after intervention. Moreover, 1, 47= 37.28 (p < 0.001) η2 = 0.44 and the following HRV parameters: rMSSD, F1, 47 = 6.73 (p= 0.013) and η2 = 0.13; SD2, F1, 47 = 20.40 (p < 0.001) and η2 = 0.30; SS, F1, 47 = 16.17 (p < 0.001) and η2 = 0.26; and Max HR, F1, 47 = 6.01 (p = 0.018) and η2= 0.11. The parameters with non-statistical differences were as follows: Min HR, F1, 47 = 0.058 (p= 0.811) and η2 = 0.001; mean HR, F1, 47 = 0.97 (p= 0.329) and η2 = 0.02; SD1, F1, 47 = 1.62 (p= 0.209) and η2 = 0.03; and S/PS ratio, F1, 47 = 2.78 (p= 0.102) and η2 = 0.05.Analysis of variance for repeated measures within the group  like the between-subjects factor, and time effects (baseline vs. intervention) like the within-subjects factor showed statistically significant differences, which were found to favor the EG in the intensity of pain perceived (NPRS) at Fp < 0.05) and a decrease in sympathetic activity (increase in SD2 and decrease in SS) in favor of the experimental group. Correlation analysis showed no statistically significant association between rMSSD and age, BMI, NPRS, RMQ, and PPAS, respectively, both at baseline and at the end of the intervention for the whole sample. A statistically significant correlation (Spearman’s Rho) was obtained between rMSSD and perceived pain (NPRS) after the intervention for the whole sample . Similarly, a statistically significant correlation (Spearman’s Rho) was reported for the experimental group between rMSSD and NPRS  and between SD1 and NPRS  at baseline. At the end of the study, a significant correlation (Spearman’s Rho) was also obtained between rMSSD and NPRS  and SD2 and NPRS .Finally, these changes reported an increase in parasympathetic activity (rMSSD) (t-test), highlighting the differences expressed in percentage observed in the parameters that reflect in parasympathetic activity (rMSSD: 54% vs. 14% and SD1: 75% vs. 43%), as well as in S/PS ratio (−65% vs. 39%).The aim of this study was to examine the effects of a single intervention of interferential current therapy (ICT) on pain perception and heart rate variability (HRV) parameters of subjects diagnosed with non-specific low back pain (NSCLPB). The findings are consistent with previous studies in suggesting the immediate influence of electrical stimulation applied on the spinal column, regarding the perceived pain intensity ,23,26,44As for perceived pain intensity, our results showed statistically significant differences between both groups, with differences in EG also appearing  above the minimum clinical important change for the numeric pain rating scale (NPRS) . The infIn particular, ICT is an intervention method that combines the advantages of high permeability from middle frequency currents and efficient tissue stimulation from low frequency currents, delivering the maximum current with high tissue permeability. Therefore, changes observed on the deep back muscles could be due to the characteristics of the current used, being consistent with previous studies developed with LBP patients, in which effects on variables controlled by nociceptive pathways were associated   with a dChanges observed in pain intensity perceived in SG could be explained by the placebo component that showed applying electrotherapy . HoweverOn the other hand, HRV was also analyzed after electric stimulation, showing increases in parasympathetic activity (rMSSD and SD1) and decreases in the sympathetic domain (SD2) . ChangesThe results showed statistically significant increases in rMSSD only in the EG. These results are consistent with the ones obtained by Abuín-Porras et al.  after apSD1 showed a statistically significant increase in both groups, between the beginning and the end of the intervention , reporting statistical differences between both groups, in favor of EG (Diff: 32%), with a moderate effect size d = 0.52). Changes observed in both groups could be influenced by the differences of the subject position, who were sitting in the baseline state and in prone position during the intervention. The position’s influence on autonomic balance recordings has already been reported, where a sympathetic dominance exists in the sitting position here as, in young and healthy men, the dominance lies in the prone position ,51,52. T. ChangesIn regard with SD2, a statistically significant decrease in sympathetic activity was observed in EG, whereas the SG showed a statistically significant increase . These sLastly, the S/PS ratio also showed changes after ICT in the autonomic balance , observing statistically significant differences between groups (26% greater reduction in favor of the EG) . A S/PS HRV can be proposed as an indirect measure of vagal activity, and perhaps a reflection of the function of downstream endogenous inhibitory systems  could alThe main limitations of the study were that the intervention was carried out in a single session and exclusively to males, which could limit the effects observed as well as the difficulty to generalize the results to female patients. as Additionally, the lack of measurement of psychosocial factors associated with persistent pain was a limitation, which could also influence HRV. Furthermore, the sensation (pins and needles) might indicate that the patients would associate this with a therapy. Likewise, the absence of any sensation during the experiment in the prone position could lead to outcome bias. In order to preserve the blinding of the sham group, future studies would benefit from applying a sham intervention that imitates the experimentation intervention. Finally, further studies are needed to determine whether there is an association between these variables and the autonomic balance of subjects with persistent pain.Based on the results observed, HRV can be considered as a factor providing diagnosis for NOS in disorders characterized by persistent pain ,10, and A single session of ICT can shift the autonomic balance towards parasympathetic dominance and decrease the sympathetic dominance and intensity of pain perceived in patients with NSCLBP. This is the first study to show that using ICT as diagnostic measure and therapy, respectively, in subjects with NSCLBP can lead to an improvement of the autonomic balance.


Neuropathic pain (NP), often treatment-refractory, is one of the most debilitating conditions contributing to suffering and disability worldwide. Recently, non-invasive neuromodulation techniques, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential therapeutic alternatives due to their ability to alter cortical excitability of neural circuits. However, the magnetic field induced in rTMS may be unsafe for patients with an implanted electrode in the head or neck area while tDCS poses no theoretical risk of injury to these patients. High definition (HD)-tDCS is a novel, more focal technique of tDCS and may be safer to the patient compared to the more diffuse stimulation of conventional tDCS. To our knowledge, no study has ever demonstrated the safety and/or feasibility of HD-tDCS in patients with spinal cord stimulation (SCS) devices using computational modeling of induced electrical fields. Furthermore, this study highlights the potential use of (HD-)tDCS as predictive tool for a positive response in chronic epidural motor cortex stimulation (MCS), especially in patients with an implanted device not suitable for rTMS. In a 54-year-old woman with an implanted spinal cord stimulation (SCS) system for another pain syndrome, HD-tDCS was initiated for refractory post-surgical inferior alveolar nerve neuropathy. She was submitted to 7 days of anodal HD-tDCS over the left motor cortex at 1.5 mA for 30 min. A notable decrease in pain perception was observed, lasting for approximately 5–6 h (Numeric Rating Score decreased from 8 to 4.34). No adverse events were reported. The stimulation parameters and clinical efficacy of the SCS system remained unchanged. Additionally, computational analysis indicated no meaningful alteration of current flow when considering a model with a SCS implant with respect to a model without implant. Regarding the positive therapeutic effect of HD-tDCS, the patient was selected for an epidural MCS trial and subsequent implantation, which showed short-term pain relief of 50–75%. Although one case does not demonstrate efficacy, tolerability, or safety to the novel intervention, it paves the way for better diagnosis and treatment for patients who are otherwise excluded from other non-invasive neuromodulation techniques, such as rTMS. A positive tDCS effect could be a potential biomarker for positive epidural MCS response in patients with an implanted stimulation device non-compatible with rTMS. Neuropathic pain (NP) is one of the most debilitating conditions contributing to suffering and disability worldwide. Unfortunately, NP can be very treatment-refractory, with many patients continuing to report significant pain and repercussions on quality of life (QoL) despite the recommended multimodal pharmacological and non-pharmacological management, including physical therapy and cognitive behavioral therapy. In recent years, non-invasive brain stimulation techniques have emerged as potential therapeutic alternatives, next to invasive neuromodulation strategies such as epidural motor cortex stimulation (MCS) and deep brain stimulation (DBS). Indeed, two non-invasive methods have received increased interest, i.e., transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). The magnetic field induced in rTMS may be unsafe for patients with an implanted electrode in the head or neck area while tDCS poses no theoretical risk of injury to these patients. Cortical modulation by tDCS may increase glutamine and glutamate under the stimulating electrode, have effects on the μ-opioid receptor, and restore impaired intracortical inhibition . The anaHigh definition (HD)-tDCS may be a safer therapeutic option compared to the more diffuse stimulation of conventional tDCS. HD-tDCS is a novel approach that uses arrays of smaller electrodes , 3 that Few studies have been published to date assessing its effects in a patient population with respect to pain –12. PatiMotor cortex stimulation (MCS) has been proposed as an invasive neuromodulation technique for chronic refractory NP since the early 1990s and with variable treatment results, for patients for whom no other treatment modality is available. In MCS, an epidurally placed electrode delivers a targeted current to the very closely located precentral primary motor cortex (M1). MCS literature suffers from low level of evidence due to small retrospective series, substantial inter-study heterogeneity and confounders, making correct interpretations difficult. A systematic review concluded it to be relatively safe and effective with a “good outcome” (≥40–50% pain improvement) in 56.7% of patients . A recenTo the best of our knowledge, HD-tDCS with superior focality, more comparable to epidural MCS, has never been applied in patients with cortical or cervical SCS implants. In order to evaluate the analgesic effects of HD-tDCS in a patient with neuropathic pain with a cervical epidural electrode, we submitted our patient to 7 days of active anodal HD-tDCS to determine if HD-tDCS (1) is a safe and effective therapeutic alternative for patients with a cervical electrode implant, capable of decreasing pain perception, and (2) may serve as a valid and reliable method to select eligible patients for epidural MCS who are otherwise excluded from other non-invasive brain stimulation techniques as a pre-operative tool.A 54-year-old woman presented with uncontrollable neuropathic pain in the lower right side of her face. Three years prior, she received an SCS system to treat CRPS, after sustaining a post-operative axillary nerve lesion. The tip of the electrode was positioned a C2 which resulted in a good pain reduction. Two months prior to HD-tDCS, she underwent apex resections of teeth 25 and 47, complicated by pain and wound infections. A computed tomography (CT) scan showed the remainder of the root of tooth 47 was in contact with the mandibular canal. After revision surgery, the pain remained unabated with a Visual Analog Score (VAS) score of 9.5. In addition, she experienced sleeping difficulties and weight loss. Her pain was triggered by chewing or changes in temperature. Clinical examination showed hypoesthesia and allodynia over the mandibular nerve region (V3), resulting from a post-surgical right inferior alveolar nerve injury. The DN4 (Douleur Neuropathique 4 Questions) questionnaire was 8, suggesting neuropathic pain diagnosis. Multiple trigger points over the right masseter muscle could elicit her typical pain pattern.She was treated at another hospital with pulsed radiofrequency to the right mandibular nerve without effect. Her medication included Paracetamol, Methadone, Clonazepam & Ketorolac. She was referred to our tertiary care center, University Hospitals Leuven, for further treatment.Our patient, RT, received 7 daily sessions on consecutive business days . We employed a 4x1 Multichannel Stimulation Adaptor  connected to a conventional 1 × 1 tDCS device  to deliver direct current to the scalp via HD electrodes. Electrodes were held in place by specially designed plastic casings embedded in a modular electroencephalography (EEG) recording cap. We positioned the center anodal electrode over C3 based on the International 10/20 EEG System  which coOutcome measures were: (1) Numeric Rating Scale (NRS) assessed daily, (2) the Short Form-36 Dutch version (SF-36), and (3) the MPQ-DLV Pain Questionnaire, the Dutch version of the McGill Pain Questionnaire (MPQ) , both asNRS is a single 11-point numeric score in which a patient rates their pain by selecting a whole number (0–10 integers) that best represents the intensity of their pain  was epidurally advanced over the precentral primary motor cortex (M1) and electrode leads were externalized. Electrode position was verified using intra-operative neuromonitoring techniques of somatosensory evoked potentials (SSEPs) with phase reversal and motor evoked potentials (MEPs) with cortical stimulation, the latter which halted contractions in the painful facial area. During the trial, pain scores (NRS) and quality of life measures were rated daily. After definite MCS implantation, follow up was organized four-weekly in the first 3 months, whereafter follow-up was extended to every 2–3 months in the first year. During clinical visits, NRS was recorded, potential side effects were monitored, and stimulation parameters were reprogrammed when needed.To investigate potential deviation (intensity or location of current flow) due to the implant, we considered a whole-body female model (“Ella”) from the Virtual Family dataset . We deveAfter an initial 3-day-trial-and-error period, our patient, RT, showed a gradual and progressive improvement on the NRS  and SF-3Similar to the tDCS results, the 4-week MCS trial halted an average pain relief of 50–75% (NRS). Therefore, a second procedure with internalization of the leads and IPG placement was performed 1 week after the trial. The beneficial effect of MCS, however, lasted only 3 months. Despite extensive follow up with multiple reprogramming efforts, which only resulted once in intermittent, non-lasting pain relief at 11 months postoperatively (NRS 4) , no effect of MCS persisted after 1 year (NRS 8). There were no adverse effects of MCS. The computational model simulating transcranial application is an implant indicated a difference of 1.1% in the maximum EF with respect to the without implant case . There wFor RT received 7 daily sessions on consecutive business days. Evidently, we cannot eliminate a placebo effect or the possibility that our patient experienced a significant decrease in pain perception unrelated to HD-tDCS. However, it seems highly unlikely that uncontrollable facial neuropathic pain felt on the lower right side of her face, with a NRS score of 8 pre-intervention, decreased spontaneously and gradually to a 4.34 in the period of maximal effect . Additionally, she notably improved on the SF-36 . The overall QoL subscale of the MPQ-DLV (from a 25 to 19) also showed some improvement while the NWC-T and PRI-T showed no difference between pre and pre and post intervention. A site-specific effect in sensory and pain threshold modulation was observed following an increase in the excitability of M1/primay sensory (S1) in healthy individuals and M1/dorsolateral prefrontal cortex (DLPFC) in patients with chronic pain . StimulaStudies in the literature that employed non-invasive neuromodulation in chronic pain patients with a permanent implanted electrode with the more focal and novel method of HD-tDCS are non-existent. Only one recent case report demonstrated that applying conventional anodal tDCS at 2 mA for 25 min over right primary motor cortex (C4) in a patient with left lower limb CRPS and implanted SCS device was feasible and safe . HoweverOur patient's steady and progressive improvement over the course of treatment implicates that with each additional treatment session, the gradual neuromodulatory effects generated by tDCS may have resulted in an additive, incremental functional brain reorganization in the motor cortex . The neuIn contrast to the case report by Houde et al. , our patOur study did not evaluate the therapeutic effects of HD-tDCS on M1 modulation beyond 6 h. Further studies are required to improve our understanding of the acute effects of HD-tDCS and the effects over time by systematically studying number of sessions, time, current intensity, and electrode size. Further, systematically searching for predictors/biomarkers  and optimal state/conditions  associated with tDCS remains crucial. Furthermore, future studies should compare the effect of tDCS over different areas of stimulation  while selecting different pain outcome measures as to better understand the responses following conventional tDCS or HD-tDCS. Finally, since pain studies predominantly use subjective outcome measures, it is paramount to include a sham condition in clinical studies and settings to warrant complete blinding.This case study highlights the potential use of non-invasive HD-tDCS as preoperative predictive tool for invasive MCS therapy, especially in patients with an implanted device. Indeed, the beneficial effect of HD-tDCS was reproduced in the epidural MCS trial with 50–75% pain relief. However, the patient showed no long-term response despite multiple reprogramming efforts , for reasons that remain elusive. The short-term MCS effect in this case cannot be seen as the “insertional effect” as reported in Hamani et al., since stimulation was immediately started postoperatively. Another non-invasive strategy, rTMS, has already been associated with positive MCS effect in some series and could serve as a potential biomarker , 19. FutOur case report demonstrates the safety and short-term efficacy of HD-tDCS treatment in a patient with an implanted SCS system. TMS, usually the preferred method of non-invasive neuromodulation , 44, 47,In conclusion, our findings, together with the similar case report using conventional tDCS in a patient with an implanted SCS device, confirms the need for sham-controlled clinical trials of (HD)-tDCS as a potential pre-operative therapeutic tool in patients with permanent electrode implants in the head area who are candidates for surgically implanted chronic epidural MCS. In addition, determining the ideal dose, duration, sessions, and maintenance protocol of tDCS remains crucial in optimizing tDCS efficacy to reduce pain intensity and maximize the QoL of patients with chronic neuropathic pain. Future studies are needed to determine if HD-tDCS could serve as an add-on treatment or biomarker to select eligible patients for MCS.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.CD wrote the manuscript, treated RT using HD-tDCS, and evaluated the acute effect of HD-tDCS. SS was responsible for the MCS data and manuscript writing and revision. BM and TT interpreted the data and revised the manuscript for intellectual content. AD and CT performed the modeling and simulation analysis. All authors participated in editing.AD and CT were employed by Soterix Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


There is a strong demand for an accurate and objective means of assessing acute pain among hospitalized patients to help clinicians provide pain medications at a proper dosage and in a timely manner. Heart rate variability (HRV) comprises changes in the time intervals between consecutive heartbeats, which can be measured through acquisition and interpretation of electrocardiography (ECG) captured from bedside monitors or wearable devices. As increased sympathetic activity affects the HRV, an index of autonomic regulation of heart rate, ultra–short-term HRV analysis can provide a reliable source of information for acute pain monitoring. In this study, widely used HRV time and frequency domain measurements are used in acute pain assessments among postoperative patients. The existing approaches have only focused on stimulated pain in healthy subjects, whereas, to the best of our knowledge, there is no work in the literature building models using real pain data and on postoperative patients.The objective of our study was to develop and evaluate an automatic and adaptable pain assessment algorithm based on ECG features for assessing acute pain in postoperative patients likely experiencing mild to moderate pain.The study used a prospective observational design. The sample consisted of 25 patient participants aged 18 to 65 years. In part 1 of the study, a transcutaneous electrical nerve stimulation unit was employed to obtain baseline discomfort thresholds for the patients. In part 2, a multichannel biosignal acquisition device was used as patients were engaging in non-noxious activities. At all times, pain intensity was measured using patient self-reports based on the Numerical Rating Scale. A weak supervision framework was inherited for rapid training data creation. The collected labels were then transformed from 11 intensity levels to 5 intensity levels. Prediction models were developed using 5 different machine learning methods. Mean prediction accuracy was calculated using leave-one-out cross-validation. We compared the performance of these models with the results from a previously published research study.Five different machine learning algorithms were applied to perform a binary classification of baseline (BL) versus 4 distinct pain levels (PL1 through PL4). The highest validation accuracy using 3 time domain HRV features from a BioVid research paper for baseline versus any other pain level was achieved by support vector machine (SVM) with 62.72% (BL vs PL4) to 84.14% (BL vs PL2). Similar results were achieved for the top 8 features based on the Gini index using the SVM method, with an accuracy ranging from 63.86% (BL vs PL4) to 84.79% (BL vs PL2).We propose a novel pain assessment method for postoperative patients using ECG signal. Weak supervision applied for labeling and feature extraction improves the robustness of the approach. Our results show the viability of using a machine learning algorithm to accurately and objectively assess acute pain among hospitalized patients.RR2-10.2196/17783 Pain assessment is a critical public health burden and is essential to effective pain management, which is associated with many illnesses . Pain isThe current and “gold standard” pain assessment relies on patient self-reporting with tools such as the Visual Analogue Scale (VAS) and Numerical Rating Scale (NRS). Although these unidimensional models are considered powerful in acute pain assessment, they are rife with deficits given their interactive communication requirement between the patient and nurses, which is a serious problem in noncommunicative patients ,9. Such State-of-the-art objective pain intensity assessment algorithms consist of analysis of physiological and physical pain indicators, as multiparameter analysis is superior to a singular physiological parameter -13. ObjeElectrocardiography (ECG) is useful for indicating the perception of pain among all of the physiological signals captured by wearable devices. Heart rate (HR) and heart rate variability (HRV) are the essential parameters that can be derived from ECG, as they are both coupled to autonomic nervous system activity, when internal body functions are involuntarily regulated, and they can provide a suitable proxy for examining pain intensity . The mosTo the best of our knowledge, this is the first work to study the relations between ECG physiological signal and pain intensity of postoperative patients to predict different pain intensity levels. This will promote advancements in both observational and physiological pain measurement. The technology used in this paper for objective pain assessment was developed by our group and presented in our previous work by Sarker et al . The proIn this paper, we looked into the ECG signal as one of the physiological signals from the human body and examined HR and HRV features extracted from ECG in several categories to assess their correlation with pain intensity for future physiological data fusion in pain intensity assessment. Due to limited available self-report pain intensity labels, we explored weak supervision, which has shown that performance of the end-model can asymptotically improve with data set size, although noisy sources of supervision are used ,23. ThusInterpretation of ECG in pain studies starts with the ability to detect the QRS complex as one of the morphological parts of the ECG waves, with the focus on the RR intervals (distance between adjacent R-waves). These peaks are essential in HRV analysis, where in literature they are usually referred to as NN intervals. HRV features have been traditionally calculated over a short period of 5 minutes or over a long period in 24 hours. However, in some cases such as acute physiological changes, some HRV features in less than a minute are also taken on as ultra–short-term analysis. Within each time window, HRV features can be extracted from NN intervals in several domains including (1) time domain features and (2) frequency domain features. HRV features in the time domain consist of statistical features including but not limited to SD of NN intervals, SD of average NN intervals, root mean square of successive differences (RMSSD), NN50, pNN50, and Max(HR) − min(HR). HRV features in the frequency domain are extracted by the Welch averaging method using power spectral density.In literature, HRV analysis has been examined as one of the main ways to measure pain in different types; in Sesay et al , for insThe study was approved by the University of California, Irvine (UCI) institutional review board (HS: 2017-3747). Candidates were selected from the Acute Pain Service (APS) patient list at UCI Health in Orange, California. The APS unit at the medical center serves approximately 100 patients weekly, enabling the lead Doctor of Medicine to recruit patients.This study is a prospective observational data collection from postoperative patients likely having mild to moderate pain. All 25 participants recruited for this study met the following criteria: (1) age at least 18 years, (2) received a consult by the APS, (3) able to communicate, (4) able to provide written informed consent, and (5) healthy, intact facial skin. They were excluded if they had (1) any diagnosed condition affecting cognitive functions , (2) any diagnosed condition affecting the central nervous system, facial nerves or muscles, (3) deformities on hand that prevent sensor placement, or (4) significant facial hair growth in the area where the sensors were going to be attached.Potential participants were selected if they were determined to be eligible to participate in this study based on the aforementioned inclusion and exclusion criteria. Patients got both oral and written information about the details of the study. Candidates were provided at least 24 hours to consider participation in the study before finalizing the consent form, and they were recruited to participate in this study after obtaining the written consent form.After obtaining the written consent form, approximately 30 minutes of continuous ECG data was collected from the patients in their private room using multiple wearable sensors in two parts. In the first part, we used a transcutaneous electrical nerve stimulation (TENS) unit to obtain the baseline of the person. Patients were asked to increase the intensity of the TENS device up to the level that was tolerable for them, hold it for at least 10 seconds, and then decrease it to level 0, including additional rest between TENS challenges. In the second part, patients were engaged with soft activities such as walking, coughing, sitting, and lifting legs that may cause pain sensation. To achieve a better statistical analysis, data collection in both parts, with and without TENS unit, was repeated two to three times. Subject's self-report of pain was recorded using NRS. The NRS for pain is a segmented numeric version of the VAS to measure pain intensity in one dimension in which a respondent points to the number on the NRS, an integer from 0 to 10, that best represents their pain intensity from “no pain” to “worst pain” . We expeTo develop an algorithm for pain assessment in hospitalized patients, we tracked physiological signals such as HR, HRV, and respiratory rate from their ECG signals. The technology used in this study to capture the aforementioned signals includes the following components:Biopotential acquisition system for ECG recording—ECG is a biopotential signal captured from the skin surface with a device developed by Sarker et al . The sysTENS unit device —TENS units work by delivering small electrical impulses through electrodes that have adhesive pads to attach them to a person's skin.The ECG signals from each patient were sampled at a rate of 500 Hz. Data from two channels  were obtained. The patient’s pain levels were simultaneously reported and saved as labels. For the purpose of synchronicity, the corresponding Unix timestamps were also obtained while extracting both ECG and label data. The ECG signals were trimmed from start to end to match the corresponding label timestamps. Since the sampling frequency was 500 Hz, each timestamp had 500 ECG samples associated with it.Once these clean signals were obtained, the second step in the pipeline was to extract peaks. To find the peaks, the signals were first sampled down to 250 Hz. A bidirectional long short-term memory network was used to obtain the probabilities and locations of peaks . A windoThe third and final preprocessing step is to remove noise from the NN interval data. NN intervals are the time intervals between two successive peaks. They are obtained by subtracting two successive peak indices. All data points that are within 2 standard deviations of the mean were selected. The rest of the data points were considered outliers and were removed. Even after removing these outliers, however, there might still be anomalous (not a number [NaN]) values in noisy sections of the data. If the proportion of NaN values exceeded 50 percent, the noisy sections were discarded. Otherwise, only NaN values were discarded, and the remaining values were interpolated. The filtered NN intervals were then saved and used for feature extraction.In the experiments conducted by Werner et al , they usIn addition to the 3 time domain features used by Werner et al , we alsoThere were 19 time domain features extracted from the NN interval series. They include the slope of the ECG signals and 18 statistical measures. These features were computed using 5.5-second sliding windows. The definitions of these time domain features are mentioned in The breakdown of the 19 aforementioned features is explained as follows: slope of NN intervals—a polynomial fit of degree 1; 5 NN interval features—total count, mean, minimum, maximum, SD; 9 NN interval difference features—mean difference, minimum difference, maximum difference, SD of successive interval differences, root mean square of successive interval differences, number of interval differences greater than (a) 20 milliseconds and (b) 50 milliseconds, and percentage of successive interval differences that differ by more than (a) 20 milliseconds and (b) 50 milliseconds; and 4 heart rate features—mean, minimum, maximum, and SD.There were 13 frequency domain features extracted by estimating of power spectral density using the Welch method. These features were computed using 250-second rolling windows with a minimum threshold of 50 values per window. The definitions of these frequency domain features are mentioned in The breakdown of the 13 frequency domain features is explained as follows: total power—total spectral power over all frequency bands; 4 HF band fast Fourier transform (FFT) features—peak, absolute, relative, normalized; 4 LF band FFT features—peak, absolute, relative, normalized; 3 very low-frequency (VLF) band FFT features—peak, absolute, relative; and FFT ratio of HF and LF bands.To ensure generalization and avoid overfitting, it is important to perform feature selection. This, in turn, reduces computational complexity and the time for training and validating models. Feature selection models can be placed under three broad categories: filter-based methods, wrapper-based methods, and embedded methods. Filter-based methods statistically determine the relationship between input variables (features) and the target variable (label). They provide a metric for evaluating and filtering out features that will be used by the model. They are also computationally cheaper than the other two methods and have a reduced risk of overfitting . Among tSince the NRS labels recorded during clinical trials were collected from real postoperative patients, there are some inherent challenges due to the distribution of data. For example, there are 83 occurrences of NRS pain label 4, but there are only 4 occurrences of NRS pain label 10 among all patients. Due to the subjective nature and the different sources of pain among our recruited patients, the imbalanced distribution of pain levels among all patients is inevitable.To compare our pain assessment algorithm’s performance with Werner et al , we downSince the patients’ NRS values were only reported after performing some activities, labels were stored sparsely. While combining ECG features with their corresponding labels, their timestamps were matched based on the nearest 5.5 seconds (labeling threshold). More precisely, any ECG feature window that was within 5.5 seconds of a reported NRS value was given that value as its label. However, as a consequence of this, all the feature windows that were not within the labeling threshold were not given a corresponding label.To label the remaining unlabeled data points, we employed Snorkel , a weak All the data points that were within the labeling threshold were considered “strong” labels, or labels used for training labeling functions. These strong labels were collected directly from the patients. The remaining unlabeled data points were considered “weak” data and were kept aside for the weak supervision algorithm to label. For the labeling process, only each patient's strongly labeled data was used to label their own unlabeled instances. This was done to avoid the possibility of data leakage during the validation process.LabelModel function. The most confident label predictions from each datapoint were considered as labels for the weak data. It is important to note that weak supervision does not compromise on the reliability of our algorithm because we use the weakly labeled data only for training our models. This way, the performance of our algorithm can be measured using only real data collected from patients.The labeling functions consist of a group of three off-the-shelf machine learning models: (1) an SVM with a radial basis function kernel, (2) an RF classifier, and (3) a k-nearest neighbor (KNN) classifier with uniform weights. Once each of these models is trained on strong labels, they are used to make predictions on the weak or unlabeled data. Their predictions are then collected and converted into a single confidence-weighted label per data point using Snorkel’s To compare the performance of our pain algorithm with Werner et al , we perfWe evaluated the performance of our pain algorithm using leave-one-out cross-validation (LOOCV) with the focus on optimizing the area under the curve (AUC) score. During each iteration of LOOCV, the data of 18 of the 19 patients, including those data points that were labeled by Snorkel, were used for training. For testing, only the strongly labeled data points from the one patient left out were used. This process is repeated for all 19 patients to estimate the algorithm’s performance on unseen data. Due to the presence of an imbalanced distribution of pain levels within patients, data points from some pain levels were nonexistent from their data. As a result, it was not possible to compute either precision or recall for most patients.The following five classification methods were deployed in our experiments to identify the best performing model for our pain assessment algorithm: AdaBoost classifier, XGBoost classifier, RF classifier, SVM classifier, and KNN classifier.We also conducted separate experiments with feature selection using the 32 features mentioned in the Feature Extraction section. To get the best set of features for classification, we run LOOCV using an RF classifier. We compute the Gini importance of each of the features at every fold and select those features that were at least one standard deviation above the mean importance score. As a result, it was possible to have different sets of features in every fold. After computing the best set of features at every fold, we consider those features that were used in most of the folds for classification. The following 8 features were used in the final feature set: (1) total spectral power, (2) absolute LF power, (3) absolute HF power, (4) mean HR, (5) relative HF power, (6) normalized HF power, (7) relative VLF power, and (8) normalized LF power.A total of 25 patients with acute pain were engaged by APS and recruited for this study at UCI Medical Center. However, the ECG data from 2 patients were missing due to connectivity issues. Moreover, we found that 3 of the patients had arrhythmia, so we removed those 3 as well. The average age of patients was 55.6 years ; 52% (13/25) of patients were male and 48% (12/25) of patients were female . All of To make a fair comparison between our pain assessment algorithm and the work of Werner et al , we replWe were able to achieve the highest accuracy on the SVM classifier for both settings, with and without feature selection. Moreover, there is no noteworthy difference in the performance of the SVM classifier in both settings. However, while comparing the other classifiers, it is evident that there is a great improvement in performance while using feature selection in the BL versus PL1 category. The performances of the AdaBoost, XGBoost, RF, and KNN classifiers have a marked increase of about 12% on average when compared to their counterparts without feature selection. However, there is a slight decrease in the AdaBoost and RF classifiers and significant decrease in the KNN performance in the BL versus PL4 category. On the other hand, there is an improvement of about 16% in the XGBoost classifier while performing feature selection in the BL versus PL4 category. We speculate that the lower accuracy scores could be due to the relatively smaller number of training examples available from the downsampled PL4. On the flip side, due to the relative abundance of training examples from PL2, there is a spike in performance for all classifiers across both feature settings in the BL versus PL2 category.While comparing our algorithm's performance to Werner et al , we can To the best of our knowledge, this is the first study that uses ECG signals from real postoperative adult patients for the purpose of developing an automatic pain assessment tool. Moreover, the use of weak supervision in our data labeling process is a novel approach that has not been implemented in pain assessment studies before. It eliminates the need for constantly asking patients for their pain levels and therefore reduces the burden placed on them during the trials. The accuracy scores for this data set with the focus of optimizing it for AUC using the SVM classifier, especially in the first three pain categories, are considerably higher than the scores achieved by Werner et al for both feature settings (with and without feature selection). We also achieve comparable results for the last pain category (BL vs PL4). Furthermore, the use of feature selection in our procedure helps determine the most informative features and reduces the complexity of our pain models. We were able to identify the 8 most informative features and improve the performance of our models in the process.The main limitation in our algorithm is the presence of noise, in the form of motion artifacts, in our physiological data. Since we collect data from real postoperative patients in a clinical setting, they were allowed to move more freely when compared to experiments performed in a laboratory setting on healthy subjects. The presence of noise diminished the quality of our data. Thus, this negatively impacted the performance of our algorithm. Another limitation in our experiments is the presence of imbalanced labels in each patient’s data. Since we did not collect data in a laboratory setting, most patients did not report all the different pain levels during the trials. Most noticeably, this led to a relatively smaller number of labeled examples from the highest pain level (PL4). This consequently decreased the performance accuracy for that pain category (BL vs PL4). In a controlled laboratory setting, one can design the study to force the pain intensity levels to be balanced, which is not feasible in real settings.Furthermore, we could not find a significant difference between different pain levels in our study. We believe this is due to the fact that variations in ECG signals in response to different pain levels are much harder to distinguish in comparison to different pain levels versus baseline. Moreover, it is worth mentioning that the state of the art in pain assessment focuses on comparing baseline with other pain levels . We belThe experiments proposed in this study show the viability of our pain assessment algorithm on data from postoperative patients. The use of weak supervision for labeling and feature extraction improves the robustness of our approach. We plan to incorporate multimodal pain assessment methods to further improve our performance and robustness.


BoNT-A has been widely used for TMD therapy. However, the potential benefits compared to dry needling techniques are not clear.  this study aimed to compare the immediate effects of botulinum toxin type A (BoNT-A) injections and Acupuncture in myofascial temporomandibular disorders (TMD) patients.n=18). AC patients received four sessions of traditional acupuncture, being one session/week during 20-min. BoNT-A patients were bilaterally injected with 30U and 10U in masseter and anterior temporal muscles, respectively. Moreover, a control group received saline solution (SS) in the same muscles. Self-perceived pain was assessed by visual analog scale, while pressure pain threshold (PPT) was verified by a digital algometer. Electromyographic evaluations (EMG) of anterior temporal and masseter muscles were also measured. All variables were assessed before and 1-month after therapies. The mixed-design two-way repeated measures ANOVA and Tukey’s post-hoc tests were used for analysis, considering a=0.05. 54 women were divided into three groups (P<.001). BoNT-A was not better than AC in pain reduction (P=0.05), but both therapies were more effective in reducing pain than SS (P<0.05). BoNT-A was the only treatment able to improve PPT values (P<0.05); however, a severe decrease of EMG activity was also found in this group, which is considered an adverse effect. Self-perceived pain decreased in all groups after one month of therapy ( after one month of follow-up, all therapies reduced the self-perceived pain in myofascial TMD patients, but only BoNT-A enhanced PPT yet decreased EMG. While the IT deliver pharmacological agents, e.g., anesthetics, botulinum toxins or other agents, with needles,5 the DN consists in the insertion of thin monofilament needles, as the ones used for acupuncture practice, without any injectate.6Masticatory myofascial pain (MMFP) has a complex pathogenesis expressed by a multifactorial etiology, which led to the proposal of numerous conservatives, reversible, and minimally invasive therapies to treat this condition.7 include immediate reduction in local, referred, and widespread pain,8 and reduction in peripheral and central sensitization.5 Although a recent randomized clinical trial reported pain reduction of 84% after one month of treatment – concluding that acupuncture was effective for MMFP pain9, available systematic reviews did not find further advantages in the use of acupuncture for MMFP over other treatments such as oral appliances, behavioral therapy, and/or pharmacotherapies.11 These controversies might be due to several methodological shortcomings, leading to inconclusive results, which expose the need for high quality studies comparing the efficacy of acupuncture with other treatments.Acupuncture is a therapeutic method of the traditional Chinese medicine which differs from conventional DN techniques since needles are not inserted just in the painful region. Its antinociceptive effects4 Animal studies have demonstrated that peripheral injections of BoNT-A have analgesic effects on pain stages by inhibiting the release of nociceptive mediators , mechanism independent of its neuromotor effect.13 Based on this data, BoNT-A has been used as an off-label treatment to control MMFP. Moreover, a few well-designed clinical trials16 have demonstrated the superiority of this substance over placebo, but not over conservative treatments like oral appliances.15 Besides, a prospective study showed that BoNT-A injections in the masticatory muscles are also effective in reducing MMFP and tension-type headache, recommending this therapy for muscle pain.17 Conversely, the lack of consensus on the effects of BoNT-A is due to the number of low-quality studies available, and especially to the post-injection adverse effects in muscle and bone tissues, being the reason why its benefits for MMFP remain unclear.19Botulinum toxin type A (BoNT-A) is an FDA-approved treatment for some pain disorders (as dystonia and migraine), becoming one of the most popular IT used to control MFP.22 Moreover, systematic reviews were inconclusive about the effectiveness of needling therapy, since it was not possible to determine if the technique (dry or wet) or the injectate were responsible for the improvements.23 Therefore, this study aims to compare the immediate effects of BoNT-A injections and acupuncture therapy in myofascial TMD patients.Studies comparing DN techniques with BoNT-A for myofascial TMD pain are scarce, and no previous study compared these treatments with an injection placebo group.This randomized single-blinded controlled clinical trial, conducted following the Helsinki Declaration, was approved by the local Research Ethics Committee (CAAE: 22953113.8.0000.5418) and by the Brazilian Registry of Clinical Trials (ReBEC RBR-2d4vvv). All individuals were informed about the research purposes and signed an informed consent form.24 and it was performed by using the G*Power 3.1.9.2 software . The following parameters were considered: a) test power of 0.9; b) 0.05 significance level; c) effect size of 0.4. Considering these standards, 15 participants per group would be sufficient to detect statistically significant differences. However, considering possible dropouts, 20% was added in each group. Thus, the final sample size comprised 54 individuals, which were randomly divided into three groups: acupuncture (n=18); BoNT-A (n=18); and saline solution (SS) (n=18), as a negative control group. For this allocation, a software was used  and the sequence was sealed in an opaque envelope, which was operated by a researcher not involved in other procedures of this study. The investigator assessing the outcomes was masked to the treatment assignments.The sample size estimation was based on the average pain scores of previous studies,25 by two calibrated raters (Kappa coefficient = 0.80). To achieve the 54 volunteers included in the study, 80 female subjects were screened for eligibility. Considering the inclusion and exclusion criteria, 65 participants were suitable to participate. However, before allocation, five individuals were excluded since they refused to participate (n=4) or to stop previous therapies (n=1). Six additional exclusions occurred due to lack of compliance, leading to a final sample of 18 volunteers per group , uncontrolled hypertension, neurological disorders, positive history of trauma in the orofacial and neck area, with dental pain, with self-reported sleep bruxism, and taking any medication for pain control were excluded from the recruitment . The diaer group .24 Disposable, sterile, individually packed, stainless steel needles  were used for this purpose by a acupuncturist. For facial points, needles had 0.22 mm of diameter and 13 mm length, and 0.25 mm diameter and 30 mm length for distal points. The needles were manually inserted and rotated in both clockwise and counterclockwise directions, until the patient related the sensation on needle site or along the meridian.Acupuncture group received four sessions of traditional acupuncture, one session per week, with 20-min each for one month. The following points were selected for this therapy: LI4 (Hegu), LI11 (Quchi), SI19 (Tinggong), LR2 (Xingjian), GB20 (Fengchi), GB21 (Jianjing), GB34 (Yanglingquan), BL2 (Zanzhu), CV23 (Lianquan), and TE23 (Sizhukong).15 by a calibrated researcher, distributed in five sites for each muscle. It was used a 1 mL syringe with a 30-gauge and 13 mm needle. Briefly, for the masseter, the injected sites were in the inferior part of the muscle (on mandibular angle), 5 mm apart from each other. For the anterior temporal muscles, sites were determined according to the functional test, considering the most prominent part, and must be 1 cm external to the eyebrow and 5 mm apart among them  was reconstituted using non-preserved sterile saline solution 0.9%. A single bilateral injection was applied in the masseter and anterior temporalis muscles using 30U and 10U of BoNT-A, respectivelyong them . InjectiThis injection technique consisted in inserting the needle into the soft tissue until reaching the bone; then, the needle was slightly moved to place the tip inside the muscle. Before injection, a careful aspiration was performed to avoid a possible intravascular administration.SS (NaCl 0.9%) was bilaterally injected into the same muscles and sites, following the same protocol and doses, as described for BoNT-A injections. Injections of BoNT-A and SS were performed in a single appointment by the same trained clinician, who was blinded to the treatment assignment.VAS is a 100 mm horizontal line, anchored by the words “no pain” at the left end, and “worst pain imaginable” at the right end. Participants were instructed to mark a line at any point, representing the level of current, worst, and average pain of the last month.2 circular flat rod, for the bilateral evaluation of the masseter and anterior temporal muscles. Patients were instructed to indicate the moment when the pressure became painful. They were sat in a chair with the Frankfurt plane parallel to the ground, and muscles should be relaxed. The circular flat rod was perpendicularly pressed to the surface skin at a 0.5 kg/cm2 rate, following the sequence: right anterior temporal, right masseter, left masseter, and left anterior temporal muscles. After a five-minutes rest, the pressure was applied again, as follows: left anterior temporal, right anterior temporal, left masseter, and right masseter.PPT was assessed by a digital algometer  with 1 cmThe bilateral EMG signals of the anterior temporal and the superficial masseter muscles were recorded by the ADS 1200 device , which has eight channels, adjusted gain of 1e16,000, band-pass filter of 20e500 Hz and sampling frequency of 2000 Hz per channel. A circular passive bipolar Ag/AgCl double electrode with 1 cm interelectrode distance was used .Before the recordings, the volunteers’ skin was cleaned with cotton and 70% alcohol, and a function test was performed to identify the center of the muscle venter, in which the electrodes should be fixed. The reference electrode was placed on the participants’ manubrium of the sternum. The electrical activity of each muscle was recorded in mandibular postural position (rest) and maximum volunteer contraction (MVC). Each activity was measured three times, for five seconds, with a two minute period of rest between them, in order to avoid fatigue. The MVC activity was obtained by requiring the patients to chew a piece of Parafilm M  that was placed bilaterally in the molar region. Participants were instructed to clench their jaw to the maximum possible extent, and to maintain the pressure for five seconds, as were verbally stimulated by the examiner.Simultaneous signals were obtained by the software Lynx AqDados 7.02 , and the root mean square (RMS) values were processed by the software Lynx AqD Analysis 7.0 . The RMS values of each acquisition were considered as those obtained in the 2s and 4s-interval. The mean values of the three acquisitions (Rest and MI) were considered.As the evaluations were carried out in different timepoints, an acetate plate was fabricated for each patient to standardize the algometer position and the electrodes’ placement between sessions. The acetate plate followed the anatomic reference lines , and was clipped where the algometer and electrodes were placed.All data for groups and periods were expressed as means ± standard deviation (SD) and were assessed for normal distribution with the Shapiro-Wilk test. A mixed-design repeated measures two-way ANOVA test was used to observe the difference among groups over time and within the group. The statistical analysis compared the results observed before the treatment (baseline) with those observed one month after the therapies. Moreover, the three groups were compared to verify a possible statistically significant difference among therapies. The ANOVA test was followed by post hoc Tukey’s test. All analyses were performed using SPSS for Windows , with a 5% significance level.P= .124).Participants’ age did not differ among the three groups. acupuncture (mean age 30.3±6.9 years); BoNT-A (mean age 34.6±6.5 years); and SS (mean age 30.8±6.9 years) (P<.001). When comparing the different treatments, improvement in pain levels did not significantly differ between the acupuncture and BoNT-A groups (P>.05), but both groups presented a significant reduction on pain compared to the SS group (P<.001)  .P=.359 and P=.220, respectively) after one-month of therapy. Notwithstanding, BoNT-A group presented significantly higher PPT values (P<.001) after one month of follow-up. Comparisons among groups, showed that acupuncture values did not differ from SS and BoNT-A  groups. On the other hand, BoNT-A values were significantly higher than those obtained in the SS group (P=.006)  .P=.415 and P=.471, respectively), after one month of evaluation. Only the BoNT-A group presented statistically significant differences from baseline to the first-month follow-up (P<.001). Intergroup comparisons reveled that acupuncture values did not differ from SS (P=1.000) and BoNT-A (P=.111) values. However, BoNT-A values were statistically significant different just when compared with the SS group (P=.016)  .P<.001). Intergroup comparisons at the one-month follow-up showed a significant decrease in the masseter muscle activity in BoNT-A group compared to acupuncture (P =.020) and SS (P <.001), and these results were also found for the anterior temporal muscles (P <.001)  .The main findings of this study were that – after four weeks – all treatment groups  were able to significantly reduce the self-perceived pain, without differences between acupuncture and BoNT-A, while both treatments were superior to the SS group. Moreover, considering the PPT values for both masseter and anterior temporal muscles, only BoNT-A group lead to a significant increase in PPT. Likewise, only patients treated with BoNT-A showed a significant reduction of the EMG activity in both studied muscles.26 All therapies used in this research were able to significantly decrease the self-perceived pain after one-month (P<.001). This was expected since the literature shows that the effectiveness of needling therapy in managing MMFP of the masticatory muscles does not necessarily depend on the needling type (dry or wet) or the injected substance, suggesting that the pain-reducing effect could be a consequence of the needle penetrating the skin.23Pain is considered one of the most common reasons for a TMD patient seek treatment.P>.05). However, both groups presented a significant reduction on pain compared to the SS group (P<.001). A previous study showed that BoNT-A injection and dry needling yield similar satisfactory therapeutic outcomes regarding pain relief in patients with MMFP.22 Nevertheless, to the best of our knowledge, this is the first study comparing BoNT-A to acupuncture  and including a placebo group. Considering that both BoNT-A and acupuncture have specific pain relief mechanisms, , this can explain the improvement in the results achieved in comparison to SS group. Furthermore, two factors should be emphasized to explain the self-reported pain reduction: firstly, the placebo effect, in which the expectations generated by receiving a therapeutic approach is able to modulate pain perception, a mechanism known as placebo analgesia;27 secondly, the natural course of MMFP, which is generally favorable and with varying symptoms.29Comparing the treatments, improvement in pain levels did not significantly differ between the acupuncture and BoNT-A groups  at the follow-up. This result can possibly be explained by the exclusive antinociceptive mechanism of the BoNT-A. After BoNT-A injection, there is a temporary inhibition of pain neurotransmitter release at the pain site, reducing peripheral sensitization. Additionally, due to the BoNT-A axonal transport by A-δ and/or C fibers to the central nervous system,33 there is an indirect or direct reduction of central sensitization, hyperalgesia, and allodynia occurs , through the reduction of the peripheral nerve over-activity, resulting in an increased pain threshold.34Considering the PPT values for the masseter and anterior temporal muscles, the intragroup evaluation demonstrated that only BoNT-A group presented significantly higher PPT values  may have influenced, as literature suggest that electroacupuncture is a technique more suitable to improve PPT.36Besides, some reasons might explain why acupuncture group did not show significant improvements in PPT: the short follow-up (one month), once a systematic review reported that dry needling treatments (such as acupuncture) may increase PPT immediately or until 12 weeks after the therapy;37 Notwithstanding, systematic reviews conclude that there is no consensus on the therapeutic benefits of BoNT-A on TMDs38 and that the efficacy-adverse effects ratio should be evaluated. Note that, in this study, BoNT-A improved all variables in a refractory MMFP population. These results reinforce that BoNT-A should not be the first option to MMFP treatment due to possible adverse effects, but it could be considered in patients that do not mitigate their pain with more conservative managements, fact that is corroborated by other studies.39Between-groups comparisons on PPT values, BoNT-A treatment led to a higher increase in PPT values than in the SS group. This result is in accordance with a previous study that showed improvements of PPT after BoNT-A injection compared with the SS group in patients with MMFP.P<.001). Intergroup comparisons showed a significant decrease in muscle activity for both muscles in BoNT-A group when compared to acupuncture and SS groups. A reduction in EMG activity of masticatory muscles is expected after an intramuscular injection of BoNT-A once this toxin inhibits the release of acetylcholine at the neuromuscular junction of presynaptic motor neurons, reducing muscle activity.39 In fact, a temporary regional weakness is one of the most common adverse effects related to the use of BoNT-A in TMD treatment.19 A recent report also showed a significant reduction in maximum occlusal force in the BoNT-A group compared to SS and no injection groups.40The EMG results for the masseter and anterior temporal muscles demonstrated that only patients treated with BoNT-A presented a significant reduction of the EMG activity one month after treatment . Based on previous investigations,15 this dosage is able to reduce pain in MMFP patients, but it also allows the full recovery of muscle activity, which returned to normal EMG values after three months.15 Anyway, a reduction in the EMG activity of masticatory muscles is an adverse effect that must be considered; once acupuncture did not promote a significant change in EMG values, this could be considered an advantage of acupuncture over BoNT-A. Notably, the reduction of EMG values in BoNT-A groups is not responsible for decreasing subjective pain. Studies have demonstrated that BoNT-A presents an analgesic effect which is independent and precedes its neuromuscular effects. The EMG results in the acupuncture and BoNT-A groups confirms the disconnection between muscle electrical activity and muscle pain. Besides EMG reduction, patients receiving BoNT-A injections also reported adverse effects like edema and pain during injection, being the last also reported by the SS group. Conversely, self-reported adverse effects for the acupuncture group comprised itching and reddening of the skin, without pain symptoms nor edema.The occurrence and the intensity of these adverse effects are directly related to higher doses and repeated injections.These results suggest that all studied needling therapies  are effective after one month of follow-up in reducing the self-perceived pain in patients with refractory MMFP; and, that BoNT-A seems to be superior due to the improvement in PPT values. Nevertheless, caution is necessary when judging these findings, since some limitations should be considered. Selecting only women as the study population hinder our results to be generalized to male patients. However, it was necessary once MMFP is more prevalent in this gender. Even though the 1-month follow-up is a restricted time of evaluation, our main objective was to assess the immediate effects of the proposed treatments; however, studies considering longer periods of evaluation should be performed. Finally, the effects of the proposed therapies on the psychosocial status of myofascial TMD patients should be also evaluated, considering that psychosocial variables generally act as chronification factors for TMDs.After one month of follow-up, all therapies reduced the self-perceived pain in patients with MMFP. BoNT-A was not superior to acupuncture in pain reduction, but both were superior to SS; moreover, BoNT-A was the only treatment able to improve PPT values. However, only patients treated with BoNT-A reduced the EMG activity in the injected muscles which should be considered as an adverse effect.


In the 1990s patients reported outcome measures (PROMS) were developed to reduce the risk of bias if outcome is rated by the surgeon. When the Swedish Knee Registry sent out a mail in 1999 to validate their registry to check the revision status of the patients, they included a simple question “How satisfied are you with your knee replacement?” 95% of all patients responded and were clearly less positive than expected. Robertsson et al.  reportedIdentifying the causes of dissatisfaction is important in order to improve patient selection for TKR, adjust treatment strategies and to support or treat dissatisfied patients with their residual complaints. Sociodemographic, preoperative, operative, and postoperative factors have been studied in large reviews. No specific single leading factor has been found, but patients expectations, higher function before surgery, lower stage of arthritic disease, complications, poor resolution of pain, and lower improvement of knee function were more common in dissatisfied patients (Gunaratne et al. Acta Orthopaedica Robertsson’ s publication (Robertsson et al. 20 years ago in The gap between the satisfaction rates of THR and TKR may be caused by the more complex nature of the knee joint compared to the hip. The anatomy of the knee ligaments and the individual form and size of femur, tibia and patella may be better addressed with a customized patient specific prosthesis implanted with a surgical robot to optimize precision (Namin et al. Until real improvements are achieved, we orthopedic surgeons should be humble and realistic. TKR is a good, but not ideal, option for patients with significant complaints due to end-stage arthritis. We need to be careful in young patients, those with unbearable pain for which narcotics are used, and patients who want to resume high level sports activities. Reduction of pain and improvement of function may be expected but some complaints may persist. There are also possible complications including infection and thrombosis, which occur in less than 5% of patients, but may create more problems than preoperatively.Pain relief and improving physical function are the main aims of TKR. Expectations should be explicitly addressed before surgery; a lesson now 20 years old, yet still true today.Department of Orthopaedics and Sports Medicine,Erasmus University Medical Center Rotterdam,the NetherlandsE-mail:j.verhaar@erasmusmc.nlJan Verhaar


Sickle Cell Disease (SCD) is a genetic progressive vascular disease that impacts patients overall health and quality of life. Sickle-cell pain crises (SCPCs) are a hallmark clinical presentation of SCD and have been associated with increased morbidity and mortality. The Sickle Cell Pain Diary- Self Report (SCPD-S) was developed as a daily patient-reported outcome (PRO) measure primarily intended to capture the frequency and severity of SCD-related pain during and outside of a SCPC. The SCPD-S also examines the impact of the pain associated with an SCPC on other health-related quality of life concepts. The objective of this study was to investigate the content validity of the SCPD-S.The content validation testing included 18 in-depth hybrid concept elicitation and cognitive debriefing interviews conducted with SCD patients in the US aged 12 years and older. Interviewers used a semi-structured interview guide and a think-aloud approach for the cognitive debriefing portion. All interviews were recorded, transcribed, coded and analyzed.n = 12) resulted in the expansion of the SCPD-S from 13 to 19 items. Items on the impact of an SCPC on social and recreational activities, sleep, and emotional well-being were added. Five items were significantly revised, as were three response choice sets. Round 2 hybrid interviews (n = 6) confirmed the comprehensiveness of the revised diary, understandability of the wording, and appropriateness of the recall period and response sets. Saturation analyses specific to concept elicitation revealed that no additional interviews were needed.Eighteen interviews across two rounds were conducted. Round 1 hybrid interviews (This study provided evidence to support the content validity of the SCPD-S, a self-report daily diary. Data gathered during patient interviews indicated that the SCPD-S is a fit for purpose measure of SCD and SCPC-related pain frequency and severity and the impact of this pain on other health-related quality of life concepts including fatigue and emotional health. The numerous changes to the SCPD-S as a result of the study findings highlight the importance of the content validation process when developing a PRO measure. Sickle cell disease (SCD) is a genetic vascular disease that affects approximately 100,000 children and adults in the US. SCD imposes a significant burden on patients, impairing their ability to function, which can lead to an inability to maintain a consistent work or school schedule, keep social engagements, and participate fully in family life . In the SCPCs are characterized by acute, often debilitating pain that prevents normal functioning, and have been associated with an increased risk of morbidity and mortality. SCPCs can lead to life-threatening emergencies such as acute chest syndrome, and stroke –10. In aVoice of the Patient Sickle Cell Disease report, patients rated pain as the most burdensome symptom they experience [As described in the US Food and Drug Administration’s perience , underscperience , 14. GivStudies often rely on acute or emergency medical visits as a way to measure SCPC-related outcomes in the SCD population , 16. TheSCPCs can be assessed through patient self-report. However, identifying the optimal way in which to collect such patient-reported outcome (PRO) data can be challenging. A retrospective format, such as that used to assess chronic pain, asks patients to report on their pain over a one-week, 1 month, or longer recall period. Retrospective formats with longer recall periods, such as 7-day or longer, may be problematic for assessing sporadic events such as SCPCs because such longer recall periods can “wash out” the severity of pain and impacts when averaged over time. Using a shorter recall period, such as “in the past 24 hours,” may be more appropriate to measure sporadic events.The Sickle Cell Pain Diary-Self Report (SCPD-S) was developed as a self-reported PRO measure that addresses these gaps and accurately captures SCD-related concepts on a daily basis. The SCPD-S was designed to be completed by patients with SCD aged 12 and older and is intended to be administered electronically. The purpose of this study was to evaluate the content validity of the SCPD-S using two rounds of qualitative hybrid concept elicitation (CE) and cognitive debriefing (CD) individual interview methods.A draft version of the SCPD-S (v.01) was developed using a multifaceted approach including a review of the literature, PRO expert input, feedback collected during a day-long patient advisory board meeting that also included clinicians, and individual discussions with clinicians. The SCPD-S v.01 included 13 items related to daily pain severity and duration, fatigue, medication use, and the impact of SCD on work/ school, daily activities, and sleep.Patients eligible to participate in the study were at least 12 years of age, had a self-reported diagnosis of SCD, experienced at least one SCPC in the 12 months prior to screening, and were willing and able to participate in a 90 min interview in English either in-person or via telephone. Patients were recruited by a company that specializes in recruitment for healthcare research using their proprietary patient database. Sampling procedures were designed to enroll patients diverse in demographic characteristics such as age and education level. Interested patients were directed to a brief online screening survey to provide initial confirmation of their eligibility. Telephone confirmation of eligibility was conducted prior to scheduling an interview. Patients provided written informed consent once enrolled. All study materials were approved by the New England Independent Review Board.An overview of the methods used for each type of interview is presented in Fig. In round 1, hybrid interviews were conducted that included both concept elicitation and cognitive debriefing methods. In the concept elicitation segment of the interview, patients were asked about their daily experiences with SCD symptoms and the impact of those symptoms on aspects of their lives such as work, school, relationships, and social and recreational activities. They were then asked to discuss symptoms experienced during a SCPC, what a typical day looks like both during and outside of a crisis, and what treatment methods they seek when experiencing a crisis. This segment of the interview served to understand which concepts were important to include in the SCPD-S.A cognitive debriefing approach was used in the second segment of the interview, during which each element of the diary  was tested to evaluate the relevance and comprehensibility of the SCPD-S. The cognitive debriefing portion used a ‘think-aloud’ process: patients were asked to complete the SCPD-S while verbalizing their thoughts about how they answered each question . PatientThe SCPD-S v.01 was revised based on patient feedback from round 1 interviews, resulting in v.02. Round 2 interviews used the same methodology as round 1 (hybrid concept elicitation and cognitive debriefing), with different patients. The SCPD-S v.02 was subsequently revised based on patient feedback from round 2 interviews, resulting in SCPD-S v1.0.After transcription of audio-recordings, data were coded and analyzed using identical methodology for both rounds of interviews. Concept elicitation data were coded using NVivo software and analyzed using a content thematic analysis method . This stAn analysis of saturation was also conducted on data from the concept elicitation portion of the interviews. Saturation is the point at which no new relevant information emerges, and provides evidence that enough interviews were completed to fully understand concepts important to patients. This strategy allows researchers to determine if new concepts are elicited as data analysis progresses, and can provide assurance that enough interviews have been conducted to fully capture the range of patient experiences –23. DataFor the cognitive debriefing segment of the interviews, narrative data were coded using a series of ratings to systematically summarize feedback. Transcripts were reviewed and coded for content related to each element of the daily diary to determine whether patients found each element to be relevant and understandable. Coding was completed using NVivo software.Eighteen total interviews were conducted in two rounds. Results from the concept elicitation portions of all interviews (rounds 1 and 2 combined) are presented first. These results are separated to discuss concepts related to SCD in general first, and then present concepts related to SCPCs.Results from the cognitive debriefing portions of interviews are separated into findings from each round of testing because patients responded to different versions of the diary in each round.n = 9, 75%) and via telephone .n = 4, 67%) and via telephone . Patients ranged from 12 to 50 years old (M = 29 years), and 72% (n = 13) of all patients were male. One patient in round 1 (8%) self-reported being of Hispanic descent, and all others across both rounds (n = 17 patients (92%) were of African American descent. Almost half of the patients had a ‘less than high school’ education level ; however, all 8 of these participants were 18 years or younger, indicating that they were still attending high school at the time of the interview. Five participants (28%) reported that they seek out clinical care every time or almost every time they experience an SCPC  and fatigue . Other commonly reported symptoms included: joint problems/stiffness , shortness of breath , and stress, headaches/migraines, and jaundice .The two most frequently reported symptoms were pain  describing considerable impacts from daily SCD symptoms. Some impacts were the result of limitations imposed by symptoms, while others were the result of self-imposed limitations due to fear of triggering a pain crisis. Six areas of impact were described during interviews: social /recreational activities , activities of daily living , physical functioning , work/school , emotional health , and relationships . Table Patients talked about how their daily lives were affected by SCD, with most . Patients described avoiding or making accommodations for activities due to symptoms or fear of triggering a pain crisis. In particular, seasonal conditions such as the weather or temperature fluctuations were reported as a major determinant of whether or not patients decided to leave their home for activities. Travel was also reportedly difficult due to concerns that the air pressure in airplanes could worsen symptoms and sitting for long periods of time could be painful.n = 12; 67%) discussed impacts on activities of daily living, including getting dressed, going to the bathroom, running errands, and lifting heavy objects. Housework in particular required either assistance from others or modifications. Adolescent patients (aged 12–17) specifically noted limitations on physical functioning, as many were unable to participate in common school activities such as extracurricular sports.Many patients . Commonly reported emotional difficulties were sadness, anxiety, and stress. Emotional impacts were typically related to limitations they experienced due to SCD, uncertainty about the future, and helplessness in dealing with symptoms and impacts. Patients also reported impacts on their relationships. Some patients  reported having one or more close friends or family members who “didn’t understand” the disease and either distanced themselves or shamed patients for needing accommodations.Patients reported that SCD took a toll on their emotional health and well-being , emotional health , sleep , medication use , physical functioning , and activities of daily living , including stress, anxiety, and helplessness when experiencing an SCPC related to the pain and uncertainty about how long the crisis would last. Patients described difficulty sleeping during an SCPC due to the pain . In some cases, pain medication was reported to improve sleep; other patients said that pain medication interfered with sleep. Most patients reported sometimes increasing the dose, frequency and types of medications they take when experiencing an SCPC .Patients reported experiencing effects on emotional health  reported ultimately seeking care outside of the home for most pain crises. For these patients, seeking care was considered to be a last resort after the pain had reached a level  of “ten and higher.” Many patients reported distress related to making decisions about whether and when to go to the hospital. Patients reported using a variety of pain crisis prevention and minimization strategies to delay having to seek care outside the home for as long as possible. Strategies included: rest, hydration, breathing exercises, applying a heating pad, music, meditation, and increased medication use. Of the subset of patients who shared reasons for delaying seeking treatment outside the home, the most commonly reported reasons included: feeling stigmatized by doctors and other treatment professionals or not being believed about pain levels  and long wait times in emergency rooms , an item was added to assess the degree to which an SCPC resulted in such difficulties. Second, patients clearly reported that they experienced impacts on activities of daily living and social/recreational activities, and that these impacts are distinct from one another. As a result, one item of the SCPD-S v.01 that asked about general activities was split into two items  to provide better and more precise coverage of these concepts. Third, two items were added because patients indicated the importance of the duration of SCPCs and healthcare utilization as a result of SCPCs.Multiple concepts emerged regarding patients’ experience of SCPCs that necessitated additions to the SCPD-S v0.1. First, because half of the patients in round 1 discussed emotional difficulties  patients in round 1.Round 1 of interviews tested the SCPD-S v.01 which consisted of 13 total items with 12 participants. Overall, the SPCD-S was generally found to be easy to understand and complete. Also, patients were relieved to hear the finalized SCPD-S would be completed electronically  and they would not have to read and follow the skip pattern. Instructions were revised after round 1 to increase clarity. The recall period was endorsed as appropriate by most , but others found it difficult to distinguish sickle cell pain that was not crisis related from crisis-related pain. In general, the modifications made were minor wording improvements for clarity. However, misunderstandings on one item related to the duration of the pain crisis within the past 24 h required more significant modification.Eight of the items were found to be easy to understand and relevant to patient experiences with SCPCs. Modifications were made to 5 items, and one item was removed. The removed item, ‘Did you have pain today?’ was well understood by some patients  agreed that the recall period was appropriate. Patients found the wording of items to be clear and well-written. One item was changed to include the addition of ‘specialist’ to a list of providers a patient might visit with during an emergency. Otherwise, no changes were made to items. Items were endorsed as relevant and patients confirmed the good fit of the response options. Patients endorsed the comprehensiveness of the diary and no additional items were added.In sum, cognitive debriefing of round 2 interviews further confirmed the relevance of the concepts measured in the SCPD-S, and the comprehensibility of the instructions, recall period, items, response sets, and skip patterns for patients with SCD.After edits from round 2 and additional minor changes as a result of proofreading and to improve adaptability to an electronic format, the SCPD-S version number was changed to 1.0, as a developed version that has evidence of content validity for clinical and research use with patients who have SCD and experience SCPCs. Contents of SCPD-S v1.0 are summarized in Table Patients in this study described the immense impact SCD and SCPCs have on their health-related quality of life. SCD significantly impacted activities of daily living, work and school, and emotional health. SCPCs greatly affected sleep, medication use, and physical functioning. With this data as the backbone of important aspects for a PRO measure for patients with SCD to be used in clinical trials, other research studies, and as part of clinical practice, we significantly expanded the SCPD-S after the first round of interviews.The SCPD-S underwent cognitive debriefing testing in two rounds of patient interviews, and the diary was revised after each round, so that the version reviewed in the second round incorporated feedback from the first round of interviews. Patients confirmed that the concepts in the SCPD-S are relevant to people who have SCD and experience SCPCs. The revised SCPD-S v.02 that was tested in the second round was well-understood by patients. Generally, the SCPD-S was regarded as appropriate, comprehensive, and true to patient experiences. The changes to the SCPD-S as a result of patient feedback highlight the importance of the content validation process when developing a PRO measure and of re-testing a PRO after modifications have been made . Had theThe SCPD-S was developed to fill three primary gaps in the ability to measure the patient experience and impact of SCPCs on patients’ health-related quality of life: (1) that research studies and clinical practice tend to rely heavily on capturing data on SCPCs requiring healthcare utilization , which does not fully capture burden of illness and misses SCPCs that are treated at home; (2) that SCPCs are of variable duration and may be associated with health-related quality of life impacts pre- and post- the acute phase requiring more granular data capture; and (3) no other daily diaries had been developed with a clear focus on the health-related quality of life of a patient before, during, after and between SCPC events. Existing PRO measures used longer recall periods (such as past week or past month) that required patients to consider their average experience during an SCPC, despite there being tremendous variation within individual (across separate pain crises) and across individual SCPCs. Further, the existing measures were not focused on measuring what would happen if the frequency of SCPCs changed. Developing the SCPD-S with a past 24 h recall period provides a significant improvement in the ability to measure the depth and breadth of patient experience including capturing at home SCPC care; critical for better understanding potential need for change in clinical care, and for research studies. Patients may also find it useful to use the SCPD-S on their smartphone, tablet, or computer to improve communications with their treatment providers about their experiences.Study limitations include only using one mode of administration (paper). In addition, our sample was 72% male yet approximately 50% of SCD patients are female , and whiPlanned future work on the SCPD-S includes development of interpretation guidelines for the SCPD-S, including a scoring algorithm and user’s manual. In addition, a research study is underway to examine tests of psychometric reliability and validity of the SCPD-S. Use of the SCPD-S is planned for use in future clinical trials enrolling patients who experience SCPCs as a way to capture the frequency, duration, severity, and health-related quality of life impacts of SCPCs whether the SCPC was treated at home or in an HCP office, SCD clinic, or an emergency room or hospital. Collecting more precise data on a daily basis may help to better define and measure clinically meaningful improvement as a result of treatment in an SCD population. The findings of this study provide evidence of content validity of the SCPD-S.This study provided evidence to support the content validity of the SCPD-S, a self-report daily diary. Evidence gathered during two rounds of hybrid, individual, qualitative patient interviews indicated that the SCPD-S is a fit for purpose measure of SCPC-related pain frequency, severity, and impact on health-related quality of life, including fatigue and emotional health. The numerous changes to the SCPD-S as a result of the study findings highlight the importance of the content validation process when developing a PRO measure.