To compare health-related quality of life (HRQOL) and pelvic pain levels over time in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) and those with other pelvic pain conditions (OPPC) including chronic prostatitis, dyspareunia, vaginismus, vulvodynia, and vulvar vestibulitis.We prospectively enrolled male and female patients from any Veterans Health Administration (VHA) center in the US. They completed the Genitourinary Pain Index (GUPI) quantifying urologic HRQOL and the 12-Item Short Form Survey version 2 (SF-12) quantifying general HRQOL at enrollment and 1 year later. Participants were classified by ICD diagnosis codes and confirmed by chart review to be IC/BPS or OPPC (308 and 85 patients respectively).At baseline and follow-up, IC/BPS patients, on average, had worse urologic and general HRQOL than OPPC patients. IC/BPS patients demonstrated improvement in urologic HRQOL measures over the study but demonstrated no significant change in any general HRQOL measure suggesting a condition-specific impact. Patients with OPPC demonstrated similar improvements in urologic HRQOL but had deteriorating mental health and general HRQOL at follow-up suggesting a wider general HRQOL impact for these diseases.We found that patients with IC/BPS had worse urologic HRQOL compared to other pelvic conditions. Despite this, IC/BPS showed stable general HRQOL over time, suggesting a more condition-specific impact on HRQOL. OPPC patients showed deteriorating general HRQOL, suggesting more widespread pain symptoms in these conditions. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic pain condition characterized by bladder-centric pain in the absence of infection or other disease. Other pelvic pain conditions (OPPC) such as chronic prostatitis, dyspareunia, vaginismus, vulvodynia, and vulvar vestibulitis can present with similar symptoms to IC/BPS, often leading to a delay in diagnosis for all these conditions. While urine cultures, cystoscopy, and urodynamics may be useful adjuncts, they cannot be used to definitively diagnose IC/BPS . AccordiWe sought to address these gaps by comparing both general health-related quality of life (HRQOL) and condition specific-HRQOL prospectively over a one-year period in IC/BPS patients and those with other pelvic pain conditions (OPPC). The heterogenous population of male and female veterans nationwide provides a representative sample of U.S. patients experiencing a wide range of pelvic pain conditions. General measures of HRQOL provide data across different conditions and encompassing the entirety of a patient's condition. Evaluation of a patient's chronic conditions, comorbidities and overall health can be evaluated with general measures. Specific measures of urologic HRQOL can be utilized to identify disease-specific symptoms and measure effectiveness of interventions and treatments related to the disease. Using these two types of HRQOL measures, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) network has acknowledged that IC/BPS can have a greater condition-specific impact on urologic HRQOL than on general HRQOL. The MAPP Network also recognized an association between chronic pelvic pain syndromes and psychosocial factors  that can impact general HRQOL , 5. TherWithin the nation's largest nationally integrated health care system, the Veterans Health Administration (VHA), we recruited veterans nationwide into cohorts of subjects with IC/BPS and OPPC. Data from all VHA sites are collated into a common electronic medical record that is accessed through the VA Informatics and Computing Infrastructure (VINCI). We identified VA patients by querying ICD-9/10 codes (Appendix 1) and categorizing patients into IC/BPS and OPPC cohorts after detailed chart review. The IC/BPS cohort consisted of patients with confirmed chart diagnosis of IC/BPS (bladder-centric pain on two different visits at least 6 weeks apart), while the OPPC cohort consisted of patients with confirmed chart diagnosis of chronic prostatitis, dyspareunia, vaginismus, vulvodynia, or vulvar vestibulitis.Female and Male Genitourinary Pain Index (GUPI) , urinary symptoms (score range 0–10), and urinary QOL (score range 0–12) resulting in a total GUPI score of 0–45. Urologic HRQOL can be quantified by the total GUPI score, quantifying the total impacts of pain, urinary symptoms, and QOL. Sub-scores and total scores were treated as continuous variables. GUPI is used to quantify condition specific HRQOL and symptom severity. Scores were reversed from standard scale so higher score indicates better health outcomes.x (GUPI) : The GUP12 Item Short-Form Survey Version 2 (SF-12)  to create a shorter questionnaire for scoring general HRQOL. The SF-12 was statistically validated for both Physical Components and Mental Components when cross-validated with the SF-36 questionnaire. The SF12 has two summary component scores: a Physical Component Summary Score and a Mental Health Component Summary Score. Scores range from 0 to 100, where zero indicates the lowest QOL and 100 indicates the highest QOL. (SF-12) : The SF-Eligible patients were sent interest and consent paperwork through the mail in accordance with IRB approved protocols, and staff followed up over the phone to obtain informed, written consent to participate in the study. After informed consent was obtained, the following study questionnaires were sent to participants at baseline and one year follow-up with responses collected via return mail:t-tests for continuous variables. The Wilcoxon signed-rank test was used to evaluate the changes in GUPI and SF-12 from enrollment to one-year follow-up within each cohort because the distributions did not follow a normal distribution. Two sample t-tests were performed to compare GUPI and SF-12 scores between cohorts. General linear regression was conducted to assess the associations of patient demographic and clinical characteristics with GUPI and SF-12 total scores at baseline and with the score changes after one-year follow-up. All the analyses were performed using SAS 9.4 . All p values reported were 2-sided. A p value < 0.05 was considered statistically significant.The IC/BPS and OPPC cohorts' demographic and clinical characteristics at enrollment were compared using Chi-squared tests for categorical variables and We enrolled 308 (78%) IC/BPS patients and 85 (22%) patients with OPPCs who completed both the GUPI and SF-12 at baseline. There was no statistical difference in demographic or clinical characteristics at enrollment between the IC/BPS cohort and the OPPC cohort . The onep < 0.001, p < 0.001) and lower SF-12 scores . IC/BPC patients reported lower (worse) mean scores on the SF-12 physical health sub-score, mental health sub-score, and SF-12 total score than patients with OPPCs , improved urinary symptom score by 0.5 (p = 0.009), improved urologic HRQOL score by 0.6 (p < 0.001), and an improved GUPI total score by 2.1 (p < 0.001). In OPPC patients, there was no statistically significant change in the urinary symptom sub-score (p = 0.303) but there was improvement in the pain symptom sub-score by 1.2 (p = 0.022), improved urologic HRQOL sub-score by 0.6 (p = 0.039), and improved GUPI total score by 2.1 (p = 0.018) (p > .999) indicating both cohorts showed equivalent improvement during the study duration.The change in GUPI scores from baseline to one-year follow-up showed that IC/BPS patients had improved pain symptom score by 1.1 (= 0.018) . The chap = 0.238), but the mental health sub-score and SF-12 total score showed significant decreases (worsening) in scores at follow-up. Despite IC/BPS having significantly worse general HRQOL at baseline (p = 0.001), the follow-up SF-12 score showed no difference in general HRQOL between the two cohorts (p = 0.294) after one-year because the OPPC patient's general HRQOL deteriorated. IC/BPS patients showed significantly higher improvements in general HRQOL over the study duration . In summary, while IC/BPS had worse health at baseline, their scores remained unchanged in all general HRQOL measured by the SF-12. Meanwhile, OPPC patients showed deteriorating mental health and general HRQOL.In analyzing these changes, IC/BPS patients showed no significant change in physical health, mental health, or total SF-12 score. In OPPC patients, the physical health sub-score remained unchanged (p < .001) and history of PTSD  while SF-12 baseline was impacted by a patient's age , race being African American/black , and a history of depression   . None ofp < .001) and a history of irritable bowel syndrome (IBS)  while SF-12 baseline scores were impacted by a history of depression  and history of PTSD  (p = 0.021).In the OPPC cohort, the baseline GUPI scores were impacted by a patient's race being African American/black  . Only agp < 0.001), suggesting that IC causes significantly worse pelvic pain than other pelvic conditions. Despite comparable improvements on the GUPI in both cohorts, we found that IC/BPS scores at follow-up were also significantly worse in every sub-score of the GUPI (p < 0.001) further supporting this conclusion that IC/BPS causes worse pain and poses a greater impact on urologic HRQOL than other pelvic conditions. Thus, during the treatment of IC/BPS, additional care towards urinary pain and management is needed to address the significant gap observed in urologic HRQOL.We had several key findings from this cohort study of heterogeneous patients seeking care in the VA system. The IC/BPS cohort had significantly worse scores for all baseline sub-scores of the GUPI  and found that significantly more patients experienced urinary-specific HRQOL improvements at follow-up than general HRQOL . In thisIn the OPPC cohort, the GUPI improved in all sub-measures except urinary symptoms, while still maintaining an improvement in total GUPI score. In this cohort, SF-12 mental health sub-scores and total SF-12 deteriorated over the span of the study. This shows that, despite improvement in urologic HRQOL and management of urinary pain, the patient's general HRQOL still deteriorated. The absence of urinary symptom improvement might have caused worsening HRQOL as patients struggle to see improvements in aspects of their condition causing greater stresses on their general health. The MAPP Network also noted that worsening general HRQOL measures were indicative of more widespread non-urologic pain and discomforts . This miComparing the two cohorts, both IC/BPS and OPPC demonstrated improvements from baseline in urologic HRQOL over a one-year follow-up, and the improvements were to the same degree, showing no difference in the change in total GUPI score. This might be due to receiving similar treatments for pelvic pain in both cohorts, but these modalities were not tracked in this study. When compared, IC/BPS patients showed 4.1 times the improvement in general HRQOL compared to the OPPC cohort, showing the significant impact that OPPC conditions have on deteriorating general health. A patient's physical and mental health needs to be a primary concern in the treatment of patients with these pelvic conditions, considering that mental health was the most significantly impacted measure at follow-up. Depression significantly impacted the SF-12 in both cohorts. Given that depression co-occurs with pelvic pain at a high frequency, mental health professionals should be included in the treatment process of these individuals to not only treat the condition but ensure a holistic approach to patients' QOL. A study from Brazil found that women with pelvic pain had a prevalence rate of 73% for anxiety and 40% for depression, significantly higher than among controls . MultiplOlder individuals with IC/BPS demonstrated higher baseline GUPI and SF-12 indicating better urinary and general HRQOL with age. One of the primary interventions for IC/BPS remains lifestyle and behavioral modifications that help patient's cope with their symptoms. Our data might suggest that these older patients have been able to positively cope with symptoms and create a positive impact on their HRQOL through these measures. Previous studies by the MAPP Network have looked at both duration of symptoms and age as effects on pain severity and symptoms and found that females better coped with advancing age, regardless of duration of symptoms . In factOur study also showed that compared with patients of other races, black patients had worse baseline SF-12 scores in the IC/BPS cohort and worse baseline GUPI scores in the OPPC cohort. A previous study noted that IC/BPS symptoms are equally common in black and white individuals , suggestHistory of other physical and mental ailments also impacted baseline scores in both cohorts. History of depression in both IC/BPS patients and OPPC patients showed significantly lower SF-12 scores—general HRQOL—at baseline. Previous studies looking at pelvic pain demonstrated that depression is independently associated with lower HRQOL and worse outcomes , supportOur study is unique in providing a cohort evenly matched for both race and gender. Historically, IC has been noted as an illness for white females –19, but In a heterogenous population of veterans nationwide we found that patients with IC/BPS had worse urologic pain compared to patients with other pelvic conditions. We also found that IC/BPS had no change in general HRQOL compared with deteriorating general HRQOL in OPPC over a one-year period. This suggests that IC/BPS has more of a condition-specific impact on urologic health while OPPC conditions may have extensive impacts on general health due to wider non-urologic symptoms. Additional research with longer follow-up is needed to better understand these factors and IC's disease specific burden on HRQOL.


Despite advancements in minimally invasive repair of pectus excavatum (MIRPE), Nuss procedure, postoperative pain control remains challenging. This report covers a multimodal regimen using bilateral single-shot paravertebral block (PVB) and bilateral thoracoscopic intercostal nerve (T3–T7) cryoablation, leading to significant reduction in length of stay (LOS) and high rate of same-day discharge.n = 12), bilateral PVB with infusion and right-side cryoablation , or bilateral single-shot PVB and bilateral cryoablation . The primary outcome was LOS with focus on same-day discharge, and the secondary outcome was decreased opioid usage. This is a comparative study of pain management protocols for patients undergoing the Nuss procedure at a single center from 2016 through 2020. All patients underwent the the same surgical technique for the treatment of pectus excavatum at a single center. Patients received bilateral PVB with continuous infusion .Eleven of 17 patients in Group 3 (65%)  were discharged the same day as surgery. The remaining Group 3 patients were discharged the following day with no complications or interventions. Compared to Group 1 (no cryoablation), Group 3 had shorter LOS  and significantly decreased median opioid use on the day of surgery (0.92 mg/kg vs. 0.47 mg/kg,  Findings demonstrate the feasibility of multimodal pain management for same-day discharge after the Nuss procedure. Future multisite studies are needed to investigate the superiority of this approach to established methods.III.The online version contains supplementary material available at 10.1007/s00383-023-05429-7. The developmental chest wall deformity known as pectus excavatum causes inward displacement of the sternum and adjacent costal cartilage . Pectus Opioids are widely used to control pain in patients who have undergone the Nuss procedure, and the side effects associated with opioid use may be severe, ranging from itching, sedation, nausea, and constipation to respiratory depression. Furthermore, the habitual use of opioids can lead to dependence. Therefore, decreasing opioid usage can provide short-term as well as long-term benefits for patient safety and quality of life. The current epidemic of opioid misuse and abuse has given urgency to move towards effective opioid-conscious protocols , 15. TheThe increasingly widespread use of cryoablation combined with the desire to reduce opioid use led us to establish a multi-modal pain management protocol. The purpose of this study was to assess if this protocol utilizing procedural based analgesia could improve pain management and lead to same-day discharge after the Nuss procedure. Therefore, in this comparative pilot study of Nuss procedure patients, we hypothesized that the use of bilateral single-shot paravertebral block (PVB) with bilateral cryoablation and an oral medication regimen would result in reduced length of stay (LOS) and decreased overall opioid usage when compared to right-side cryoablation and bilateral paravertebral block with continuous infusion catheter (PVBc) and compared to bilateral PVBc alone (no cryoablation).This was a comparative study of pain management protocols for patients undergoing the Nuss procedure at a single center during the period from 2016 through 2020. The study was approved by the institutional review board of Children’s Hospital of Orange County . All patients underwent the Nuss procedure with the same surgical technique for the treatment of pectus excavatum. Data collected for study inclusion included demographics, Haller index, presenting symptoms. All patients included in the study participated in a mentorship program where each patient had a chance to connect with other patients and families who had recently undergone the Nuss procedure at our institution. All participants underwent full pulmonary and cardiology evaluations (including cardiac magnetic resonance imaging [MRI]) preoperatively.n = 12) was a retrospective cohort, with bilateral PVB with placement of PVB-catheter (PVBc) for continuous analgesic infusion and no cryoablation; Group 2 (n = 9), also retrospective, had combined bilateral PVB with PVBc and right-side thoracoscopic cryoablation only. During this time period, only single side cryoablation was performed given the paucity of information regarding the safety of cryoablation specifically as it related to recovery of sensation and concerns over lifelong chest wall numbness. Since that time, there was a study that reported complete recovery of sensation in pediatric patients under 21 years of age  or median [interquartile range (IQR)] for continuous variables. The primary outcome in this study was postoperative LOS, which is an objective measure that synthesizes numerous aspects of a patient’s postoperative course, including adverse events andpain control.. Secondary outcomes included narcotic usage (mg OME/kg), pain scores, side effects related to use of paravertebral regional anesthesia or cryoanalgesia and procedural complications.U-test. All analyses were conducted using SPSS V .Differences between treatment groups in gender distribution and use of narcotic medication were assessed for significance with Fisher’s exact test. Analysis of variance (ANOVA) was performed to identify group differences in age and weight; differences in LOS were assessed with the Kruskal–Wallis test, with two-group comparisons based on the Mann–Whitney p < 0.001. No patients in Groups 1 and 3 required hospital LOS >  = 3 days compared to a third of patients in Group 2, p = 0.010.In patients who underwent the Nuss procedure for the treatment of pectus excavatum, 12 had no cryoablation (Group 1), 9 had right-side cryoablation (Group 2), and 17 had bilateral cryoablation (Group 3). No patients in Group 3 required hospital LOS >  = 3 days (Table p < 0.001 (Table p < 0.001). Nearly 65% (11 of 17) of patients in the bilateral cryoablation group were discharged home on the day of surgery compared to no patients in the other procedure groups. No patients were readmitted.Patients who had bilateral cryoablation (Group 3) had significantly reduced average LOS  compared to those who had right-side cryoablation  on the day of surgery . Notably, Group 3’s total opioid use was significantly decreased compared to other groups throughout their hospitalization, while Groups 1 and 2 had high opioid use on postoperative days 1–3. Group 3 had adequate pain control on oral medications and minimal reported opioid use after discharge .As previously noted all administered opioid medications were converted to daily OME doses in milligrams per kilogram for ease of comparison . The opip = 0.034) (Table N = 6), although the trend was not significant  bilateral PVB with in-dwelling catheter infusion, and (2) bilateral PVB with in-dwelling catheter infusion along with right-sided thoracic intercostal nerve cryoablation. Our results showed shorter LOS and decreased postoperative opioid requirement in patients who received bilateral intercostal cryoablation and bilateral single-shot PVB, compared to the approaches used previously, with no readmissions. This is the first study to show that combined pain block treatment with bilateral PVB and bilateral cryoablation allows for same-day discharge after the Nuss procedure for repair of pectus excavatum.The results of our comparative study support other published reports of significant decreases in LOS and opioid usage in patients treated with cryoablation for pain management after the Nuss procedure , 18. HowIn a comparison of paravertebral to epidural blocks, Aydin et al. reported that patients had better pain management, decreased LOS, and increased satisfaction if they were administered either PVB or epidural block, compared to neither, prior to surgery . However Hypotensive episodes can occur with high paravertebral catheter placement infusions and are reported in the literature; the use of clonidine patches could simultaneously aid in pain control as well as decrease the risk of hypotension . In thisWhile this study presents pilot feasibility data that multimodal pain management protocols can provide improved pain control and, in some patients, allow for same-day discharge, this should in no way be taken as evidence that all patients should be discharged on the same day. The optimization of a same-day ERAS protocol is multifactorial. In this study, reasons unrelated to pain for why some patients did not meet same-day discharge criteria included anxiety about going home, urinary retention. No patient returned for readmission, and no missed or delayed complications specific to the multimodal pain bundle were identified during outpatient follow-up.The substantial improvements in pain management, with the possibility of same-day discharge, and substantially decreased opioid usage reported here are critical to optimizing the core component of ERAS guidelines. Rettig et al. recently investigated the effect of intraoperative intercostal nerve block injection on same-day discharge after the Nuss procedure , 29. TheWe would like to note that there are multiple limitations to this study. This is a pilot study reflecting our evolving experience. The findings presented above may lay the foundation for a larger multi-institutional study. While our results showed that it is feasible to discharge Nuss procedure patients on the day of surgery, this finding should be interpreted with caution, and not all patients will be eligible for early discharge. We acknowledge that this multimodal approach, and not the cryoablation alone, contributed to same day discharge. Patients were specifically scheduled as first case operations to allow adequate time during the day for the patient to recover, achieve pain control with oral medications, be seen by physical therapy and be able to spontaneously void. The criteria to meet same day discharge required at least 6 h and did not allow us to consider this in patients undergoing operations later in the day as part of our pilot study. This was a focused effort to achieve same day discharge which was not considered on the previous group of patients.The limitations of this study also include the lack of analysis of additional costs related to use of the cryoablation. As noted above, cryoablation added approximately 30 min of operating room time. Future research should include a cost–benefit analysis of the proposed protocol as well as a comparison of intercostal vs. paravertebral nerve block in terms of patient outcomes. A multi-site study with a larger sample size may elucidate the effects of multimodal pain management after the Nuss procedure on patient satisfaction as well as the cost savings associated with decreased LOS.The results of this pilot study demonstrate that combining intraoperative bilateral intercostal nerve cryoablation with PVB shortens LOS and reduces opioid use after the Nuss procedure, compared with PVBc alone or with PVBc plus right-side cryoablation. The combination of bilateral cryoablation and PVB provided superior pain control, compared with the pain management approach used for historical cohorts of Nuss procedure patients at our institution. Finally, this improved multi-modal analgesic approach does not appear to be associated with increased risk of complications, as there were no readmissions.Supplementary file1 (DOCX 223 KB)Supplementary file2 (DOCX 774 KB)Supplementary file3 (DOCX 16 KB)Below is the link to the electronic supplementary material.


Failed back surgery syndrome (FBSS) refers to a condition where symptoms such as low back pain, leg pain, and numbness persist or recur after lumbar surgery; it has been reported to occur in 10%–40% of patients who have undergone lumbar surgery. Spinal cord stimulation (SCS) has been reported useful for low back and leg pain due to FBSS. In this study, we studied the efficacy and safety of SCS for FBSS in older adults.  Among FBSS patients who underwent an SCS trial between November 2017 and December 2020, those with at least 50% pain reduction during the trial phase who requested spinal cord stimulator implantation underwent implantation of a stimulator under local anesthesia. The patients were divided into two groups: patients aged <75 years (<75-year-old group) and patients aged ≥75 years (≥75-year-old group). The male/female ratio, symptom duration, operative duration, visual analog scale (VAS) scores before and after one year of surgery, responder rate (RR), complications one year after surgery, and stimulator removal rate were analyzed. P < 0.001). There were no significant differences in low back pain VAS, leg pain VAS, overall pain VAS, RR, complications one year after surgery, or stimulator removal rate between the two groups.  There were 27 cases in the <75-year-old group and 46 in the ≥75-year-old group, with no significant differences in male/female ratio, duration of pain, or operative time between the two groups. VAS scores for low back pain, leg pain, and overall pain one year after surgery were improved significantly from respective preoperative scores in both groups ( SCS reduced pain effectively in both <75-year-old and ≥75-year-old groups with no differences in complications. Therefore, spinal cord stimulator implantation was considered a viable option for FBSS treatment in older adults because it can be performed under local anesthesia and is associated with a low incidence of complications. FBSS, a condition where symptoms such as low back pain, leg pain, and numbness persist or recur, has been reported to occur in 10%–40% of the patients who had lumbar surgery –6.SCS is widely used for treating chronic intractable pain , and ranIn this study, we compared outcomes of percutaneous SCS implantation, a minimally invasive procedure under local anesthesia, between older patients with FBSS aged <75 years and those aged ≥75 years to clarify the efficacy and safety. The primary outcome was the comparison of VAS scores for low back pain, leg pain, and overall pain before and one year after surgery and RR (percentage of patients whose pain decreased by ≥50%) between the <75-year-old and ≥75-year-old groups of patients who underwent spinal cord stimulator implantation.UMIN000050979).It was a single-center retrospective study in FBSS patients who underwent permanent spinal cord stimulator implantation between November 2017 and December 2020 at the Akita Cerebrospinal and Cardiovascular Center. This study was conducted with approval from the ethical review board of the Akita Cerebrospinal and Cardiovascular Center . The ethical review board registration number for the study is 22-21. It has been registered in the UMIN Clinical Trials Registry  score of at least 50 mm for low back or leg pain. The interval between the last block injection and SCS implantation in the included patients is at least one month. Before the trial, all subjects underwent the Hasegawa dementia scale-revised (HDS-R) and Minnesota Multiphasic Personality Inventory (MMPI) administered by a clinical psychologist. The HDS-R features a scoring system that ranges up to 30, whereby any score below 20 is indicative of suspicion of dementia. Additionally, ten clinical scales of the MMPI were assessed, with specific attention given to the detection of elevated levels of depression as manifested on the second scale. After patients with severe cognitive impairment or severe depression were excluded, only those psychologically appropriate for the treatment underwent an SCS trial. The patients who responded to a 7-day percutaneous trial with at least 50% pain reduction and requested stimulator implantation underwent permanent spinal cord stimulator implantation.μg/kg administered over a period of 10 minutes, followed by a continuous maintenance infusion of 0.2 to 0.7 μg/kg/hour. However, the dose was individually determined based on the patient's clinical response and potential adverse event. Tuohy needles were inserted under fluoroscopic guidance until the tip reached the epidural space via the L1/2 interlaminar foramen, and two leads  were then inserted. The leads were placed using an anatomical placement technique without paresthesia mapping. The first lead was placed median, and the electrode at the most cranial position was located in the center of the T8. The second lead was placed paramedian, and the electrode at the most cranial position was positioned at the cranial end of the T9   between the low end of the costae and the iliac crest or in the gluteal region . A 5-cm Adults aged ≥65 years are defined as elderly in many countries; however, clear global criteria to define older adults have not been established. In Japan, where the population is aging more rapidly than in other countries, older adults have improved physical functions in recent years, and the Japan Geriatrics Society has proposed to define adults aged ≥75 years as being elderly . TherefoThe following parameters were compared between the <75-year-old and ≥75-year-old groups of patients who underwent spinal cord stimulator implantation: male/female ratio, symptom duration (since diagnosis), the operative time for permanent implantation, VAS scores for low back pain, leg pain, and overall pain before and one year after surgery, RR (percentage of patients whose pain decreased by ≥50%), complications at one year after surgery, and stimulator removal rate. As more than half of the participants in this study were aged 75 years or older, age-related comorbidities and functional decline made it difficult to adjust for age differences in functional assessments such as the Oswestry Disability Index (ODI), Short Form (12) Health Survey (SF-12), Short Form (36) Health Survey (SF-36), and EuroQol-5 Dimension 5-Level (EQ-5D-5L). In addition, older individuals may have difficulty completing such functional assessment questionnaires due to potential cognitive impairment. Therefore, only pain intensity was reported as an outcome measure in this study.t-test were used to compare categorical variables and preoperative/postoperative VAS scores. Mann–Whitney U test was used for intergroup comparisons of other variables. Differences with P < 0.05 were considered statistically significant. Kaplan–Meier curves were used to analyze the difference in explantation rates and adverse event rates over time between the <75-year-old and ≥75-year-old groups of patients who underwent spinal cord stimulator implantation. SPSS  was used for data analysis.Fisher's exact test and P=1.000), symptom duration (P=0.489), and operative duration (P=0.163) (Seventy-three patients (33 men and 40 women) with a mean age of 74.8 ± 10.5 years underwent spinal cord stimulator implantation between November 2017 and December 2020. The number of patients, mean age, symptom duration, and operative duration were 27 patients (12 men and 15 women), 63.6 ± 8.2 years, 67.6 ± 93.2 months, and 55.2 ± 22.8 minutes, respectively, for the <75-year-old group, and 46 patients (21 men and 25 women), 81.3 ± 4.4 years, 66.0 ± 81.9 months, and 57.7 ± 19.2 minutes, respectively, for the ≥75-year-old group. There were no significant differences between the two groups in the male/female ratio (P=0.163) .P < 0.001). One year after surgery, the RRs for low back, leg, and overall pains were 81.5%,81.5%, and 81.5% for the <75-year-old group and 80.4%, 82.6%, and 82.6% for the ≥75-year-old group. For the primary outcome measure, there were no significant differences between the <75-year-old group and the ≥75-year-old group in low back pain VAS scores before and one year after surgery (P = 0.936 and 0.391), leg pain VAS scores before and one year after surgery (P=0.995 and=0.598), overall pain VAS scores before and one year after surgery (P=0.775 and P=0.511), and RRs   .P=1.000), implant-related pain , infection , and metal allergy . No cerebrospinal fluid leaks and nerve injuries occurred. Implant-related pain was defined as pain associated with the component site of the device, such as pain around the IPG site or at the lead anchor site. Within one year after surgery, a total of five patients, two (7.4%) in the <75-year-old group and three (6.5%) in the ≥75-year-old group, underwent stimulator removal for implant-related pain (2 cases), infection (1 case), metal allergy (1 case), and loss of therapeutic effect (1 case). The complications and stimulator removal incidence rates did not differ significantly between the two groups (P=1.000) (P=0.617) (P=0.875) (The following complications occurred within one year after surgery (cases in the <75-year-old group versus the ≥75-year-old group): lead migration  . Kaplan–P=0.617)  and explP=0.875)  between The evidence available for the effectiveness of conventional drug therapy and repeated surgery for FBSS is weak . On the The <75-year-old and ≥75-year-old groups in this study did not differ significantly in the male/female ratio, symptom duration, and operative duration. This study also showed no age-dependent differences in the treatment outcomes measured as VAS and RR. The data available in the literature about SCS outcomes in patients aged ≥75 years are limited, and there is a paucity of reports on whether age has effects on treatment outcomes. The issue remains controversial because studies report the absence of age-dependent differences in treatment outcomes –28, thosIn recent studies using the stimulator removal rate to evaluate outcomes in patients who underwent SCS, the explant rate ranged from 5.96% to 11.6% , 33–37. As to complications, lead migration is generally most common (15%), followed by lead fracture, malfunction, implant-related pain, and infection (5%–6%) . PercutaNo global consensus about age to define older adults has been established. In this study, the <75-year-old group had a mean age of 63.6 years old and included many subjects who would be classified as older in other studies using a lower age to define older adults. This may explain why there were no differences in treatment outcomes and the device removal rate.The diagnostic label “failed back surgery syndrome” may be considered unsatisfactory, inaccurate, and potentially problematic by medical professionals managing patients with persistent pain after spine surgery. The International Association for the Study of Pain has recommended the use of the term “persistent spinal pain syndrome (PSPS) type 2” as a more appropriate diagnostic label than FBSS. The term PSPS encompasses the various potential symptoms of a syndrome of chronic pain  or recurrent pain of spinal origin, paresthesias, numbness, stiffness, muscle spasms and weakness, and in some cases sphincter dysfunction .Limitations of this study are the absence of functional outcome data, its retrospective nature, the small sample size, and the inclusion of a single center. Functional outcome is a crucial point in the treatment of patients with chronic pain as functional improvement is as important as pain reduction. It was evaluated 12 months after SCS implantation, and it would be of interest to follow patients over a longer period. Moving forward, it is desirable to conduct a prospective multicenter study on the relationships between age and SCS outcomes, along with other potential predictors.In this study, the treatment outcomes and complications after SCS implantation did not differ between the <75-year-old group and the ≥75-year-old group. Since spinal cord stimulator implantation can be performed under local anesthesia and is associated with a low incidence of complications, therefore, SCS can be a highly effective treatment option for FBSS in older adults.


No differences were found in any of the other variables such as diagnosis, pain severity, onset, and treatment outcome. This minimal difference may be explained by the equal accessibility to medical services for all citizens, and the diversity of our staff that includes Jew as well as Arab service providers. These factors minimize or even eliminate racial bias, language, and cultural barriers, and is reflected in the minor differences in orofacial pain characteristics found between the two main ethnic groups in Israel.The relationship between ethnicity and chronic pain has been studied worldwide. The population of Israel includes two main ethnic groups, 75% Jews and 21% Arabs. The purpose of this study was to compare orofacial chronic pain characteristics and treatment outcomes between Jewish and Arab Israeli citizens. Two hundred patients admitted to the Orofacial Pain Clinic at Hebrew University–Hadassah School of Dental Medicine between 2017 and 2022 were selected randomly for this historical cohort study. Our cohort included 159 (79.5%) Jews and 41 (20.5%) Arabs. Twenty-six pain-related variables were compared of which only two differed significantly between the two groups, awakening due to pain and mean muscle sensitivity; both indicators were higher in the Arab group ( Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue injury, often described in terms of such damage . ChronicPain experience can be influenced by ethnic factors like socioeconomic status, expectations language, spirituality, etc. ,7,8,9.There are numerous studies on the relationship between ethnicity and the nature of chronic pain ,11,12,13These studies emphasize the differences in pain characteristics, such as perception, frequency, severity, and spreading, between ethnic groups in terms of population majority vs. minority. Edwards et al.  demonstrIsrael is a multiethnic state known for its heterogenic population, with a majority of Jews (75%) and a minority of mainly Arabs (21%). Previous publications comparing the diagnosis of TMD in relation to Jews and Arabs in Israel revealed no differences regarding pain duration, intensity, and disability period, yet significant differences in chronic pain behavior and disability scores were recorded ,16.The aim of this study is to delve into the distinct features and treatment outcomes of chronic orofacial pain conditions among the Arab minority and Jewish majority populations in Israel. By conducting a comprehensive analysis, this research seeks to shed light on the potential variations in the nature and management of orofacial pain experienced by these two communities.The study was approved by the Ethical Committee Hadassah Medical Center, request no. 329-21. The medical records of 200 OFP patients meeting our inclusion criteria attending the OFP Clinic at the Hebrew University–Hadassah School of Dental Medicine were reviewed. Patients were selected in a quasi-random manner based on their order of presentation to the clinic from February 2017 to June 2022 until the desired sample size of 200 patients was achieved. The number and proportion of Arabs and Jews in the cohort were matched to the population (approximately 75% Jews and 21% Arabs) and therefore the clinical records of 159 (79.5%) Jews and 41 (20.5%) Arabs were further studied. The data were anonymized, with all members of the cohort given a reference number.Inclusion criteria: over 18 years of age; diagnosis of chronic, non-dental-related OFP, for at least 3 months; definite ethnicity; at least one recall visit.The exclusion criteria for this study included patients with orofacial pain lasting less than 3 months, pain due to dental causes, patients with unclear origin or ethnicity, patients with no recall visits, patients with a history of drug abuse, and pregnant or lactating patients. Additionally, patients whose pain was found to have a systemic pathologic cause based on history, examination, or imaging were also excluded. All diagnoses were confirmed in the clinic and later re-examined by the senior author (YH) after data tabulation and summary.Primary and resultant data were taken from the standard intake form used in our clinic ,18,19. DPain characteristics included onset (months); laterality, i.e., whether the pain is unilateral or bilateral; whether the pain is constant, comes in attacks or a combination; pain quality—burning, electrical, pressure, throbbing, and stabbing sharp; pain intensity rated using an 11-point verbal pain scale (VPS), where 0 is no pain and 10 is the worst pain imaginable . Health-Clinical examination included masticatory apparatus palpation, as previously described ,22,23. BMusculoskeletal Group—Temporomandibular Disorders (TMD) based on the diagnostic criteria for temporomandibular disorders (DC/TMD), often associated with pain in the pre-auricular region and/or masticatory muscles, TMJ and mandibular movement dysfunction .Neurovascular Group—including migraine  —neurologNeuropathic Group—Post-traumatic Trigeminal Neuropathy (PTN) , unilatep < 0.05.SPSS software version 22.0 was used for the analysis. Continuous variables were described as means and standard deviations, while categorical variables were described as absolute numbers and percentages. Two-tailed statistical significance (α) level was defined as p < 0.05. The following statistical tests were used for nominal variables, Chi-square significance test was performed, and for ordinal variables, non-parametric Mann–Whitney and Wilcoxon rank tests were performed. For normally distributed continuous variables, t-test and Pearson correlation were performed, and for non-normally distributed variables Spearman correlation and non-parametric Mann–Whitney and Wilcoxon rank tests were used.Descriptive analysis was used for qualitative variables and presented in absolute numbers and percentages . Means aThis study included 200 patients from the two largest ethnic groups in Israel, 159 (79.5%) Jews with a mean age of 48 ± 17.20 years old and 41 (20.5%) Arabs with a mean age of 44.3 ± 15.61. The study included 66 (33.3%) males and 164 (66.6%) females. The Jewish group had 53 (33.3%) males and 106 (66.6%) females, and the Arab group had (31.7%) males and 28 (68.3%) females.The distribution of specific pain diagnoses in each ethnic group is provided in the The only variable that was significantly different between the ethnic groups was total muscle score. The score of (6.0897 ± 9.32023) in the Arab group was significantly higher than that of the Jewish group (2.8547 ± 3.3938).p > 0.05) were both higher than Arab primary VPS and final VPS means . The differences between the groups were not statistically significant; the changes in VPS within each group showed that there were significant improvements from the treatments given for both groups. It is important to note there are other indices for success such as improved function and restored social functioning that were not assessed in this study.When comparing primary VPS and final VPS means, the Jewish primary VPS and final VPS means  (see No significant differences were found between the two ethnic groups for any of the other variables examined (.05) see .During the last two decades, the number of academic publications focusing on the racial and ethnic differences in the experience of chronic has grown . Some stIn light of the inconsistency, we compared the prevalence of a wide range of OFP entities and treatment outcomes between the two main ethnic groups that are citizens of Israel, namely the Jewish population and the largest minority group, the Arab population.Although the differences did not reach statistical significance, neuropathic pain and musculoskeletal pain were more common in the Arab group, whereas the Jewish group had higher incidences of neurovascular pain and TN (12% of Jews versus 2% of Arabs). It is possible that the small sample size caused the statistical insignificance.Pain types, especially with hereditary components, are more common in some populations; for example, migraine prevalence is lower in Asians compared to other ethnic groups . While tThere is a growing body of evidence that ethnicity influences the response to experimentally induced pain . StudiesThis study has several limitations including its retrospective nature and lack of data on socio-economic variables such as education level, income, family status, and employment status. There are several factors that may influence pain characteristics, diagnosis, and treatment in addition to specific ethnicity, such as prior treatments the patients may have undergone, employment status, profession, level of education, marital status, financial status, religious beliefs, etc. However, for the purpose of this study, we have chosen to focus solely on ethnicity-specific factors.Differences in pain characteristics between majority and minority groups may be attributed to expectations for pain relief , social The National Health Insurance program in Israel aims to provide equal access to medical services for all citizens, but there may be variations or limitations in practice.A recently published report noted that the health of the Arab population in Israel is improving at the same rate as the improvements in the health status of the Jewish population, and that the health challenges of populations in the social and geographic periphery of the state are the same for Arabs and Jews .As an academic institution, the Faculty of Dental Medicine of the Hebrew University and Hadassah Medical Center complies with the vision, mission and values of “perceiving diversity as a condition for academic excellence and for realizing the human potential of the Israeli society” and “treating all patients without discrimination or bias, and maintaining fairness and respect for patients and staff members ”. The dental faculty includes undergraduate and postgraduate students and residents of all ethnicities and diversity and, as such, minimal racial bias and stereotyping, as well as language and cultural barriers exist between the patients and the caregivers.In contrast to these findings, we only discovered minor differences in pain characteristics between the Jewish and Arab populations in the current study. These may be attributed to several factors:In conclusion, orofacial pain is a common condition that affects a significant portion of the population of all ages, ethnicities and genders. The demographics of OFP may have an impact on the quality of life, daily functioning, and overall well-being of the individual patient. No significant differences were found between Arab and Jewish population in Israel regarding OFP diagnosis and characteristics. However, pain in general is a complex and multifaceted phenomenon that can be influenced by a wide range of factors, including cultural and social factors, as well as individual differences in pain sensitivity and coping strategies. The study is exploratory in nature, which means that we cannot prove the hypotheses based on the results. While our research provides valuable insights into the potential role of ethnicity in orofacial pain, further research using more specific and systematic methods may be needed to confirm our findings and establish causal relationships.


In complex regional pain syndrome (CRPS), the representation area of the affected limb in the primary sensorimotor cortex (SM1) reacts abnormally during sensory stimulation and motor actions. We recorded 3T functional magnetic resonance imaging resting‐state data from 17 upper‐limb CRPS type 1 patients and 19 healthy control subjects to identify alterations of patients' SM1 function during spontaneous pain and to find out how the spatial distribution of these alterations were related to peripheral symptoms. Seed‐based correlations and independent component analyses indicated that patients' upper‐limb SM1 representation areas display (i) reduced interhemispheric connectivity, associated with the combined effect of intensity and spatial extent of limb pain, (ii) increased connectivity with the right anterior insula that positively correlated with the duration of CRPS, (iii) increased connectivity with periaqueductal gray matter, and (iv) disengagement from the other parts of the SM1 network. These findings, now reported for the first time in CRPS, parallel the alterations found in patients suffering from other chronic pain conditions or from limb denervation; they also agree with findings in healthy persons who are exposed to experimental pain or have used their limbs asymmetrically. Our results suggest that CRPS is associated with a sustained and somatotopically specific alteration of SM1 function, that has correspondence to the spatial distribution of the peripheral manifestations and to the duration of the syndrome. This study demonstrates disturbances in the function and functional connectivity of the primary sensorimotor cortex of complex regional pain syndrome patients, likely contributing to their spontaneous pain. The pain is typically enhanced by limb movements and sensory stimuli  of healthy individuals has unraveled several brain‐networks that are synchronized at low frequencies (<0.1 Hz) as a sign of “functional connectivity” (FC). One example is the sensorimotor network (SMN) that involves the SM1 of both hemispheres  between SM1 representation areas of different body parts, (2) between SM1 and insula, and (3) between SM1 upper‐limb areas and all other parts of the brain, as well as (4) of the SMN in general. We further examined the covariation of the observed FC alterations with pain intensity, spatial extent of pain, motor symptoms, and disease duration.22.1t = 0.36, p = .92, two‐tailed independent sample t‐test). All subjects were right‐handed according to the Edinburgh Handedness Inventory. Twelve patients (71%) had CRPS in their right upper limb and five (29%) in the left one. Table We studied 17 unilateral upper‐limb CRPS type 1 patients  and 19 healthy control subjects ; ages did not differ between the groups (Inclusion criteria for patients were (1) the diagnosis of upper‐limb CRPS type 1, (2) moderate or severe pain at rest or movement , (3) duration of CRPS of >6 months, (4) right‐handedness, (5) age 18–65 years, (6) no other major neurological or psychiatric diagnosis, (7) no drug or alcohol addiction, and (8) no contraindication for MRI. From the pool of 96 CRPS patients treated at the Pain Clinic of the Helsinki University Hospital, and from 19 patients referred to us from other clinics in the Helsinki and Uusimaa district, we invited 35 eligible candidates for examination. From these, 17 patients who fulfilled the inclusion criteria and were willing to participate were included in the study.At the inclusion examination, the patients were interviewed and clinically examined by a neurologist. Sixteen of the 17 patients fulfilled the “research criteria” and one the less stringent “clinical criteria” of CRPS , gabapentinoids (8), nonsteroidal anti‐inflammatory drugs (7), acetaminophen (6), tricyclic antidepressants (5), serotonin‐norepinephrine reuptake inhibitors (3), tizanidine (2), buprenorphine (2), mirtazapine (1), and lamotrigine (1).http://www.dash.iwh.on.ca/home; Hudak et al., To assess motor symptoms, patients completed an upper‐limb‐disability questionnaire  patients and 14 (74%) healthy control subjects were measured with a Signa HDxt 3.0T scanner  with a 16‐channel head coil, and five patients (29%) and five healthy control subjects (26%) with a Magnetom Skyra 3T scanner  with a 30‐channel head coil (modified from the 32‐channel coil to optimize field of vision).2 with no gap, number of slices 50 (GE) or 47 (Siemens). The number of time points was 190. The first four images were discarded to ensure stabilization of the MR signal. During the same scanning session, anatomical high‐resolution 1 × 1 × 1 mm3 T1‐weighted MR images (176 slices with matrix size of 256 × 256) were acquired, using ultrafast gradient‐echo 3D sequences  with TR 10.0/2530 ms, TE 3.0/3.3 ms, flip angle 15°/7° for GE/Siemens.The following parameters were applied for functional T2*‐weighted gradient‐echo echo‐planar images: TR 2.5 s, TE 30 ms, flip angle 75°, matrix size 64 × 64, field of view 24 cm, slice thickness 3.0 mm, in‐plane resolution 3.75 × 3.75 mmDuring the 8‐min resting‐state fMRI measurement, the subjects were instructed to avoid head and hand movements, to remain awake and to keep eyes open and fixated on a cross projected on a screen 34 cm in front of their eyes. Soft padding inside the head coil minimized involuntary head movements. We monitored signs of drowsiness (transient eye closure) with an infrared eye camera . We also monitored hand movements by fixing MR‐compatible custom‐made accelerometers to both hands (Velcro strap around fingers 3–5) and leading the signals to BrainAmp ExG MR amplifiers .2.32.3.1http://www.fil.ion.ucl.ac.uk/spm/software/spm8/), including slice‐time correction, motion correction , and coregistration of the mean functional images with skull‐stripped T1 images. The T1 images were segmented into separate areas of cerebrospinal fluid and gray and white matter; this segmentation was later applied as a structural template in denoising the fMRI data (see below). Finally, the data were normalized to the Montreal Neurological Institute (MNI) anatomical space ; the parameters derived from the normalization of T1 images were applied for the normalization of functional images. The normalized voxels were 3.75 × 3.75 × 3 mm3 in size. Functional images were smoothed with a 6‐mm full‐width at half‐maximum isotropic Gaussian kernel. According to the estimates of the head motion , the maximum translational head motion was <1.5 mm  in all subjects. The time series of translational motion did not differ between the CRPS patients and the healthy subjects . For anatomical validation of the preprocessing, see Supplementary methods We preprocessed the fMRI data with SPM8 (2.3.23) with Mango software (http://ric.uthscsa.edu/mango/). These seven adjacent ROIs covered the SM1 from its dorsomedial to its ventrolateral parts, and each ROI was designed to include a representation area of an anatomically distinct body part, according to the MNI coordinates reported by Roux et al. , the torso , the upper limb from the shoulder to the wrist , two ROIs for the hand , and two ROIs for the lips and face . We mirrored the ROIs on the right SM1 by the brain's midline to create the corresponding left SM1 ROIs. Figure https://neurosynth.org/), see Supplementary Methods For the seed‐based analyses, we delineated 14 regions of interest (ROIs) in the SM1 and one in the right aINS as follows. First, to study FC within the SM1, we manually split the right SM1 into seven similar sized ROIs .Second, to study the FC of the representation area of the upper‐limb with the rest of the brain in seed‐to‐voxel analysis, the ROIs ArmROI) with a radius of 12 mm , we performed two selective analyses to minimize and explore the nuisance effects caused by the heterogeneous lateralization of pain in our patient sample: (1) full‐group comparison with flipped data for the five patients with left upper‐limb CRPS and for five age‐, sex‐, and scanner‐matched healthy control subjects (17 vs. 19), and (2) a subgroup comparison including only the patients with right upper‐limb CRPS .http://www.nitrc.org/projects/conn; Whitfield‐Gabrieli & Nieto‐Castanon, We performed all the seed‐based analyses with standard protocols and tools of the SPM‐compatible CONN toolbox v.18a  and physiological noise estimated with the CompCor method implemented in the CONN toolbox  between the average BOLD signals of selected seeds were calculated subject‐wise. The correlation values were then subjected to Fisher transformation before the second, group‐level, analysis. We studied group FC differences (1) between the SM1 ROIs and (2) between aINSROI and SM1 ROIs. For the former, we analyzed the FC between each pair of the 14 SM1 ROIs (91 comparisons) using CONN toolbox general linear modelling (GLM) implementation, with t‐statistics at the second level. We applied false discovery rate (FDR) corrections for multiple comparisons with a statistical significance level of q < .05. For the latter, we analyzed the FC data between the aINSROI and each of the 14 SM1 ROIs with SPSS to enable flipping only the SM1 ROIs and not the aINSROI. In this analysis, we applied repeated measures 2 × 2 × 7 (GROUP × SIDE × SM1 ROIs) multivariate analysis of variance (MANOVA), and for the effects of disease duration, MSSI and pre‐experiment pain in the patient group, we applied repeated measures 2 × 7 (SIDE × SM1 ROIs) MANOVA.In the first, subject‐level, seed‐to‐seed analyses, the temporal correlations (ROI + Hand2ROI vs. ArmROI). As the measure of the combined effect of pain intensity and extent on FC, we used “pain load,” the product of intensity and extent . We analyzed the effects of pain intensity, extent, and load, as well as of disease duration and motor symptom severity, on the interhemispheric FC with partial correlation in SPSS, while controlling for nuisance covariates  level, temporal correlations were calculated between the average BOLD signal in the seed region and the BOLD signals of each voxel in the gray matter. At the second level of group‐fMRI random‐effects GLM analysis, Fisher‐transformed correlation values were compared between the groups. Voxel‐level statistical significance was set at p < .001 (uncorrected), together with cluster‐level FDR‐corrected q < .05. In addition, as the main analysis of the patient group displayed, intriguingly, increased FC between the left UpperLimbROI and an area in the periaqueductal gray matter (PAG), we used PAG as a seed area in a post hoc seed‐to‐voxel analysis.In the seed‐to‐voxel analysis  on our fMRI data preprocessed with SPM8 and de‐noised with CONN. First, we used FSL's MELODIC tool to decompose the fMRI data of 34 subjects  into 30 group‐level components, using a temporal concatenation approach. Next, we applied the dual‐regression method, which provided subject‐wise spatial maps of beta values describing how strongly each voxel of each subject was associated with each of the 30 group‐level components. We visually identified the group‐level SMN from these components (first component) and subjected the corresponding subject‐wise maps to group comparisons with GLM analysis. The probability of group differences was assessed by permutation testing (5000 permutations). We applied threshold‐free cluster enhancement to correct for multiple comparisons with a threshold of statistical significance of p < .05.To study the functioning of the SMN, we applied a model‐free data‐driven method, the independent component analysis (ICA) as implemented in FSL  limb, we compared, using GLM in SPSS, the subject‐wise dual‐regression mean beta values from the appropriate UpperLimb2.3.4For all analyses, we applied age, scanner (GE/Siemens), and percentage of eyelid closures  as nuisance covariates, and additionally, if applied, flipping of the fMRI data (yes/no).U‐test. We applied PERCLOS as a covariant in fMRI analysis to account for effects of drowsiness on FC. See Supplementary Methods The level of alertness can affect the FC of the sensorimotor and other brain networks , we calculated the accelerometer magnitude vector am, to index hand movement at each time point separately for both hands, with the following formula:ax, ay, and ay are the recorded accelerometer signals in three orthogonal spatial dimensions. As an index of the total amount of hand movements, we applied the mean power of the magnitude vector. To reduce signal artifacts , we filtered the raw accelerometer data to a frequency band of 0.1–8 Hz, which includes the majority of voluntary hand movements  reduced interhemispheric FC between SMI upper‐limb areas, documented by both seed‐to‐seed and seed‐to‐voxel analyses, (2) increased FC of the SMI cortex with PAG and the right aINS, and (3) disconnection of the SMI upper‐limb areas from the rest of the SMN.Before describing our results in detail, we want to note that it is unlikely that the observed abnormalities in fMRI‐detected FC would reflect trivial differences between the groups, for example in vigilance levels or in the amount or timing of inadvertent hand movements. To rule this out, we first demonstrated that drowsiness—quantified by the percentage of eyelid closure during the fMRI recording—did not differ between patient and control groups. Second, we found that the amount and synchrony of inadvertent left‐ and right‐hand movements—monitored with accelerometer recordings—did not differ between the groups. Supplementary Tables 3.1seed‐to‐seed analysis that assessed the FC between the SM1 representation areas of different body parts. Here, the group differences manifested specifically between the left and right hemisphere upper‐limb ROIs  displayed reduced FC between the homotopic left and right SM1 upper‐limb areas. In addition, patients showed reduced FC between the right UpperLimbROI and the right dorsolateral prefrontal cortex (DLPFC). For the group‐specific seed‐based FC maps, see Figure Figure ROI FCs.In the seed‐to‐voxel GLM analyses, none of the factors we studied  correlated statistically significantly with the patients' abnormal UpperLimb3.2ROI and the PAG .In the seed‐to‐voxel analysis, the CRPS patients displayed increased FC between the left SM1 UpperLimbG Figure . In the G Figure . In the G Figure . To explROI and the SM1 ROIs ; post hoc analysis of significant interaction effects indicated that this general effect derived especially from FC with the bilateral Hand1ROI, Hand2ROI, and Face1ROI . This FC did not correlate statistically significantly with pain intensity, pain extent, pain load, CRPS duration, or motor symptom severity.The analyses specifically addressing the relationship of the UpperLimb4Our study on patients with upper‐limb CRPS type 1 revealed multiple alterations in FC of the primary sensorimotor cortex; some of these findings are novel and associated with the clinical features of the patients. Specifically, the patients' interhemispheric FC between homologous upper‐limb SM1 areas was abnormally reduced, corresponding to the peripheral location of the limb pain. This reduction was stronger the higher the patients' spontaneous pain load (intensity x extent of the pain) was. Upper‐limb SM1 areas also displayed reduced FC with the rest of the SMN but increased FC with the PAG. While the patients' whole SM1 showed increased FC with the right aINS, for the hand SM1 this increase was associated with the duration of the syndrome. Figure 4.1In healthy humans, the SM1 shows a prominent interhemispheric FC during rest  and the distributed SMN. To our knowledge, this is a novel finding in patients with unilateral chronic limb pain. For the SM1 corresponding to the painful limb, the reduced FC may reflect nociception or sensorimotor deprivation affecting the SM1 and other parts of the SMN to different degrees. Similar reduced FC has previously been observed in healthy persons under sustained experimental pain  of the rolandic magnetoencephalographic 20‐Hz activity following tactile stimuli  perception, for example distorting the body image, although somatosensory input as such is not modified, and the alteration is considered to emerge within the predictive‐coding framework  and the SMA. Normally, in healthy persons during rest, both PAG–SM1 and PAG–SMA FCs are negative  which then showed FC changes with SM1 subareas that matched somatotopically the peripheral CRPS manifestation . Second, we collected pain ratings before and not during fMRI measurements, limiting our conclusions on the relationship between pain levels and brain abnormalities. Third, although our seed areas should be valid for group‐comparison purposes (see Supplementary Methods 4.7In conclusion, our findings of the decreased FC within SM1 and the strengthened FC between SM1 and the aINS and PAG provide novel insights into the pathophysiology of CRPS. Specifically, our results suggest that the chronic pain reshapes the cortical SMN, with somatotopic emphasis. The observed increase of the alterations with disease duration indicates that some of the effects may be secondary to the chronic pain. As the observed FC alterations may be involved in initiation, maintenance, and manifestation of CRPS symptoms, they might have clinically relevance in the prognosis of the disease and in pinpointing targets for intervention.Jaakko Hotta contributed to the conception and design of the work, the acquisition, analysis, and interpretation of data and drafting the article. Jukka Saari contributed to the acquisition and analysis of data, as well as to drafting the article. Hanna Harno and Eija Kalso contributed to the conception and design of the work, and the acquisition of data. Nina Forss and Riitta Hari contributed to the conception and design of the work, the interpretation of data and to drafting the article. All authors have contributed to critical revision of important intellectual content of the article and approved the final version.The authors declare no conflicts of interest.Prior to participation, subjects gave written informed consent.DATA S1: Supplementary methods.Click here for additional data file.FIGURE S1: Supplementary figures.Click here for additional data file.TABLE S1: Supplementary tables.Click here for additional data file.


Conclusion: Our results demonstrate that pregabalin and duloxetine are effective medications for treating pain in PDPN in more than 86% of all randomised patients.Introduction: Our trial  evaluates the efficacy of two generic medications, pregabalin and duloxetine, for treating pain in PDPN patients. Methods: The patients were randomised either into the pregabalin (99) or the duloxetine (102) arm. Pain was evaluated using the DN-4 questionnaire, and visual analogue scales  were used to measure the average pain intensity (API), worst pain intensity (WPI) in the last 24 h and current pain intensity (CPI). Results: The proportion of patients with a clinically significant improvement in the API at Week 12 was 88.3%  in the pregabalin arm and 86.9%  in the duloxetine arm. After 12 weeks, the CPI, API, and WPI decreased by −35.3 , −37.0 , and −41.6  in the pregabalin arm, and by −35.0 , −36.9 , and −40.0  in the duloxetine arm (all in mm, all  Diabetic polyneuropathy (DPN) is the most common cause of neuropathy worldwide, affecting approximately half of the patients with diabetes mellitus (DM) . PainfulThe prevalence of PDPN varies across studies, affecting between 13% and 63% of patients with DM, depending on the study population and diagnostic criteria ,5. The rPDPN can be debilitating, impacting patients’ physical, psychological, and emotional well-being . PDPN isThe effective management of PDPN requires a stepwise approach that includes accurate diagnostics, glycaemic control, education and counselling on foot care and safety measures, and symptomatic treatment of pain with medicines ,10.The efficacy of pregabalin and duloxetine has been extensively studied. Parsons and Li  includedDue to the high prevalence of PDPN, there is a need for more affordable treatment options. Several reasons exist for conducting a multi-centre study with generic pregabalin and duloxetine to treat PDPN. First, such research can help determine their effectiveness in treating PDPN and identify potential side effects associated with their use. Secondly, it can help to identify which patients may benefit the most from this treatment and whether any factors may influence the effectiveness of the treatment such as age, gender, or severity of the condition. Additionally, it may provide valuable experience to physicians who are managing patients with PDPN and increase confidence in their use among patients and clinical bodies.®). The objectives of the study are to assess the efficacy of both medicines in patients with PDPN; investigate their effect on pain and quality of life (QoL), depression symptoms, cognitive functions, sleep quality and daytime sleepiness; and assess their safety in patients with PDPN. Here, we present the efficacy and safety results of both drugs.We conducted a multi-centre open-label study to evaluate the efficacy and safety of two generic drugs—pregabalin  and duloxetine  were assigned to the study treatment; 201 patients were analysed for main safety endpoints. A total of 201 patients provided sufficient efficacy data for inclusion in the Full Analyses Set (FAS). Out of the 53 (20.9%) patients who were not randomised, 6 (2.4%) patients withdrew their Informed Consent Forms (ICFs), 43 (16.9%) patients were screening failures (SFs), and 4 (1.6%) were classified as other exclusions . Out of the 201 randomised patients constituting the FAS, 158 (78.6%) completed the study , while 43 (21.4%) were prematurely excluded .The majority of patients included in the study were female. The primary objective of our study was fulfilled by 88% of patients who had a clinically meaningful improvement in the 24 h-API after a 12-week treatment in the pregabalin arm . In addiSimilarly, 87% of patients in the duloxetine arm had a clinically meaningful improvement in the 24 h-API after 12 weeks . A cliniAround 80% of patients in the pregabalin arm had a reduction in the 4 wk-API and 4 wk-WPI by at least 30% and/or did not exceed 30 mm between Week 8 and Week 12 . A totalOur results also indicate reduced subacute pain in the duloxetine arm. Almost 80% of patients had a reduction in the 4 wk-API and 4 wk-WPI by at least 30% and/or did not exceed 30 mm between Week 8 and Week 12 . More thIn both groups, approximately 32% of patients experienced non-serious AEs. In the pregabalin arm, the most commonly reported AEs were nervous system disorders and ear and labyrinth disorders. In the duloxetine arm, the most commonly reported AEs were gastrointestinal disorders and nervous system disorders . There w®. The patients in both arms reached primary and secondary goals. In addition, almost 90% of the patients treated with either drug had a clinically significant reduction in acute pain  concentrations, excessive alcohol consumption, vitamin B12 and folic acid deficiency, uncontrolled type 2 diabetes mellitus), we performed an extensive laboratory evaluation at the beginning of the clinical trial.Our study results are similar to those of previously published research, which demonstrated the beneficial effect of pregabalin on PDPN. Derry et al. recently performed a meta-analysis of the double-blind clinical trials evaluating the efficacy of pregabalin . Their rIn our study, patients were recruited from several different countries, similar to the placebo-controlled trials. In addition, compared to the placebo-controlled trials, we evaluated pain parameters such as the API, CPI, and WPI .In addition, our results demonstrate that patients in the duloxetine arm had significantly less CPI, 24 h-API, and 24 h-WPI during and at the end of the clinical trial than at the beginning . When weIn contrast to the previous studies, we also evaluated the effect of pregabalin on subacute pain. Patients from the duloxetine arm in our study experienced a significant improvement in the 4 wk-API and 4 wk-WPI . Such reHowever, directly comparing our results with previous studies is impossible. In previous studies, patients evaluated their pain in one week  or as paIn our study, patients from the duloxetine arm also reported improved chronic pain . HoweverThere are a few studies in which authors evaluated the efficacy of duloxetine and pregabalin in patients with PDPN with regard to disease characteristics; e.g., Ziegler et al. analysed data from three randomised control trials and found no associations between the efficacy of duloxetine and the patient’s age, type or duration of diabetes, severity of diabetic neuropathy, HbA1c baseline levels, or baseline insulin levels. The only significant interaction was related to pain severity, where patients with more severe pain had better treatment outcomes . SimilarThe patients included in this study tolerated pregabalin and duloxetine well. Approximately two-thirds of the patients did not report any AEs, and only 3% had serious AEs.Similar to previous studies, the most common treatment-related AEs in the pregabalin arm were somnolence and vertigo  14,18].,18.14,18One patient who received pregabalin completed suicide. There were five deaths in the previous trials . It is kIn the duloxetine arm, the most common treatment-related AEs were nausea, dizziness, and somnolence , similarDue to therapy-emergent AEs, 13% of patients discontinued the clinical trial, similar to the previous studies . The mosWhile our clinical trial was not explicitly structured to assess the comparative efficacy of the two drugs, it is essential to take into account the potential side effects when determining the optimal treatment for individual patients. For instance, patients with PDPN who also have a history of mood disorders might experience adequate pain relief from either medication. However, prior research indicated that while duloxetine could potentially ameliorate depressive symptoms , pregabaOur study has several strengths. First, it is a multi-centre clinical trial. Second, we included a homogeneous sample of patients with type 2 DM and used a dynamic treatment regime. In this way, we replicated a real-life situation. In addition, we assessed changes in subacute neuropathic pain, which has not been carried out before.As with every study, ours had some limitations as well. First, it was not a double-blind clinical trial, and the achievement of better results compared with the placebo-controlled trials may be partly due to the placebo effect. Another reason may be a different population. However, with well-known benefits from the previous trials, it would be unethical to conduct a placebo-controlled study. Another drawback is that all the patients in our study were white. Therefore, we may not be able to expand our results to other races, and the study results are within our sample’s limits.This study is an interventional, open-label, prospective, international, multi-centre, phase IIIb (Poland)/IV  clinical study. Both generic medications are manufactured by Krka, d. d., Novo mesto, Slovenia. The complete protocol is available at clintrials.gov  ; for detThe protocol originally aimed to have 280 patients complete the efficacy assessments, with a per-protocol population of 160 patients. We assumed a 40% dropout rate for the sample size of 280 participants. The minimum required number of treated participants per protocol was 160. However, due to recruitment challenges during the COVID-19 pandemic, fewer patients were enrolled, and when the required number of patients was reached, we terminated the clinical trial with no effect on sample power. Nonetheless, the study could still provide meaningful results with the same statistical power as initially intended, justifying the early termination.We included men and women aged 18–85 years with PDPN caused by type 2 DM. Acute pain had to be scored ≥4 on the Douleur Neuropathique questionnaire (DN-4) , and theThe clinical trial lasted 12 weeks, similar to previous clinical trials aimed at assessing the efficacy and safety of pregabalin  and duloDuring the screening visit (Visit 1), the investigator conducted laboratory analyses (concentrations of the thyroid-stimulating hormone (TSH), vitamin B12, folic acid, glucose, glycated haemoglobin (HbA1c), pregnancy test for women of childbearing potential), a PDPN assessment (DN-4), a cognitive assessment using Montreal Cognitive Assessment (MoCA) , a medicOn Visit 2 , the investigator assessed the results of the laboratory tests, vital signs, pain intensity, previous analgesic therapy, and concomitant medications.® in all other countries) or the duloxetine arm . The investigator additionally assessed the QoL  [Patients who met all inclusion criteria and did not meet any exclusion criteria were randomly assigned to the pregabalin arm  , sleep q, SF-36)  and Epwo, SF-36) , depress, SF-36) , and advAt Week 1 (7 ± 3 days after Visit 2), the investigator contacted the patients by phone  to evaluate pain intensity and adverse events recorded in Patient Diary 1.At Visit 3 (14 ± 3 days after Visit 2), compliance monitoring was performed, pain intensity was evaluated, and concomitant therapy, vital signs, and adverse events were assessed. The doses of the investigational medicinal product (IMP) were adjusted.At Week 6 (28 ± 3 days after Visit 3), the investigator contacted patients by phone  to evaluate pain intensity and adverse events, which were recorded in Patient Diary 2.At Visit 4 (42 ± 3 days after Visit 3), the investigator conducted a pregnancy test for women of childbearing potential, conducted compliance monitoring, assessed concomitant medications, measured vital signs, evaluated pain intensity, adjusted the doses of IMP, and assessed adverse events. The investigator collected Patient Diary 2.At Visit 5 (28 ± 3 days after Visit 4), the investigator assessed QoL, sleep quality and daytime sleepiness, depression, cognition, and PDPN using various questionnaires. Pain intensity was evaluated using VAS and DN-4, and adverse events were assessed. A pregnancy test for women of childbearing potential was also conducted. Completing all procedures at Visit 5 marked the end of the patient’s involvement in the clinical study.The investigators evaluated current pain intensity (CPI), average pain intensity in the last 24 h (24 h-API), and worst pain intensity in the last 24 h (24 h-WPI) at all visits and phone calls according to VAS. They also evaluated average pain intensity (4 wk-API) and worst pain intensity (4 wk-WPI) in the last 4 weeks at Visit 4 and Visit 5.The full treatment protocol is presented in Efficacy was evaluated using several parameters, such as average pain intensity (according to VAS) in the last 24 h and 4 weeks, current pain intensity, worst pain intensity in the last 24 h and 4 weeks, assessment of peripheral diabetic neuropathy (using DN-4 questionnaire), assessment of cognition (using MoCA questionnaire), assessment of the QoL (using SF-36 questionnaire), assessment of sleep quality and daytime sleepiness (using ISI and ESS questionnaires), and assessment of depression (using MDI questionnaire).The primary study endpoint was to determine the proportion of patients with PDPN who showed a clinically meaningful improvement in pain. Improvement in pain was considered as clinically meaningful if the reduction in 24 h-API was equal to or more than 30% in comparison to the baseline and/or if the 24 h-API did not exceed 30 mm after the 12-week treatment.The secondary efficacy endpoints  were used to determine the proportion of patients with a clinically meaningful improvement in CPI, 24 h-API, and 24 h-WPI separately during all time points; 4 wk-API and 4 wk-WPI at Weeks 8 and 12; mean absolute change from baseline for all time points in CPI, 24 h-API, and 24 h-WPI separately, and in 4 wk-API and 4 wk-WPI for Weeks 8 and 12; the proportion of patients with reduction in pain by 50% or more in CPI, 24 h-API, and 24 h-WPI on all time points and in 4 wk-API and 4 wk-WPI at Weeks 8 and 12; the proportion of patients with pain not exceeding 10 mm (via VAS) in CPI, 24 h-API, and 24 h-WPI at Weeks 6, 8, and 12, and in 4 wk-API and 4 wk-WPI at Weeks 8 and 12; and to determine the mean difference in the DN-4 questionnaire from baseline and Week 12.Safety was evaluated by recording and assessing adverse events (AEs) throughout the study, up to Visit 5. In addition, vital signs  were measured at each study visit, while clinical laboratory tests were conducted at Visit 1, evaluating the concentrations of TSH, vitamin B12, folic acid, glucose, and HbA1c. Laboratory analyses served to verify eligibility of patients and exclude other possible causes of painful polyneuropathies. No further analyses between laboratory parameters and pain were performed.The Full Analysis Set (FAS) was used for primary and secondary efficacy evaluations and safety analyses. However, due to missing values in the patient records, any required data not available for a given patient at any time point from Visit 2 onwards were considered missing data regardless of the reason for the missing data . To address this, multiple imputation (MI) was employed, using specific statistical inference methods designed for MI estimates.Summary statistics were generated for categorical and numerical variables, including the number of patients/observations, frequencies, percentages, mean, median, standard deviation, minimum and maximum, and first and third quartiles. Microsoft Visual Basic for Applications and IBM SPSS 28.0 were utilised for these calculations.®, in managing PDPN. Despite both drugs demonstrating efficacy in managing PDPN, the frequency and nature of adverse reactions might differ between them. This difference could play a role in determining the optimal therapy for each individual patient. This information can potentially benefit doctors and patients by setting expectations for treatment outcomes.The results of our study offer valuable insights into the effectiveness and safety of two generic drugs, Pregabalin Krka and Dulsevia


The purpose of the present observational multicentric prospective study was to evaluate the efficacy and safety of a new infiltration device  based on hydrolyzed collagen in the treatment of rotator cuff tendinopathy.Seventy-one patients (53.3 ± 11.6 years old) affected by rotator cuff tendinopathy were treated in 2021 with two subacromial injections of CHondroGrid at 13 ± 2.9 days apart. The outcomes measured were the visual analog scale (VAS) score , the Constant Score, the Simple Shoulder Test, and patient satisfaction. The outcome variables were measured before each injection, at 1 month and at 6 months after the last injection.P < .001), while the VAS score at rest and during the night had ameliorated by 91% and 87%, respectively (P < .001). The Constant Score and Simple Shoulder Test improved by 32% and 61%, respectively (P < .001). No adverse events were reported.The treatment was significantly effective from the first injection and up to the six-month follow-up. At the last follow-up, the VAS score on movement had improved by 71% (CHondroGrid resulted in a safe and effective treatment in pain relief and for the functional recovery of rotator cuff tendinopathy. The study was conducted in agreement with the Helsinki Declaration. Two centers participated to the study: Poliambulatorio Arcella  and Orthopedics and Traumatology Department, San Martino Hospital . All consecutive patients who referred to each of the participating centers between January 2021 and December 2021, and who were treated with periarticular, subacromial injections of CHondroGrid for painful shoulder, were screened for eligibility.Inclusion criteria were persistent shoulder pain for at least three months, unresponsive to conservative treatments , and clinical diagnosis of RCT or partial thickness tear detected with high field magnetic resonance imaging.Exclusion criteria were previous treatment with subacromial injections of steroids or HA in the previous three months, history of shoulder trauma, age < 18 years old and > 70 years old, complete RC tears, calcifying tendinitis, previous arthroscopic or open shoulder surgery, shoulder instability, adhesive capsulitis, infections or neoplasm, symptomatic cervical spine disease, rheumatoid arthritis or immune diseases, gout and uric acid diseases, severe medical conditions, pregnancy, denied informed consent.CHondroGrid was prepared accordingly to its instruction for use, namely dissolving the 4 mg of product provided in 2 ml of water for injection. All patients received two 2 ml (4mg) ultrasound-guided CHondroGrid injections in the subacromial bursa just above the involved tendon through a lateral or posterior approach. The second injection was performed between 9 and 17 days after the first one .The main measured outcomes were changes in pain severity and functional recovery. Secondary outcomes were patient satisfaction and adverse events.The following variables were collected: demographic data  and medical history (chronic diseases and onset of symptoms); pain severity and functional disability according to the visual analog scale (VAS) score measured at rest, moving, and during the night, Constant Score (CS), and Simple Shoulder Test (SST) recorded just before the first (baseline/T0) and the second (T1) CHondroGrid injections as well as at one-month (T2) and six-month (T3) follow-ups from the last injection; the percentage of patient satisfaction was reported at a six-month follow-up after the last injection.All patients provided their informed consent to treatment with CHondroGrid. The authors followed the ‘Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)’ statement guidelines for observational cohort studies.t-tests. Multiple data comparisons on VAS, CS, and SST at different time points (T0-T3) were performed with the analysis of variance for repeated measures, and the Bonferroni post hoc test was used when indicated. All statistical tests were 2-tailed and statistical significance was defined as P < .001.Statistical analysis was conducted using R . The Kolmogorov-Smirnov normality test was used to examine if variables were normally distributed. Normally distributed continuous data were reported as mean ± standard deviation and categorical variables as numbers and percentages. Comparisons of normally distributed variables were performed using unpaired A total of 73 patients referred to one of the participating centers were treated with periarticular injections of CHondroGrid for painful shoulder during the study period. Among them, two patients were lost to follow-up: one decided to undergo surgery and another received a corticosteroid injection and was, as such, excluded. Therefore, 71 patients were finally included in the analysis.The mean age of the study population was 53.3 ± 11.6 years and 43 (61.6%) patients were female. In 61% (42 patients), the dominant arm was affected by tendinopathy and treated with CHondroGrid. Baseline demographic and clinical characteristics are presented in Overall, CHondroGrid significantly reduced pain severity and improved functional recovery from the first injection. In detail, pain severity at rest was 44% lower after the first application and progressively improved, reducing by up to 71% and 91% at the 1-month and six-month follow-ups, respectively ; Fig. 1.Concurrently, CS and SST improved by 12% and 19% after the first treatment, and up to 21% and 32% at the 1-month follow-up. At the six-month follow-up, the CS and SST had improved by 32% and 61%, respectively . A notewThe whole population comprised patients with different grades of initial pain that had a different initial functionality, which was measured by the SST. We divided the whole population into three groups in order to analyze if CHondroGrid had the same efficacy in the improvement of functionality and pain relief in all types of patients. In particular, we defined a group 1 , a group 2 , and a group 3 . In each group, we analyzed the % of improvement at each time point of the measured variables  see . Interes,The present clinical study is the first study ever published on the efficacy and safety of the use of hydrolyzed collagen in RCT. RCT is the most common tendon disorder of the shoulder, causing pain and dysfunction.The results obtained with hydrolyzed collagen are encouraging. Indeed, our data indicate a pain reduction and functional recovery already after the first injection. The treatment effect increased progressively with the therapy and appeared to be still ongoing even after 6 months from the last injection. At the six-month follow-up, there was a pain reduction of > 70% during movement and of 91% and 87%, respectively, at rest and during the night. In addition, the CS and SST had progressively improved by up to 32% and 61% after six months. The results here presented show that CHondroGrid is effective also in patients with low initial functionality. Indeed, by dividing the whole study population into 3 groups , the SST score at six months had improved by 154% in patients with low initial functionality . In the ,,The results on periarticular use of CHondroGrid presented here are in agreement with the data available on the intra-articular use of CHondroGrid. Indeed, two observational studies have demonstrated its safety and efficacy in the treatment of 90 patients with knee osteoarthritis (OA).Considering that pain reduction is achieved without significant adverse effects, the treatment with hydrolyzed collagen is a valid alternative to corticosteroids. Indeed, although intra-articular corticosteroid injections greatly reduce the risk of systemic undesirable reactions while still obtaining local anti-inflammatory effects, the numerous and potentially severe complications of corticosteroid-induced adverse events should not be underestimated.in vitro and preclinical studies,,,,Other types of treatment based on collagen, following the promising results of ,In fact, intra-articular injections of a γ-irradiated mixture of porcine type I atelopeptide collagen and polyvinylpyrrolidone showed effective results in 10 patients with knee OA.,,,,,,,However, the growing literature about hydrolyzed collagen highlights the major differences compared to native collagen. First, pure native collagen has a complex triple helical structure that needs specific enzymes to be incorporated into the ECM., which it extends toward the reactive oxygen species generated in rotator cuff tendinopathy ,In comparison with native collagen, hydrolyzed collagen has another advantage, namely its antioxidative properties The present study confirmed that CHondroGrid, as observed in the previous studies on knee OA, is efficient and safe in the treatment of rotator cuff tendinopathy and opens the possibility to the treatment of other types of tendinopathy in different anatomical districts.Limitations of this study are the lack of a control group, the limited number of included patients, and the lack of post-treatment magnetic resonance imaging control.Nonetheless, it is one of the largest studies on the periarticular injection of collagen and, more interestingly, it is the first one on the use of hydrolyzed collagen in RCT.It would be interesting to evaluate the efficacy of hydrolyzed collagen in other tendinopathies as well as to compare its efficacy with other treatments.Results of the present study on 71 patients indicate that two periarticular injections of hydrolyzed collagen  administered about 10 days apart are safe and able to reduce pain and improve function at least in a short-term follow-up in the treatment of symptomatic rotator cuff tendinopathy.Furthermore, controlled prospective studies including a higher number of patients should be carried out to compare hydrolyzed collagen effectiveness with other non-pharmacological treatments already available in the clinical practice.Funding: No funding was disclosed by the authors.Conflicts of interest: The authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.