Change on the Numeric Rating Scale (NRS) is based on subjective pain experience, hampering the establishment of clinically important improvement. An anchor‐based method, the Patients’ Global Impression of Change (PGIC), is often added to determine whether a patient has improved. A two‐point change on the NRS has been shown to be equivalent to a moderate clinically important improvement in randomized controlled trials (RCT’s) on medication effects. We contemplated whether these findings could be reproduced in cohort and data and in non‐drug interventional RCT’s.The NRS change was quantified by subtracting the NRS of baseline from the NRS at 6‐month follow‐up. Categorization of success/nonsuccess was applied on the PGIC, and their average NRS raw changes were calculated. The Spearman correlation coefficient quantified the overall relationship, while the discriminative ability was explored through the receiver operating characteristic curve. Data were stratified on design, sex, and pain intensity at baseline. Besides, the cohort evaluated treatment status at follow‐up.The records of 1661 patients were examined. Overall, the observed NRS change needed for moderate clinically important improvement was larger than the average two points. Yet, the changes in the cohort were smaller compared with the RCT’s. Moreover, it modified with pain intensity at baseline and treatment statuses indicated differences in mean clinical importance of −4.15 (2.70) when finalized at 6 months and −2.16 (2.48) when treatment was ongoing.The moderate clinically important improvement varied substantially, representing heterogeneity in pain relief and its relation to treatment success in chronic pain patients. Patients reported clinically important improvement at a larger pain relief than the average decrease of 2 points on the NRS.The amount of pain relief needed differed substantially between cohort and RCT patients.Pain severity at baseline modified the amount of pain relief needed for a clinically important improvement.Many chronic pain patients do not obtain adequate or equivalent pain relief from existing interventions. Due to the highly subjective nature of pain, the meaningfulness of changes in pain is often difficult to interpret.Several studies have quantified the clinically important improvement for several core domains in the chronic pain population.However, the chronic pain population is heterogeneous in pain relief and burden, and it is unclear whether these findings can be generalized toward patients included in interventional studies that analyze the effect of non‐drug treatments , cohort data or subgroups of the chronic pain population. The aim of this study was to assess the generalizability of the aforementioned definition of the clinically important improvement on the NRS to non‐drug interventional RCT’s and heterogeneous cohort data. We expected to find a two‐point difference on average on the NRS as a moderate clinically important improvement in both interventional studies of non‐drug treatments and cohort data. However, we expected to find differences between subgroups of chronic pain populations, such as a larger difference than two points on average for women when compared to men. These results may contribute to the design of future studies, inform sample size calculations, and may set specific criteria for cohort studies. Such information will facilitate comparison of the results across studies and set the value for therapeutic meaningfulness in clinical practice.PAIN cohort, initiated in 2003 by the Comprehensive Multidisciplinary University Pain Center Maastricht.For more than 20 years, the Department of Anaesthesiology and Pain Medicine of the Maastricht University Medical Center+in the Netherlands has routinely collected both the NRS and PGIC of chronic pain patients for both interventional studies and a cohort data. For this study, we used data of the RCT’s of van Eerd, et al.,The 11‐point NRS was used to quantify pain intensity ranging from zero (no pain) to ten (the most pain imaginable).The PGIC was used to collect the status of the patient's global impression of change on a 7‐point Likert scale ranging from “very much improved” to “very much worse”. In addition, a dichotomous PGIC score was computed in which “very much improved” and “much improved” indicated a successful treatment outcome and “minimally improved,” “no change,” “minimally worse,” “much worse,” and”very much worse,” a non‐successful outcome. The PGIC was used as an anchor‐based criterion to distinguish between successful and non‐successful treatment at follow‐up.PAIN cohort, patients could have been treated for more than 6 months (the follow‐up time used to compute change from baseline) due to receiving more than one treatment or elongation of a specific treatment. Therefore, the cohort was stratified on treatment status at follow‐up; completed; or ongoing.Because the literature suggests analyzing both sexes separately as there may be different values for clinically important improvement on treatment outcome,t‐test was applied.Study‐level characteristics  were described as means and standard deviations (SD) or percentages. The NRS change was quantified by subtracting the baseline NRS from the follow‐up NRS and described as a mean difference with 95% confidence interval (CI). To test within‐group changes, the paired sample Average raw and relative changes in the NRS were calculated for each of the 7 outcome categories of the PGIC, and the Spearman correlation coefficient was calculated to quantify this relationship. Furthermore on the PGIC, patients were classified into treatment success or nonsuccess and the respective NRS changes were calculated. To assess the discriminative ability of the NRS for treatment success, the area under the curve receiver operating characteristic curve was computed, or AUC, with 95% CI. The AUC can range between 0.5 (no discriminative ability) and 1.0 (perfect discriminative ability).Subsequently, the data were stratified and analyses were repeated for the study designs (RCT and cohort), sex categories, baseline NRS categories, and treatment status in the cohort data. The statistical analyses were executed in R, a language for statistical computing, version 3.6.1.Table p < 0.001). Hence, cohort participants reported treatment success at smaller changes in pain relief, on average. Moreover, the percentage of treatment success diverged considerably between the cohort with 316 (22.19%) patients and 81 (34.18%) in the RCT’s (p < 0.001).When comparing the cohort data with the RCT’s, the average NRS changes differed for each of the PGIC categories Figure . SimilarPAIN cohort; −3.38 (SD: 2.82) for women and −3.28 (SD: 2.61) for men, nor in the RCT’s; −4.49 (SD: 1.84) for women and −4.65 (SD: 1.88) for men.In both the cohort and RCT’s, the stratification on sex resulted in different mean values of clinically important improvement in the”very much improved” categories of the PGIC Figures  and 3. Wp < 0.001)  was needed for the completed group and a −2.16 (SD: 2.48) for the ongoing group. Thus, the ongoing treatment group reported to experience treatment success at a much lower average NRS change compared with those with completed treatment.In the cohort, the treatment duration resulted in considerably different NRS changes between baseline and follow‐up. The average raw NRS change, for the completed treatment group, was −2.13  and −0.79  for the ongoing treatment group  Figure . BesidesDifferences in pain severity at baseline were more prominent in the cohort data than in the RCT’s Figures  and 6. AThe main objective of this study was to assess whether an average decrease of two points on the NRS was found to be clinically important, in chronic pain patients who participated in a large observational cohort and in patients included in RCT’s of non‐pharmaceutical treatments. In this study, patients reported clinically important improvement at a larger pain relief than the average decrease of two points on the NRS. The amount of pain relief needed differed substantially between study designs. In both cohort and RCT’s, pain severity at baseline modified the amount of pain relief needed for a clinically important improvement. Furthermore within the cohort, considerable differences were found in treatment status.In the RCT’s, strict inclusion criteria were applied before administering a single intervention, while personalized care was provided to every patient in the cohort, as these patients received care of a multidisciplinary pain team. Therefore, cohort patients may have had more than one intervention or have been treated intermittently, leading to patients in treatment at 6‐month follow‐up. We believed that this had an influence on the NRS change and the value given to the clinical importance of the improvement. Stratification revealed that the change in pain relief was reduced significantly when observing clinically important improvement for those still being treated. Illustrating that patients in treatment at 6 months were satisfied with their treatment progress at a much lower rate in pain relief. Notwithstanding, the association between the NRS change and clinically important improvement decreased substantially in the AUC, specifying that for these patients other underlying factors may play an important role when answering the PGIC. Therefore, the need for further investigation on factors that contribute in answering the PGIC is warranted.The stratification on baseline NRS indicated that NRS change is non‐uniform across these groups.Stratification on sex revealed no differences at the two‐point raw change representing the two successful categories of the PGIC. Furthermore, a patient characteristic that may play a role as well is age. We observed on the cross‐sectional level in our tertiary pain population patients of older age have a lower average pain intensity at presentation.The results of this study show different outcomes when compared to the results of Farrar et al; this may be due to the type of study design or intervention under analysis. Expectations on the effect of treatment on pain decrease seems dependent on many characteristics of patients and the setting they were recruited. It seems that patients are not satisfied with just a two‐point difference. An option would be to adjust the definition of clinical important improvement. Nevertheless, in clinical practice, only a low rate of the pain population obtains a successful intervention. By increasing the clinical importance, to for example a three‐point raw change, this will have a negative impact on our view of their efficacy and it may have implications for future study design, such as necessary sample sizes. Another option could be to analyze the importance and sensitivity of composite scores or quality of life scores as pain outcome measures.In general, the Spearman correlation coefficient suggested that pain change is an important component measured by the PGIC, yet the lack of strong correlations shows that pain relief cannot explain treatment success in full. Moreover, relative changes were omitted in the results as they were interchangeable with the raw changes, making the interpretation easier when only the latter were included. This is due to the high baseline pain scores of the patients we have at the tertiary pain clinic, making the relationship between the raw change and PGIC as stable as the percent changes and PGIC. The questionnaires applied in both methods were validated for the chronic pain population and recommended by the IMMPACT guidelines, reducing the probability of errors in data collection. In both methods, application of stratification controlled for confounding.In conclusion, the change in NRS scores associated with clinically important improvement was larger than is stipulated in the literature and the amount of pain relief needed was substantially larger in RCT’s than in cohort data. Stratification on study design and sex showed the presence of heterogeneity in the pain relief and its significance in relation to treatment success, calling for caution in the interpretations as is it may be dependent on study design, NRS at baseline, or treatment status.The authors have no conflicts of interest to declare.All authors have contributed to the conception of the study design. Data collection and statistical analyses were carried out by the first author, with critical discussion and revision from all authors. All authors have read and approved the manuscript.


Less-invasive thoracotomies may reduce early postoperative pain. The aims of this study were to identify pain trajectories from postoperative days 0–5 after posterolateral and axillary thoracotomies and to identify potential factors related to the worst trajectory. Patients undergoing a posterolateral (92 patients) or axillary (89 patients) thoracotomy between July 2014 and November 2015 were analyzed in this prospective monocentric cohort study. The best-fitting model resulted in four pain trajectory groups: trajectory 1, the “worst”, with 29.8% of the patients with permanent significant pain; trajectory 2 with patients with low pain (32.6%); trajectory 3 with patients with a steep decrease in pain (22.7%); and trajectory 4 with patients with a steep increase (14.9%). According to a multinomial logistic model multivariable analysis, some predictive factors allow for differentiation between trajectory groups 1 and 2. Risk factors for permanent pain are the existence of preoperative pain ) and scar length (OR = 1.20 (1.05–1.38)). In contrast, ASA class III is a protective factor in group 1 (OR = 0.02 (0.001–0.52)). In conclusion, early postoperative pain can be characterized by four trajectories and preoperative pain is a major factor for the worst trajectory of early postoperative pain. Effective postoperative analgesia plays a major role in the prevention of major morbidity and mortality  and is pA better understanding of postoperative pain could make it possible to treat or even prevent it and, therefore, improve the postoperative experience . UsuallyThis method was used to identify patient subgroups based on pain in various surgeries and notably after breast cancer surgery . In a reHaving conducted a prospective study regarding the risk of developing chronic pain after the axillary approach, a standard mini-invasive procedure, and posterolateral thoracotomies in thoracic surgery, we used the early postoperative data to establish the trajectories in post-operative pain and to identify their pre- and intraoperative predictive factors.The present study reports the postoperative findings of a prospective, observational, single-center study performed in a tertiary care university hospital and was approved by the Ethical Committee Ile-de-France XI  on 16 January 2014. The study was designed in accordance with the STROBE Standard for Observational studies) and published on the Clinical.trials.gov (accessed on 12 September 2014) website (NCT02237963).Patients were approached for consent before surgery and gave their written informed consent to participate. To be eligible, patients had to be at least 18 years old; French−speaking; and scheduled for lung surgery with a muscle-sparing posterolateral (PL group) or axillary thoracotomy (AX group) for lobectomy, pneumonectomy, wedge resection, bulla resection, or pneumothorax surgery for cancer or a non-cancer condition. Patients were excluded (a) if the planned procedure was a video-assisted thoracoscopic procedure, a partial or total pulmonary decortication, or a procedure extending to the chest wall; (b) if they had limitations of self-expression or communication by phone, or a severe psychiatric illness; and (c) if they had chronic thoracic pain before surgery . Pregnant and lactating women, and other vulnerable persons as defined by French regulation were not eligible.For each patient, PL thoracotomy or AX thoracotomy was chosen by the participating surgeons according to their experience.For patients undergoing PL thoracotomy, the skin incision spanned the width of the latissimus dorsi. The latissimus muscle was completely divided, but the serratus anterior was spared if possible and reflected anteriorly. The chest was opened in the fifth intercostal space, and a rib retractor was systematically used.The incision for the AX approach extended approximately 7 cm caudal from just below the axillary hairline along the anterior border of the latissimus. The latissimus was completely spared and did not require mobilization. The insertions of the serratus anterior muscle on ribs 4 and 5 were dissected from these ribs, allowing the muscle to be lifted from the chest wall to allow the intercostal incision to be made in the fourth intercostal space. A rib retractor was only used if required by the surgeon.For both approaches, the intercostal incision was extended far anteriorly and posteriorly beyond the limits of the skin incision.A small portion of the posterior sixth rib was occasionally resected (shingled) during PL thoracotomy. Both types of incisions were closed with three or four interrupted pericostal or intracostal sutures. A running absorbable suture was used on the muscle, subcutaneous, and skin layers of the PL thoracic incision and on the subcutaneous and skin layers of the axillary thoracic incision.Postoperative chest tube management was at the discretion of the surgical team.Anesthesia and pain management were standardized for all patients.Anesthesia was total intravenous anesthesia by propofol and remifentanil, the doses of which were titrated according to hemodynamic stability and to maintain a Bispectral Index between 40 and 60, a range corresponding to the desired depth of anesthesia.The usual pain management was thoracic patient-controlled epidural analgesia associated with co-analgesics  given IV first and then orally as soon as possible. The epidural catheter was inserted before surgery at the T5–T6 or T6–T7 level; a first bolus of ropivacaine 0.375% mixed with 5 µg/mL (3 to 5 mL) of sufentanil was administered prior to anesthetic induction and was followed by a 5 mL/h infusion of 0.2% ropivacaine and 0.5 µg/mL of sufentanil. As soon as the patient was able to use the patient-controlled function, 3 mL boluses with a refractory period of 20 min were provided. In the case of contraindication to epidural analgesia , a paravertebral catheter was placed during surgery and allowed for 0.375% (3 to 5 mL/h) ropivacaine infusion. In the case of failure of epidural analgesia despite routine procedures, intravenous morphine patient-controlled analgesia or oral morphine was started. As specified in our institutional protocol, the epidural catheter was removed after the last chest tube was removed, typically on postoperative days 3 to 5, and oral analgesics (opioids and acetaminophen) were used alone.Post-operative analgesia was given by nurses who specialize in pain management. This allowed for therapeutic adaptation.Data were collected at inclusion, during surgery, and during the postoperative period. A complete assessment was performed on the 6th ± 1 postoperative day.Demographic variables, history of cancer and tobacco use, pain, and anxiety were collected at inclusion. Regarding pain, patients were asked to respond to the question “Do you regularly suffer from pain?”. In the case of a positive response, they provided a self-assessment of pain at rest during the visit and the mean value of pain score during the prior week using an 11-point numerical rating scale (NRS) from 0 = no pain to 10 = maximum imaginable pain. They were also asked to locate the pain and to report their painkiller use using the World Health Organization analgesic classification. A neuropathic pain was defined by a DN4 score ≥ 4 [The duration of anesthesia and surgery as well as the particularities of the surgical techniques were noted.Postoperative pain was assessed each day from day 0 (day of surgery) to day 6 ± 1 at rest, when coughing and during ipsilateral shoulder mobilization using NRS . The latIn addition, at day 6 ± 1, the postoperative analgesia technique; the DN4 score; the skin anesthesia or hypoesthesia around the scars using a 10 g Von Frey filament on three vertical measures at the midclavicular, midaxillary, and scapular lines; the total length of the scar; and patient satisfaction with pain management using a NRS from 0 = totally disappointed to 10 = totally satisfied were recorded.Finally, the duration of postoperative stay and postoperative complications were collected using the Clavien classification .The number of patients to be included was calculated using the occurrence of chronic pain after PL and AX thoracotomies as the main outcome. When planning the study as a randomized controlled trial, the sample size was calculated based on a preliminary report from our group showing a 48% prevalence of chronic pain one year after a posterolateral thoracotomy . It was All statistical analyses were conducted on an intention-to-treat basis.Categorical variables are presented as number (proportion); continuous variables are presented as median (25th percentile–75th percentile).The statistical analysis was carried out in three steps: comparison of patients according to their surgical incision, identification of postoperative pain trajectories, and comparison of patients according to their pain trajectories.Comparisons of variables between patients who had a PL or an AX thoracotomy used a Chi2 or a Fisher test for categorical variables and a Mann–Whitney test for continuous variables. Mixed model repeated measures were used to compare pain scores at mobilization during the early (day 0 to day 5) postoperative days. The surgery group and the days were used as fixed factors.p-values < 0.20 were included in the multivariable model.In the primary analysis, to identify clusters or subgroups of patients with similar progressions, defining trajectories of pain after surgery (measured from day 1 to day 5), a mixed ascending hierarchical classification was implemented with PROC CLUSTER in SAS software (SAS Institute). Each patient was clustered into the trajectory group to which they had the highest posterior probability of membership. First, a principal component analysis (PCA) was applied on postoperative pain variables. Then, factor axes were used to determine a dendrogram using a mixed ascending hierarchical classification. The dendrogram was cut using the Euclidean distance between each point with the Ward method to identify the best number of subgroups . Comparisons of variables between all trajectories used a Chi2 or a Fisher test for categorical variables and a Kruskal–Wallis test followed by a Dunn’s multiple comparisons test. Finally, a multivariable multinomial logistic model was performed to identify risk factors for trajectories. All factors associated with clusters in the univariate analysis with p-values < 0.05.All statistics tests were two tailed, and P was considered significant when the Analyses were performed using SAS 9.4  and R software  using the application GMRC Shiny Stat .Two hundred and fifteen patients were approached from July 2014 to November 2015, with one hundred and ninety-six finally included. Ninety-six patients underwent surgery through an AX incision, and one hundred underwent surgery through a PL incision. Initially, 25 patients (13 in the AX group and 12 in the PL group) were excluded from analysis due to missing pain scores. However, after imputation of the missing data, ten patients (six in the AX group and four in the PL group) were retrieved for data analysis. The analysis concerned 89 patients in the AX group and 92 patients in the PL group .p = 0.041)  .p < 0.001 and p = 0.004, respectively), and latissimus dorsi preservation and transcostal suture more frequent in the AX group (p < 0.001)) ) .p = 0.83, Pain scores for mobilization of the ipsilateral shoulder from the day of surgery to postoperative day 5 were similar in both groups . Height of the hypoesthesia area around the scar was lower in the AX group (p = 0.016). Finally, the scar length was significantly greater in the PL group: median size 17 cm vs. 8 cm in the AX group (p < 0.001)  .The best-fitting model included four pain trajectory groups, with a combination of linear and quadratic trajectory groups. Those who partly or fully resolved their pain over five days had negative slopes, and those who demonstrated a pattern of increasing pain over days had positive slopes. Pain trajectory group 1 corresponds to patients with permanent significant pain from day 0 to day 5 (29.8% of the patients), pain trajectory group 2 corresponds to patients with moderate pain from day 0 to day 5 (32.6%), pain trajectory group 3 corresponds to patients with steep decreases in pain across the five days after surgery (22.7%), and pain trajectory group 4 corresponding to patients with steep increases in pain across the 5 days after surgery (14.9%) .p = 0.031), more patients with neuropathic pain (p = 0.013), and more patients having taken at least one analgesic medication before surgery (p = 0.022) in group 1. The percentage of preoperative painful patients was greater in group 1 than in the other groups . The preoperative neuropathic component of pain was not included in the analysis because of the large number of missing values. The permanent non-significant pain trajectory group (group 2) is the reference group for multinomial logistic regression.Variables in the multinomial logistic regression were age, preoperative state of health qualified by the ASA score, presence of preoperative pain, use of at least one pain medication, and preoperative anxiety. Three entities relevant to thoracic surgery were also analyzed: rib fractures, transcostal suture, and scar length. This corresponds to the variables reaching the defined threshold for inclusion ) and scar length (OR = 1.20 (95% CI (1.05–1.38))). In contrast, ASA class III is a protective factor in group 1 ) .No predictive factor could allow for differentiation between trajectory group 2 and groups 3 or 4.To our knowledge, this is the first description of pain trajectories during the early postoperative period after lung surgery. For patients operated by PL or AX approaches using a mini-invasive technique like video-assisted thoracoscopic surgery, in terms of early complications, pain, performance status, and quality of life , four paDefining acute postoperative pain as a trajectory rather than as one or more simple point estimates of intensity increases the information yield of pain assessment and improves measurement precision ,16. ThusThere are numerous studies of the risk factors of postoperative pain using pain as the main outcome. Ip et al., studying 48 eligible studies with 23,037 patients, identified preoperative pain, anxiety, age, and type of surgery, but not gender, as significant predictors for postoperative pain . A similRegarding the specific question of postoperative pain after lung surgery, the work carried out by Kwon et al. must be underlined since it compared pain after robotic, video-assisted thoracoscopic surgery and open anatomic pulmonary resection and reported that female gender, younger age, and baseline narcotic use were associated with acute postoperative pain .Replacing the measurement of postoperative pain with the determination of pain trajectories has little effect on the determination of risk factors. Thus, Vasilopoulos et al. also reported that risk factors for the stable moderate-to-high and high pain groups are female gender and young age while preoperative high anxiety and depression and greater pain behaviors and pain catastrophizing were linked to the stable high group . After lAmong behavioral factors that have been reported as strongly associated with acute postoperative pain intensity, preoperative anxiety is highlighted ,19,21. TThe strength of our study is that it was conducted under real-life conditions, with the data collected reflecting the vagaries of management, including the successes and failures of surgical procedures and analgesia techniques.On the other hand, our study suffers from several important limitations.As specified before, this study is an ancillary study from another that studied the development of chronic pain after PL and AX approaches for thoracic surgery.This study established four clusters describing postoperative pain by mixing patients operated on by PL thoracotomy or by AX thoracotomy. Posterolateral thoracotomy is increasingly being replaced by video-assisted thoracoscopic surgery and robot-assisted thoracic surgery, which result in less acute pain . On the Our study did not include randomization for the choice of approach because the surgeons considered it unethical to use approaches they were unfamiliar with. It was decided that participating surgeons would use the approach they routinely used and were familiar with. Such conduct is usual since most studies comparing PL thoracotomy and VATS do not include randomization.Our preoperative screening of potential factors linked to postoperative pain was obviously incomplete. The evaluation of anxiety was rather short, and we did not evaluate psychological factors such as depression, pain coping and catastrophism, and sleep disorders. A genetic study is also missing.Our study combined patients having had a large surgical approach and a mini-invasive one. These two approaches are being progressively discarded and replaced by video-assisted thoracoscopic surgery and robot-assisted thoracic surgery; our results cannot be generalized to the whole lung surgical population.Moreover, most of our patients benefited from a thoracic epidural postoperative analgesia. This was the choice of our team at the time of this study, but this strategy has evolved towards less-invasive techniques ,6.In conclusion, we identified four trajectories for early postoperative pain after lung surgery performed by posterolateral and axillary approaches. The major risk factor for permanent pain trajectory is preoperative pain, which should lead to a more aggressive pre-operative management unless it represents a constitutive factor, perhaps genetic. We confirmed the benefit of mini-invasive surgery since scar length is also reported as a risk factor for postoperative pain. On the other hand, it is difficult to explain why ASA class III is a strong protective factor unless it is related to more careful management.


Kinesiophobia was found to be related to the dominant lateral epicondyle , the non-dominant knee  and the dominant forearm . Self-Efficacy showed a low level of association with the non-dominant supraspinatus  and the non-dominant medial epicondyle . Psychological factors and the elastic properties of tissue seem to be associated in patients suffering from FM. The most profound association between psychological factors and non-dominant parts of the body could be related to neglect and non-use of those parts of the body.Nowadays, there is evidence related to the impact that psychological factors have on symptoms, specifically vegetative ones, and on the autonomic nervous system in patients with fibromyalgia (FM). However, there are no studies to correlate the level of association between psychological factors and the elastic properties of tissue in the FM population. Elastic properties of soft tissue reflect age- and disease-related changes in the mechanical functions of soft tissue, and mechanical failure has a profound impact on morbidity and mortality. The study has a cross-sectional observational design with 42 participants recruited from a private clinic and rehabilitation service. The Pain Catastrophizing Scale, Tampa Kinesiophobia Scale and Self-Efficacy Scale were used to assess psychological factors. The elastic properties of the tissue in the characteristic painful points, which patients suffering from FM described, were assessed by strain elastography. A low and significant level of association was found between pain catastrophising scale (PCS) and the non-dominant lateral epicondyle (r = −0.318;  Fibromyalgia (FM) can be defined as a multi-symptom disorder of uncertain origin that manifests with widespread pain, fatigue and sleep problems, anxiety, cognitive disturbances and degenerative or inflammatory behavioural disturbances ,2,3,4,5.The prevalence of FM in the general population varies from 0.5% to 5%, and can be up to 15.7% in a clinical setting, with the prevalence in Spain being 4.2% in women and 0.2% in men ,8. AlthoEven though the origin of FM remains unknown, current evidence defines it as a central sensitisation syndrome which involves an alteration in the hypothalamic–pituitary axis (HPA). Hence, ascending and descending pain pathways, as well as neurotransmitters, can be altered, which could be the cause of increased pain responses and the altered circadian variations in blood pressure in patients suffering from FM ,11.Furthermore, chronic pain is a condition that includes multiple factors such as central sensitisation, the presence of a low-grade inflammatory state, and alterations in regions of the brain responsible for pain processing and behaviour . The relThe elastic properties of soft tissue can be measured by ultrasound elastography and loss of elasticity indicates disease progression and/or the effects of non-successful aging . There aWhilst several studies on chronic pain and elastic properties have been published , there aThe present study was a cross-sectional observational design. A sample, comprising 42 participants, was recruited from a private healthcare centre in Málaga, Spain. Participants were informed through trial information sheets and formal meetings.Ethics permission was obtained from the Ethics Committee of Human Research at the University of Granada, Spain, (1044/CEIH/2020) and conducted in accordance with the Declaration of Helsinki. This study is reported in line with the Statement of Recommendations for Intervention Trials (STROBE).A sample comprising 42 women with FM participated in the study. All participants were recruited from a private physiotherapy centre in Málaga, Spain, by a physiotherapist. The physiotherapist was in charge of providing information about the study to the participants and examining which volunteers met the inclusion and exclusion criteria. Two participants were excluded from the study due to some exclusion criteria not being met.Aged between 18 and 65.Diagnosed with FM by a rheumatologist following the ACR classification .Suffering from any inflammatory, neurological or orthopaedic disease that may impaired balance, hearing, or vision or cognitive impairment that may affect the ability to answer questions.Psychological factorsPsychological factors were measured using the Pain Catastrophizing Scale, the Tampa Kinesiophobia Scale (TSK-11) and the Self-Efficacy Scale. Pain Catastrophizing ScaleThis validated questionnaire consists of 13 items divided into 3 subsections and aims to measure how catastrophism affects the experience of pain. The first subsection, which includes questions 1 to 5, is called “helplessness” and assesses how the person believes he or she was able to influence their pain . QuestioTampa Kinesiophobia Scale (TSK-11)This questionnaire, adapted and validated to the Spanish language, was used to measure fear of movement in the participants in this study since it was proved to be a suitable, reliable and consistent tool to use in people with FM . A totalSelf-Efficacy ScaleThe Self-Efficacy Scale was used in this study to measure the perception participants have about their competence to handle a stressful situation efficiently . There iElastic properties of soft tissueThe elasticity of tissue was assessed by ultrasound elastography (SEL). All measurements were taken by a physiotherapist with 11 years’ experience in ultrasound imaging, using the Logiq S7 with a 15 MHz linear probe . The measurements were obtained by taking images with the transducer placed longitudinally on the muscle fibres, with the centre of the probe positioned on the Myofascial Trigger Points (MTrPs) according to the control point locations , and witIn line with the manufacturer’s instructions, and in accordance with previous studies, a 5 mm circular region of the area was selected to measure the exact value of tissue deformation. The resulting values refer to the deformity of the tissue and range from 0 to 6, with 0 being the softest and 6 being the hardest. The value obtained at each point is the average of 3 measurements which results in a more reliable value. Furthermore, only high-quality images were used.p-value was <0.05 [p-value <0.05 was considered statistically significant [The statistical analysis was performed using the SPSS program, version 23.0  for Windows. The W of the Shapiro–Wilk test was used to evaluate the normality of the sample. The level of association between the variables  was calculated using the Pearson correlation coefficient for those that followed a normal distribution; for those that did not follow a normal distribution, the Spearman correlation coefficient was used. The results were considered statistically significant when the as <0.05 . A correnificant .The sociodemographic characteristics of the sample are shown in The associations between the Pain Catastrophizing Scale, Tampa Kinesiophobia Scale (TSK-11), Self-Efficacy Scale and strain elastography in the different painful points are presented in p = 0.045). Kinesiophobia was found to be related to the dominant lateral epicondyle , the non-dominant knee  and the dominant forearm . Self-Efficacy showed a low level of association with the non-dominant supraspinatus  and the non-dominant medial epicondyle .A low and significant level of association was found between pain catastrophising (PCS) and the non-dominant lateral epicondyle  and the elastic properties of soft tissue in the characteristic painful points that people with FM present.p = 0.045). Kinesiophobia was found to be related to the dominant lateral epicondyle , the non-dominant knee  and the dominant forearm . Self-Efficacy showed a low level of association with the non-dominant supraspinatus  and the non-dominant medial epicondyle . The repetitive association between psychological factors and the pain points of non-dominant extremities in patients with fibromyalgia can be explained by different mechanisms. Chronic pain can be caused by movement neglect [Our findings show that there is a relationship between psychological factors and the elastic properties of soft tissue, measured by SEL, in patients with FM. We found a low and significant level of association between pain catastrophising (PCS) and the non-dominant lateral epicondyle (r = −0.318;  neglect . The assThe elasticity and stiffness of soft tissue in fibromyalgia patients have been studied before; however, there is no research studying the relationship between elastic properties of tissue and psychological factors. For this reason, a comparison of our results with other studies is difficult. It is well known that as a consequence of an altered central nervous system, patients with FM exhibit neurovegetative symptoms and both central and peripheral sensitisation, as well as irritable bowel syndrome and the affected gynaecological area, chronic fatigue syndrome, postural orthostatic tachycardia, variations in circadian blood pressure or an excessive response to stimuli such as auditory, cold or mental stress ,11,20,36Although not investigated in relation to the elastic properties of soft tissue, other studies already showed a correlation between factors such as pain, vegetative symptoms, disability, kinesiophobia, catastrophism and stress in patients with fibromyalgia. Significantly, Bruna et al. found a correlation between disability, kinesiophobia and psychological factors such as stress in people with FM .To the best of our knowledge, there are no studies analysing the correlation or presence of specific symptoms based on specific psychological factors of interest. In this vein, a unique temporal brain activation of the frontal cortex, and areas of the motor and cingulate cortices during pain anticipation and the subsequent increase in the pain experience, has been seen in patients with FM . FurtherCurrent studies have measured elasticity and stiffness, in relation to changes in soft tissue properties, using different ultrasound techniques, without finding any significant differences between healthy people and patients with FM ,42. HoweIt is important to highlight that this is the first study analysing the relationship between psychological factors and the elastic properties of the characteristic painful points in patients with FM. Furthermore, all the ultrasound measurements were carried out by an expert with 11 years of experience in this field. On the other hand, some weaknesses must be acknowledged. The study sample is small, only includes women with fibromyalgia and is of a cross-sectional design. In addition, the significance levels of most of the variables were only slightly lower than 0.05; thus, the sample size determination and effect size should become more important in future research. Therefore, the results shown must be interpreted with caution. Additionally, a correlation was only found between psychological factors and the elastic properties; thus, there is no evidence if a causal relationship exists between these three parameters in people suffering from FM.Future research with a higher number of participants is needed to shed light on these first results which show a relationship between psychological factors and the elasticity of painful points in subjects with FM. These studies should also include follow-up results after successful psychological interventions in patients with FM and the impact of the psychological improvement on elastic properties of soft tissue and pain. Furthermore, it would be of great interest to current research to explore whether specific symptoms and brain areas, including psychological factors, are related. Potential causal relationships between elastic properties and psychological factors could be found through successful intervention studies of both the psychological and tissue factors. These studies would shed light on the impact of the skin–brain axis and its possible bidirectional influence.A relationship between pain catastrophising, kinesiophobia, self-efficacy and tissue properties has been found in patients with fibromyalgia. Although only correlated, these results could be used to study the impact of successful psychological interventions on pain and elastic properties of soft tissue in FM patients. The results would clarify a possible causal relationship between psychological factors such as kinesiophobia and elastic properties of soft tissue. More studies are needed to corroborate our findings and shed light on the proposed and as yet unknown underlying mechanisms.


Fibromyalgic Syndrome is an important public health burden and affects up to 5% of the world population. It requires a complex treatment plan, possibly including antidepressants, anticonvulsants and benzodiazepines, which may in turn affect the patients’ quality of life: hence the need to find additional therapies. The current pilot randomized-controlled study analyzes the effect of electromagnetic field locally administered as add-on therapy in the treatment of cervico-facial pain in patients with fibromyalgic syndrome. 17 patients were selected and low-frequency electromagnetic field was applied via small patches worn in the neck area, between vertebrae C3–C4. Patients were divided into 2 groups, Treated, receiving the therapy, and Placebo, receiving an identical device which was not working,, with respectively 8 and 9 patients. The whole follow up period was 12 months and facial/cervical pain levels were rated using VAS scale. Significant differences were found between patients who received placebo and those treated. Treated patients showed statistically significant improvements in facial/cervical pain at each time-point, both with respect to the previous one and if compared to placebo. In conclusion, low frequency electromagnetic field emerged as beneficial in treating cervico-facial pain in patients with Fibromyalgic syndrome, with no side effects. Fibromyalgic Syndrome (FS) is a disease that commonly affects the general population. It represents a complex painful syndrome. Long-lasting, widespread and symmetric non-articular musculoskeletal pain are the major features. Furthermore, for diagnosis, generalized tender points at specific anatomical sites are required ,2. FS afOn the other hand, non-invasive brain stimulation techniques have already been shown to be useful in treating chronic pain ,15. The In a previous pilot study, we proved the potential effectiveness of low and very low EMF as adjunct treatment in the therapy of chronic orofacial pain in patients with FS and orofacial neuropathic pain . With thThe purpose of our trial was to analyze the usefulness over time of HO-ONP in facial and cervical pain treatment in individuals with FS as additional therapy to first line medications.The current study is a pilot randomized and controlled trial. The good clinical practice guidelines for Randomized-controlled trials were followed . Search Inclusion and exclusion criteria are reported in Individuals of both genders were recruited to participate. The initial sample numbered 32 individuals, of whom 29 were women and three men. All the patients were recruited at the Pain Center of the University of Cagliari. All the patients were sent to us with the diagnosis of FS and with complaints of cervical and facial pain. 15 individuals were then excluded because of incompatibility with the inclusion and exclusion criteria, 12 because of concomitant TMDs or neuropathic pain and 3 because of low compliance. Finally, a total of 17 individuals were selected, all females, between 30 and 78 years old .Patients were randomized by the independent coordinator (ES) who was not involved in the selection, treatment or follow-up of patients. A list of patients was created and a computer-generated sequence randomized them in a 1:1 ratio to either medical therapy or placebo. Randomization codes were obtained after patients were recruited to the trial. The randomization sequence was held by the independent coordinator (ES). Both participants and researchers (MS and BS) were unable to foresee the assignment. All participants’ data was pseudoanonymised with personal information removed and replaced by a coded identifier. Because of the nature of the study, both investigators (MS and BS) and patients were blinded regarding their allocation. Individuals were firstly grouped in subcategories according to age, such as 18–40; 41–60; +61, in order to have in both groups at least 1 patient from each of these subcategories, in equal number as far as possible.(a) Treated Group: 8 patients received EMF-delivering patches; one patch for each patient was delivered; (b) Control Group: 9 patients received placebo patches, absolutely indistinguishable from functioning ones without being informed.In order to avoid a statistically significant difference between the 2 groups at the beginning of the trial, pain levels were evaluated by the program Ranksum, described below, and drug intakes were listed, in order to have similar drugs and dosages in both groups.The current trial was developed according to the good clinical practice guidelines of the Declaration of Helsinki . The stuTwo researchers (MS and BS) followed the patients during the trial, that is for a year, at the Orofacial pain center of the University of Cagliari. The whole trial was developed under the supervision of an independent coordinator (ES). To define agreement rates between the researchers, the kappa test was applied and it emerged as moderate (0.55). Any disagreements were discussed by all the authors.The low and very low frequency EMF, kept at very low intensity to maintain the localized effect, was delivered through a system of nanocrystals interacting with semiconductors targeted with appropriate signals. The signal traced the calcium ion’s own signal to create a locally selected and controlled incoherence with the endogenous calcium itself. The objective was to reduce the calcium flow by intervening indirectly on the pro-nociceptive modifications induced in both voltage-gated and ligand-gated calcium channels. As we exploit wavelengths built to mirror calcium’s, a very important ion for several functions, we use very low-intensity EMF so as not to disturb other calcium-related activities. This technique involves only the selected ionic activities that express pain signals downstream of the nerve branch on which the EMF was induced.The trial was structured through six consecutive steps. (1) Medical examination: patients’ signs and symptoms were investigated. Pain characteristics were detected and the average pain level was rated on the VAS scale . The VASDefinitely the 17 patients were deemed satisfactory to allow for an adequate value of the non-parametric statistical analysis selected for the study as the aforementioned was a pilot study.p < 0.05 and the software Stata  was used to analyze all data.Data were organized into a spreadsheet (MS Excel Office 365 MSO). The significance of changes in VAS score were evaluated using the Ranksum Statistical Method in particular, for independent samples, the test of the sum of the ranks of Wilcoxon or Mann-Whitney, while, for dependent samples, the Wilcoxon test by signs ,32. StatThe present trial evaluated the responsiveness rate of a total of 17 individuals with FS to a new nanotechnological device based on Low-Frequency Electromagnetic Waves, called “HO-ONP”.Patients belonging to the Treated Group mostly reported improvements in pain intensity immediately after the application and confirmed the same at all the subsequent checks, appreciable by observing signed VAS scales. However, symptoms in the other parts of the body did not improve. By contrast, the Control Group patients did not report significant improvements. In any case, all individuals, regardless of the group they belonged to, reported any complaints concerning the ergonomics of the patch. No side effects were reported by any patients.p value 0.6644). Following the administration the data show that there was a statistically significant difference  between the two groups already in the first month of treatment (T1). The difference remained significant  even after six months (T2), and still persisted at a distance of one year (T3) .Non-parametric tests were carried out in order to verify whether the investigated treatment was effective. This test was chosen due to the small sample size. Indeed this particular type of test, based on ranks, does not need to make assumptions about the distribution of the population. To understand whether there are differences between the control group (Placebo) and the one that received the treatment (Treated), the test we carried out, for independent samples, was the sum of the ranks of Wilcoxon or Mann-Whitney. It was thus possible to verify whether there were statistically significant differences between the two groups before and during the different stages of administration of the treatment. The results summarized in p value 0374, 0.5529, 0.9528, respectively at T1, T2 and T3). By contrast, among patients who received the treatment, statistically significant differences emerged from the first month of administration and persisted over the follow up period .Following this first verification, which informed us that after treatment the treated and control groups differed, we proceeded with further analyses based always on non- parametric tests, but in this case for dependent samples. We investigated whether the perception of pain in the different stages of treatment had changed within the groups, using the Wilcoxon test by signs . In the A simpler analysis can be seen in The authors’ purpose was to establish the validity of the HO-ONP as adjuvant therapy in the treatment of pain in the orofacial district in patients affected by FS.EMF has proved to be a valid, noninvasive and accessible method used for the treatment of pain, and its effectiveness in the management of various painful and inflammatory disorders has been well assessed ,35,36,37Interestingly, but as might have been expected, these effects were felt only in treated parts, that is above the shoulders, while the overall symptomatology remained unchanged in other body regions.Despite these important, but localized, improvements, patients who received the functioning device needed to continue their current drug-based therapy to reduce complaints related to the rest of the body. This aspect however requires additional analysis because patients belonging to the Treated Group decreased the physical therapy exercises usually done to reduce cervical pain and improve neck and shoulder movements. It may be reasonable to assume that applying the same patches to multiple body parts could bring benefits in symptoms while reducing drug dosages. No individual who took part in the study complained about the ergonomics of the device. The patch appeared practical, it did not [seem to] inflict any discomfort and it does not require any sort of power supply, unlike other medical equipment delivering electromagnetic waves. Last, but not least, no side effects were reported by patients in either group.An important feature of our study concerns the population studied. Indeed, only female individuals met the inclusion criteria and were recruited into the analysis. This feature is justified by the higher attested prevalence of FS in women than in men. In a recent update of the literature review on the prevalence of FS, it was found that this pathology has a frequency between 2.4% and 6.8% in women, especially after menopause, compared with a prevalence between 0, 2% and 4.7% of the general population . SimilarFurthermore, despite the small number of the sample due to the application of selective inclusion and exclusion criteria in the face of an uncommon pathology, we consider the results achieved to be significant. Statistical analysis has in fact highlighted that adjuvant therapy with EMF can be inserted as a valid therapeutic option additional to the more traditional pharmacological therapy in cranio-cervical-facial pain in patients with FS.In conclusion we can support the benefits given by the Holographic Information Transfer Analgesic Patch in alleviating head and neck pain in patients affected by FS. Additionally the localized effect requires further research to investigate possible systemic coverage in order to improve the overall lifestyle of such patients.


The median MED (mg/kg) in the gabapentin (0.12) and placebo arms (0.13) was similar (p = 0.9). However, in the subset of patients with the HbSS genotype (n = 45), the mean (SD) absolute pain score decrease by the time of discharge was significantly greater in the gabapentin arm (5.9 [3.5]) than in the placebo arm (3.6 [3.3]) (p = 0.032). Pain scores in the overall study population were not significantly reduced when gabapentin was added to standard treatment; however, gabapentin benefited individuals with the more severe genotype, HbSS, during acute VOC. Larger, prospective studies are needed to confirm these findings.Pain in sickle cell disease (SCD) can have a neuropathic component. This randomized phase II double‐blinded placebo‐controlled study evaluated the efficacy of gabapentin in reducing pain and opioid consumption  during acute vaso‐occlusive crisis (VOC). Of 90 patients aged 1–18 years with VOC pain, 45 were randomized to a single gabapentin dose (15 mg/kg) and 45 to placebo, in addition to standard treatment; 42 and 44 patients were evaluable in the gabapentin and placebo arms, respectively. A decrease in pain of ≥33% was reported in 68% of patients in the gabapentin arm and 60% of those in the placebo arm (one‐sided  These pThe backbone of treatment of acute pain crisis has been intravenous opioids. Patients with SCD often require large opioid doses because of increased opioid metabolism and clearance , as wellGabapentin has been used successfully to treat neuropathic pain in various clinical settings, including complex regional pain syndromes, diabetic neuropathy, and postherpetic neuralgia , 18, 19.Gabapentinoids bind to presynaptic neurons at the alpha2‐delta subunit of voltage‐gated calcium channels and reduce calcium influx into presynaptic terminals and therefore reduce excessive release of excitatory neurotransmitters ; their effects on central sensitization and hyperalgesia are indirect rather than direct , 24. GabThis randomized phase II double‐blinded placebo‐controlled study tested the hypothesis that gabapentin (in comparison to placebo) used in addition to standard treatment during an acute VOC in children with SCD would (1) reduce pain scores and (2) reduce opioid consumption.22.12), a history of seizures, current pregnancy or breastfeeding, or treatment with gabapentinoid or other anti‐epileptic drugs.This randomized phase II double‐blinded placebo‐controlled trial was conducted at St. Jude Children's Research Hospital after approval by the Institutional Review Board (IRB). An Investigational New Drug approval (IND119125) was issued by the Food and Drug Administration. The study was registered at clinicaltrials.gov (NCT01954927). All authors had access to primary clinical trial data. The data analysis was performed by Jeffrey M Gossett and Guolian Kang. A full description of the study's methodology has been published . ChildrePatients were enrolled and randomized to receive either a single oral dose of gabapentin (15 mg/kg) or a similarly formulated dose of placebo in addition to standard treatment for VOC as per our institutional St. Jude Sickle Cell Disease Pain Management Guidelines. Standard treatment for acute VOC in patients at our institution includes intravenous hydration and analgesic management with nonsteroidal anti‐inflammatory drugs (ketorolac) and opioids (morphine or hydromorphone). In the acute care outpatient clinic, opioids are usually administered in a structured fashion . For analysis, all opioid doses were converted to intravenous morphine equivalent doses (mg/kg) by opioid equianalgesic potency. The following ratios were used: fentanyl:morphine, 100:1; hydromorphone: morphine, 5:1 .2.2Deidentified participant data and study protocol will be available beginning 9 months and ending 36 months following article publication. These data will be available to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose. Requests should be directed to the corresponding author; to gain access, data requestors will need to sign a data access agreement.2.3a ≥ 33% decline in pain score between baseline and assessment at 3 h poststudy drug administration. Pain scores were collected at four time points: T0, baseline ; T1, at the time of study drug administration; T2, 3 h poststudy drug administration; and T3, at the time of decision for disposition from the acute care setting either to discharge home or to admission to the hospital  and that at each of the other time points . Pain score outcomes were examined for the overall study group.The primary endpoint was defined as 2.4T0) to 3 h post‐study drug administration (T2) in the gabapentin group was compared with that in the placebo group.The opioid consumption in morphine‐equivalent dose (MED) during the duration of VOC from presentation  of falsely concluding that adding gabapentin to standard treatment increases the proportion of patients with a decrease in pain score when there is no difference between gabapentin and placebo groups and to have at least an 80% ( = 1 − β) power to correctly conclude that gabapentin increases the proportion of patients with a decrease in pain score from 45% to 65%. Block randomization with block sizes of four and six was used to randomize participants stratified by age and baseline pain score ) of 8 (7–10) in the gabapentin arm and 8 (6.5–10) in the placebo arm. The primary outcome  was achieved in 67.5% (27/40) of patients in the gabapentin arm and 59.5% (25/42) of patients in the placebo arm  to discharge from the acute care setting (T3) was noted in 75% (30 of 40) of patients in gabapentin arm and 61.4% (27 of 44) in the placebo arm (p= 0.18) (Table T0) to 3 h post‐treatment (T2) was not significantly different in the two arms (p = 0.25), and the median (IQR) decrease was 4.0 (1.5–7.0) in the gabapentin arm and 3.0 (1.0–6.0) in the placebo arm.Pain scores at presentation were similar for each group (p = 0.31) (Table T0) to 3 h poststudy drug administration (T2) was not significantly different between treatment arms but may suggest a trend, with mean (SD) pain score decrease of 5.5 (3.4) and 3.6 (3.1) in gabapentin and placebo arms, respectively (p = 0.061). Importantly, the mean (SD) absolute decrease in pain score from presentation (T0) to discharge from the acute care setting (T3) was significantly higher in the gabapentin group (5.9 [3.5]) than in the placebo group (3.6 [3.3]) (p = 0.032).We performed a sub‐analysis of participants with the most severe sickle genotype, HbSS. Although the proportion of patients with HbSS in whom the primary endpoint was achieved was higher in the gabapentin arm than in the placebo arm (76.5% 13 of 17] in HbSS and 61.5% [16 of 26] in the placebo arm), the difference was not statistically significant ( of 17 in3.3T0) to 3 h poststudy drug administration (T2) was similar between the two treatment groups (p = 0.90). The median (IQR) MED was 0.12 mg/kg (0.09–0.22 mg/kg) in the gabapentin arm and 0.13 mg/kg (0.09–0.22 mg/kg) in the placebo arm. Likewise, MED for the HbSS subgroup did not differ significantly between treatment arms, with a median (IQR) MED of 0.11 mg/kg (0.09–0.23 mg/kg) in the gabapentin arm and 0.12 mg/kg (0.08–0.23 mg/kg) in the placebo arm (p = 0.93).Opioid consumption, as measured by MED (mg/kg), from presentation (3.4p = 0.71). In the HbSS genotype subgroup, 34.6% of patients (9 of 26) in the placebo arm and 11.1% of patients (2 of 18) in the gabapentin arm were admitted (p = 0.16)  in the gabapentin arm and 27.3% (12 of 44) in the placebo arm (6) Table .0 thalassemia did not yield any significant differences in the primary or secondary outcomes between the gabapentin and placebo groups.A combined analysis of participants with HbSS and HbS/β3.5n = 2), fatigue (n = 1), pneumonitis (n = 1), itching (n = 1), dizziness (n = 1), and headache (n = 1). Adverse effect in the placebo arm included vomiting (n = 1) and pneumonitis (n = 1). All were grade 1 and no serious adverse effects were noted.Adverse effects noted in the gabapentin arm included vomiting , so access to opioids was standardized for all patients and did not allow the flexibility of self‐administration offered by a patient‐controlled analgesia design.Gabapentin use did not influence the rate of hospitalization for the overall study group, as admission rates were similar for both study arms. Nevertheless, among those with the HbSS genotype, the admission rate was higher in the placebo arm than in the gabapentin arm, without reaching statistical significance.Based on the interim analysis results, and in accordance with the study design, the study team decided to stop enrollment due to clinical futility . While the study closed early for futility and had only modest efficacy, it is an important study advancing the use of alternative analgesics for acute SCD‐related pain.Some limitations of our study warrant discussion. The study population was small, and our target enrollment was not met due to several challenges common to research in an acute pain setting in patients with SCD. Study enrollment was limited to regular clinic hours and research personnel generally were not available after hours. Participants were allowed enrollment in the study only once. Thus, the overall eligible study population was limited and exhausted after a few years of ongoing study because, in general, the same subgroup of SCD patients tend to have repeated VOC‐related visits. Furthermore, only a short time window was allotted for the administration of study drug , which was logistically challenging. Another challenge was obtaining consent from children and young adults who presented in distress, which made eliciting assent from children and consent among those at the age of majority problematic. Occasionally, patients had received opioids and were sleepy before being approached for enrollment. To overcome this, we worked closely with the IRB to include provisions protecting patients under these circumstances. Approval was obtained to allow candidates 18 years or older to consent via surrogate decision‐makers whenever they believed their pain experience or the effects of the pain medications were hindering their ability to give consent independently. An additional challenge was posed by enrollment limited to a single institution, which reduced the patient pool from which the subjects were recruited. Children with SCD have elevated GFR . Thus, tOur study design was based on the assumption that patients studied had a neuropathic pain component. A better study design may be focused on studying the efficacy of gabapentin in patients with and without neuropathic pain, as determined by clinical neuropathic pain assessment tools such as PainDetect .Overall, our study was a rigorously conducted randomized double‐blinded placebo‐controlled trial with an objective pain reduction end point. All VOC episodes were treated in a standardized fashion followed with high fidelity.Gabapentin could be a useful adjunct to standard management for patients with the HbSS genotype, but future studies in a larger cohort of patients with the HbSS genotype and known neuropathic pain might better evaluate gabapentin's utility. The authors assumed that patients studied had a neuropathic pain component. Future studies should focus on patients with known neuropathic SCD‐related pain and compare the efficacy of gabapentin in patients with and without neuropathic pain.Latika Puri, Doralina L. Anghelescu, Kerri Nottage, Jane S. Hankins, Winfred C. Wang, Guolian Kang, and Jeffrey M. Gossett designed the study, analyzed the data, and contributed to the manuscript. Olivia McGregor assisted with study coordination.D.L.A., L.P., W.C.W., G.K., J.M.G., and O.M. have no conflict of interest. J.S.H. receives research support from Global Blood Therapeutics and consultant fees from Global Blood Therapeutics and MJ Lifesciences. K.N. is a Janssen R&D employee and a JNJ stockholder.Supplemental Table 2. Admission rates at the end of acute care visit for the entire cohort and HbSS subgroups.Click here for additional data file.


Capsaicin is a chili peppers extract, genus Capsicum, commonly used as a food spice. Since ancient times, Capsaicin has been used as a “homeopathic remedy” for treating a wild range of pathological conditions but without any scientific knowledge about its action. Several studies have demonstrated its potentiality in cardiovascular, nephrological, nutritional, and other medical fields. Capsaicin exerts its actions thanks to the bond with transient receptor potential vanilloid subtype 1 (TRPV1). TRPV1 is a nociceptive receptor, and its activation starts with a neurosensitive impulse, responsible for a burning pain sensation. However, constant local application of Capsaicin desensitized neuronal cells and leads to relief from neuropathic pain. In this review, we analyze the potential adjuvant role of Capsaicin in the treatment of different pathological conditions either in internal medicine or dentistry. Moreover, we present our experience in five patients affected by oro-facial pain consequent to post-traumatic trigeminal neuropathy, not responsive to any remedy, and successfully treated with topical application of Capsaicin. The topical application of Capsaicin is safe, effective, and quite tolerated by patients. For these reasons, in addition to the already-proven beneficial actions in the internal field, it represents a promising method for the treatment of neuropathic oral diseases. Capsicum annuum L. family  with a hydrophobic group, located between the fifth and sixth transmembrane regions (TM5/6) i mobilization from endoplasmic reticulum storage. The increased [Ca2+]i level induces saliva secretion by activating calcium-activated chloride channels (CACC) [2+]i level by TRP channels i levels in cells isolated from the human submandibular gland (SMG) [In an in vitro study, it has been observed that Capsaicin enhances [Cand (SMG) . On the nd (SMG) .+ channels in taste receptor cells (TRCs), isolated from circumvallate papillae in rats. The inhibition of the K+ channel may induce TRC excitation, activating the solitary nucleus tract (SNT) in the brain [In addition to the role of TRPV1 in saliva secretion, the interaction between TRPV and CACC has also been explored. The chemical sensation or taste are strong agonists of salivation. It has been found that Capsaicin inhibits outward-rectifying Khe brain . Varioushe brain .Another relevant topic is oral carcinogenesis, which is induced by many factors, among which is diet. Oral squamous cell carcinoma (OSCC) is one of the most widespread cancers in the world, whose incidence is highly variable. OSCC records low rates in some countries, such as Mexico, where people consume a large number of chilies daily ,139,140.Capsaicin seems to act as a cancer-suppressing agent through its antioxidant and anti-inflammatory action, blocking several signaling pathways .In addition, a lower incidence of oral epithelial dysplasia (OED) is reported after Capsaicin treatment . The preConsidering all available information, we can speculate that dietary Capsaicin consumption could provide a chemo-preventive effect for OSCC .It is interesting to propose our personal experience, which has matured during the last few years, about Capsaicin topical application in PTTN. In this manuscript, we present five clinical cases, in which topical application of Capsaicin gel was used to treat uncontrollable oro-facial pain of iatrogenic origin.All patients developed PTTN after post-endodontic treatment and all of them were previously treated with infraorbital nerve or sphenopalatine ganglion block, using 1 mL of 0.5% lidocaine or 1 mL of 0.5% mepivacaine with a 27-gauge needle, but only with transitory benefits. Patients were then treated with repeated courses of radio frequency (RF) pulses with a 24-gauge needle on their terminal nerve, also without substantial benefits. After these procedures, patients were treated with a topical application of Capsaicin gel.Mucosal hyperemia.Acupressure with fovea sign or transient ischemia of the oral mucosa.Swollen or raised mucosa.Tactile allodynia.Thermic allodynia performed with a wet cotton wad at a known temperature (42 °C for hot and 2–4 °C for cold).Before the beginning of Capsaicin treatment, we performed, as common clinical practice, an oral examination to evaluate the presence of:We tested patients’ sensibility to vanilloid receptors using a stress test with methyl acetate. All patients were sensitive to menthol and therefore to Capsaicin.Capsaicin gel was applied to the painful mucosal area, three times a day, every 8 h. We used increasing concentrations of Capsaicin, starting from 0.01%, through to 0.05% and up to 0.5%. Patients indicated a total remission of pain within 5 min after the application and mild hypersensitivity after 120 min. After 4 h, the pain reappeared, and another application was necessary.No patients presented adverse local or systemic effects. Capsaicin seemed to be well-tolerated by patients, despite local burning pain and other local side effects observed during the first applications.Currently, there is no contraindication in the use of local Capsaicin, except the presence of mucosal lesions at the site of application. No cases of intoxication or systemic side effects related to local Capsaicin use are known.Even if more clinical studies are needed to confirm these data, local Capsaicin application is sufficiently safe and effective for the treatment of oral neurosensitive pain, and it represents a promising method for the management of neuropathic oral diseases.Since ancient times, Capsaicin has been used for its particular beneficial properties. However, only recently have its mechanisms of action and potentialities been highlighted. In addition to the healthy properties already studied , Capsaicin would seem to be a valid therapeutic option for the treatment of PTTN.In this regard, we present our experience in the local use of Capsaicin in the treatment of PTTN. Initially, in our study population, Capsaicin’s contact with oral mucosa caused hyperalgesia and increased neuropathic pain in some patients. However, its continuative application desensitized neurosensitive fibers, showing pain relief.In conclusion, Capsaicin seems to be well-tolerated by patients, despite the local burning pain and other minor local side effects observed during the first applications, making it a valid new therapeutic agent, free from side effects, not only in internal medicine but also in dentistry.ACEAngiotensin-converting-enzymeAHArterial hypertension AOAtypical odontalgiaBMSBurning mouth syndromeCACCCalcium-activated chloride channelsCGRPCalcitonin gene-related peptideCKDChronic kidney diseaseCVDCardiovascular diseaseEGFEpidermal growth factorFDAFood and drug administrationGFRGlomerular filtration rateGECsGingival epithelial cells GLUT2Glucose transporter 2HDLHigh-density lipoproteinsHIV-DSPNHIV-associated distal sensory polyneuropathy HOMA-IRHomeostasis model assessment of insulin resistanceJAK/STATJanus kinase/signal transducer and activator of transcription LDLLow-density lipoproteinsLXRLiver X receptormAChRsMuscarinic acetylcholine receptors NF-kBNuclear factor-kB NGFNerve growth factorNONitric oxideOH-1Heme oxygenase-1OEDOral epithelial dysplasia PDX-1Pancreatic duodenal homebox-1pERKphosphorylated kinasePHNPost-herpetic neuropathyPI3/AKTPhosphoinositide 3-kinase/protein kinase BPPARαPeroxisome proliferators-activated receptor-αPTNNPainful post-traumatic trigeminal neuropathyomaSMGSubmandibular glandSNTSolitary nucleus tractSPSubstance PTAK1/MAPKTransforming growth factor-β-activated kinase 1/mitogen-activated protein-kinase TGTriglyceridesTJsTight junctionsTM1-66 transmembrane regions TMDTemporomandibular disorderTNTrigeminal neuralgiaTNF-αTumor necrosis factor-α TRCsTaste receptor cellsTRPVTransient receptor potential vanilloidVcCaudal trigeminal subnucleus


BackgroundAloe vera gel with that of amlexanox 5% oral paste in the treatment of recurrent small-type aphthous ulcers.Recurrent aphthous ulcers are one of the most common lesions of the oral mucosa. Most currently available treatment methods aim to relieve symptoms, speed up healing and prevent ulcer recurrence. The current study aimed to compare the effectiveness of Materials and MethodsThe study was conducted on 60 patients  attending the Department of Oral Medicine at the Faculty of Dentistry at Damascus University. The sample age ranged between 15 to 25 years, with an average age of 20.3 ± 2.4 years. Patients were diagnosed with recurrent aphthous ulcers of the small type. The sample was divided into three groups with equal numbers of patients (n=20 for each group) according to the provided drug: Aloe vera, amlexanox, and the placebo groups. Patients' ulcer size was measured on day 0 of treatment, and the ulcer size reduction was assessed on day 3 and day 5. The pain was also recorded at the first visit, and then pain reduction was assessed during follow-up visits.Results2, 4.05 mm2, and 6.20 mm2 in the Aloe vera, the amlexanox, and the placebo groups, respectively. The differences between groups were significant (p=0.003). The mean pain on the fifth day was 0.80 cm, 1.60 cm, and 3.20 cm in the Aloe vera, the amlexanox, and the placebo groups, respectively. The differences between groups were significant (p=0.026).The mean ulcer size on the fifth day of treatment was 1.85 mmConclusionsWithin the limits of the current trial, both treatment groups proved effective in accelerating ulcer healing with the superiority of Aloe vera compared to amlexanox, as it achieved a greater reduction in ulcer size and pain when assessed on the fifth day of treatment. Recurrent aphthous ulcers are a common cause of oral ulcers. The etiology of these lesions that occur only in the oral mucosa is unknown . It is aAphthous ulcers are divided into three clinical types: minor and major aphthous ulcers and herpetiform ulcers. Minor aphthous ulcers, the most common, are small in size (less than 5 mm in diameter) and have a form of a single ulcer or several ulcers ,5. MajorAloe vera is also one of the most important topical remedies, an aloe-like plant that has been widely used as a cosmetic moisturizer, toothpaste, food flavoring, and preservative in the pharmaceutical and food fields. It has an antiviral effect and antitumor properties . ,21. 9,21Pain PerceptionThe effect of pain reduction was assessed for each patient using a numeric rating scale (NRS). A line of 10 cm in length was used, and the patient was asked to select the number which best reflected her/his state for the following assessment times: day 0, day 3, and day 5. Patients' responses ranged from (0): no pain, to (10): the highest pain level. This numeric rating scale was converted into a 4-point Likert scale as follows: 0, no pain; (greater than 0 and less than 4), mild pain; greater than or equal to four and less than 7, moderate pain; and greater than or equal to 7, severe pain.Statistical analysisSPSS® program Version 13.0  was used for statistical analysis. The Kolmogorov-Smirnov test was used to examine the normality of the distributions. One-way analysis of variance (ANOVA) or its alternative nonparametric test  was utilized to compare the three groups. For post-hoc pairwise comparisons, the Bonferroni test or its alternative nonparametric test  was applied. The level of significance was set at 0.05.Basic sample characteristicsSixty patients  participated in this trial, with 20 patients in each group. Regarding gender distribution, there were 10 males (50.0%) and 10 females (50.0%) in the Aloe vera group, eight males (40.0%) and 12 females (60.0%) in the amlexanox group, and nine males (45.0%) and 11 females (55.0%) in the control group. The age ranges were 16-24 years, 16-24 years, and 15-24 years in the Aloe vera, the amlexanox, and the control groups, respectively. There was no patient withdrawal from the study; consequently, all 60 patients were included in the data analysis  and gibberellin (a growth hormone) in Aloe vera extract promote collagen synthesis, and gibberellin interacts with growth factor receptors on fibroblasts, stimulating their activity and proliferation. Aloe vera also increases the synthesis of hyaluronic acid and dermatan sulfate in the granulation tissue of the wound, which promotes wound healing. Aloe vera also contains a series of components, such as acemannan, that have wound-healing potential by promoting the repair process and proliferation of epithelial cells by stimulating factors contributing to wound repair, including fibroblasts and collagen ,15. The Also, the values of aphthous ulcer size on the fifth day in the group treated with amlexanox were smaller than in the group treated with a placebo. Amlexanox is known to potentiate its effect by increasing the intracellular concentration of adenosine monophosphate (AMP) or by inhibiting the influx of calcium into cells . Both thLimitationsOne limitation of the current study is that the application of treatment depended on the patient compliance with the instructions. Therefore, patient adherence to the given instructions was not assessed. The observation period was confined to five days only. This period could have been extended more, and insight into the level of recurrence could have been established. Other patient-reported outcomes, such as mastication difficulties or speech problems, should be evaluated in future research. The oral health-related quality of life could be another area of investigation in this context.Significant differences were observed between the Aloe vera, the amlexanox, and the placebo groups regarding the mean ulcer size after five days of observation. The Aloe vera gel and amlexanox effectively accelerated the healing of aphthous ulcers, with the Aloe vera gel group showing a greater decrease in ulcer size. Significant differences were also observed between the Aloe vera, the amlexanox, and the placebo groups regarding pain intensity at five days following gel application. Aleo vera and amlexanox effectively reduced the perceived pain, with the Aleo vera group showing a greater reduction in pain compared to the amlexanos group.


The PEricapsular Nerve Group (PENG) block is a novel regional analgesia technique that provides improved analgesia in patients undergoing hip surgery while preserving motor function. In this study the PENG block was investigated for analgesia in elective total hip arthroplasty (THA).In this multi-centre double-blinded randomized-controlled trial, in addition to spinal anesthesia and local infiltration analgesia (LIA), THA patients received either a PENG block or a sham block. The primary outcome was pain score  3 h postoperatively (Day 0). Secondary outcomes were postoperative quadriceps muscle strength, postoperative Day 1 pain scores, opiate use, complications, length of hospital stay, and patient-reported outcome measures.p = 0.03). There was no difference in quadriceps muscle strength between groups on Day 0 (PENG: 23 (77%) intact versus sham: 24 (80%) intact; p = 0.24) and there were no differences in other secondary outcomes.Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperative Day 0, the PENG group experienced less pain compared to the sham group (PENG: 14 (47%) patients no pain, 14 (47%) mild pain, 2 (6%) moderate/severe pain versus sham: 6 (20%) no pain, 14 (47%) mild pain, 10 (33%) moderate/severe pain; Patients receiving a PENG block for analgesia in elective THA experience less postoperative pain on Day 0 with preservation of quadriceps muscle strength. Despite these short-term benefits, no quality of recovery or longer lasting postoperative effects were detected. Total hip arthroplasty (THA) is a cost-effective treatment for osteoarthritis through reduction in pain and improvement in quality of life . It is iAdequate pain management following THA is important as quality analgesia has been shown to decrease complication rates and facilitate postoperative mobilization , 7. PrevIn 2018, Giron-Arango et al. described a novel regional technique for hip analgesia; the pericapsular nerve group (PENG) block . The PENA common technique used for THA is spinal anesthesia in combination with local infiltrating analgesia (LIA). However, this approach is largely based on favourable results of LIA in knee arthroplasty with limited effect in postoperative pain control in THA . Little The primary outcome was the NRS pain score at Day 0. Secondary outcomes were: NRS pain score (at Day 1), Day 0 and 1 quadriceps muscle strength, perioperative opiate use, postoperative complications, length of hospital stay, patient satisfaction and PROMs.th of December 2020, URL: https://www.trialregister.nl/trial/9147). This study conforms to the Consolidated Standards of Reporting Trials (CONSORT) and the CONSORT extension for trials reporting patient-related outcomes [This multi-centre double-blinded randomized-controlled trial was conducted at two teaching hospitals in Adelaide, Australia; Noarlunga Health Services (NHS) and Flinders Medical Centre (FMC). Institutional ethics approval was obtained (SALHN/HREC/292.20) and written informed consent was acquired from all participants. The trial was registered prior to commencement  and contraindications for or patient refusal of spinal anesthesia and/or regional analgesia.www.sealedenvelope.com) on a 1:1 basis. Members of the surgical team, members of the Acute Pain Service (APS), nursing staff and patients were all blinded to the intervention. To ensure blinding, the anaesthesiologist performing the preoperative block was different from the anaesthesiologist managing the patient intraoperatively and conducting the postoperative assessments.Patients were randomized to either PENG block (intervention) or sham block (control). Randomization was performed by the principal investigator only via an online randomization computer generator .PENG: 20 mL of ropivacaine 0.5% (100 mg) prepared by the anaesthesiologist performing the block was used. The area was aseptically prepped and draped. The curvilinear probe was placed transversely, medial to the anterior inferior iliac spine with the medial end of the probe rotated in a caudad direction to align to the superior pubic ramus. A 100 mm sonoplex needle was inserted in-plane under ultrasound guidance. 20mLs of local anaesthetic was injected as a plane block between the psoas fascia and superior pubic rami.This block was simulated by the anaesthesiologist by prepping, scanning and draping as per PENG block protocol. The probe and a blunt needle, with a 20 mL syringe filled with saline attached, were held against the skin similar to the PENG block and a sufficient pause to simulate the block being performed was conducted, without actual administration of any medicine.Following placement of either block, a small cross was drawn with a surgical marker to cover the puncture site or absence thereof.The study was designed to represent daily practice and to achieve high external validity. Anaesthetic technique was standardized to a spinal anaesthesia with 0.5% Isobaric bupivacaine (range 10-14 mg) without use of intrathecal opioids. A single 8 mg intravenous dose of dexamethasone was administered at the time of the block. Surgical technique was performed at the discretion of the treating orthopaedic surgeon, including routine use of LIA in all patients at a dose of 100 mL of 0.1% ropivacaine with 1 mg epinephrine. Postoperative analgesia regime was standardized with round-the-clock acetaminophen and NSAIDs if no contraindication, and if needed tramadol, oxycodone, and/or fentanyl on a nurse administered basis.The rationale for using isobaric bupivacaine is to reflect usual practice at our institution, where the longer duration is suited to the surgery .Preoperatively, individual patient pain experience was evaluated using the Pain Catastrophizing Scale . Pain scPerioperative opiate doses were recorded preoperatively, intraoperatively, on day 0 and each postoperative day for three days with quantities converted to oral morphine equivalents. Chronic opioid use and chronic preoperative pain were defined as daily opioid use or pain interfering with activities of daily living for a duration of greater than three months.Mobilization: Postoperatively at Day 0 once the spinal had recessed, and Day 1, a blinded anaesthesiologist assessed quadriceps muscle strength using the Oxford muscle strength grading with grouping of results into intact (5/5), reduced (1–4/5) and absent (0/5). If a patient reported reduced or absent quadriceps muscle strength, the test was carried out on the non-operative side to ensure it was not due to residual spinal effect. Day 0 measurements of dynamic pain and quadriceps strength were standardised to three hours from end time of surgery. A Timed Up-and-Go test was conducted preoperatively and on Day 1 postoperatively by physiotherapists. In this test, the patient starts in a seat at standard height, stands, walks ten feet, turns around, walks back, and sits back down .Baseline preoperative anxiety and depression were noted using the validated Patient-reported outcomes measurement information system (PROMIS) anxiety and depression item banks . These PThe APS assessed patient satisfaction and pain management on Day 1 in a blinded fashion. Pain scores as a maximum on movement, quadriceps muscle strength, patient satisfaction and PROMs were collected using a scripted format. Complications throughout hospital admission, according to Clavien-Dindo classification grade, time to first mobilization and time to discharge were also recorded . First mThe primary outcome was the NRS pain score at Day 0. Secondary outcomes were: NRS pain score (at Day 1), Day 0 and 1 quadriceps muscle strength, perioperative opiate use, postoperative complications, length of hospital stay, patient satisfaction and PROMs.priori power calculation was carried out using PASS 14 Power Analysis and Sample Size Software  based on pain scores from a pilot study and a previous PENG randomized-controlled trial. This showed a mean pain score of 4 out of 10 points after THA on Day 0 without placement of PENG block. This was reduced to a score of 2 out of 10 points with placement of PENG block, with a standard deviation (SD) of 2 [A SD) of 2 , 14. A t2 test or Fisher’s exact test (for n < 10) for categorical variables, and the Mann–Whitney U-test for nonparametric continuous variables or the Student’s t-test for parametric continuous variables. A p-value of < 0.05 was considered statistically significant.Data collection and entry, and statistical analyses were conducted in a blinded fashion. The analysis was performed on an intention-to-treat basis using SPSS version 27  and GraphPad Prism version 9 . Parametricity of continuous variables was determined using the Shapiro–Wilk test. Normally distributed continuous variables are expressed as mean (SD), and nonparametric variables as median (range). Univariate analysis was carried out using the chiDuring the study period, 75 patients were admitted for elective THA and screened for eligibility. Seven patients were excluded on the basis of cognitive impairment or a language barrier. Eight patients declined to participate, due to a preference for general anesthesia instead of the standardized spinal anesthesia, leaving 60 patients who were consented and randomized equally between both groups. Fig.  All patiThe preoperative demographics of both groups were similar, including baseline NRS pain scores, pain catastrophising scores, incidence of chronic pain and anxiety or depression. Table .Table 1Pp = 0.03). In both groups, 14 patients (47%) reported mild pain, and 2 patients (6%) in the PENG group experienced moderate or severe pain, compared to 10 patients (33%) in the sham group. (Table Day 0 pain scores in PENG block patients were significantly lower than in the sham block group: 14 patients (47%) in the PENG group reported no pain, compared to 6 patients 20%) in the sham group (0% in thep = 0.82). Quadriceps muscle strength was preserved in the PENG group and was similar when compared to the sham block group on Day 0 (p = 0.24) and Day 1 (p = 0.75): On Day 0, 23 (77%) PENG patients and 24 (80%) sham block patients had intact quadriceps muscle strength (p = 0.24), and on Day 1 this was 24 (80%) and 22 (73%) respectively (p = 0.75). . The direct postoperative analgesic advantage of the PENG block in this setting does not remain after surgery on Day 1.This double-blinded randomized-controlled trial shows that the PENG block significantly reduces short-term postoperative pain in elective THA when spinal anaesthesia and LIA are used. . This could reflect a reluctance to actively move the newly operated hip, or possible spread from the LIA to the femoral nerve, consistent in both groups. Notably, no adverse events directly related to block placement were reported and patient satisfaction was similar across both groups.The motor sparing effect is consistent with previous studies focused on anatomy suggesting that the PENG block targets the articular branches of the femoral, obturator, and accessory obturator nerves . It mustA variety of PROMs and outcome measures were used with the aim to objectively quantify possible recovery benefits of the PENG block. Preoperative patient PROMs, quantified using the Pain Catastrophizing Scale, PROMIS anxiety and depression item banks, were all similar between groups. Postoperative PROMs, quality of recovery and the Timed Up-and-Go tests were also similar. This could possibly be due to the timing of these tests on Day 1 postoperatively, after the analgesic effect of the PENG block had finished. A recent RCT comparing PENG to sham in combination with intra-articular injection also showed only short term benefit, without differences in longer term outcomes .The similar opiate use in both groups, despite a difference in pain scores, may be due to the advanced age of the included patients and their low baseline opiate use. It is also important to note that the study was not powered to detect a difference in opiate use nor in PROMs between both groups, for which larger studies will be required to investigate this in the future.Some limitations have to be addressed. As indicated above, this trial was conducted on a relatively small number of patients and could not identify differences in secondary outcomes. However, it was powered on the primary outcome, showing a significant difference between both groups.Quadriceps strength was measured by a blinded clinician. A standardised dynamometric measurement tool would have been more accurate, but this was not available. We recognise that this makes the secondary outcome less reliable due to interobserver variation, but have addressed this by grouping the intermediate scores together.Due to the standardized spinal anaesthesia in the study protocol, 11% (8/75) patients approached, chose not to participate, potentially inflicting some selection bias. However, randomization took place after inclusion to reduce this bias. In the future, a next randomized-controlled trial to further investigate the efficacy of PENG block in THA patients could therefore be in patients having either spinal or general anesthesia.Patients receiving an additional PENG block for analgesia during total hip arthroplasty experience less direct (Day 0) postoperative pain, with preserved quadriceps muscle strength and similar time to mobilization compared to patients having spinal anesthesia and local infiltration analgesia only. For total hip arthroplasty, the PENG block should be considered as part of multimodal analgesia.