Pain is an important yet undertreated complication of cancer that has been shown to affect patients’ quality of life. For patients presenting in an acute care setting with cancer-related pain, there have traditionally been two routes to management: inpatient or outpatient. However, with the advent of observation units, there is now an opportunity for these patients to utilize hospital resources without an inpatient stay. To better understand the role of an observation unit in pain management, this study analyzed charts for patients who had their pain managed in an observation unit. Patient characteristics and outcomes were statistically analyzed and summarized. Predictors of admission or discharge from the observation unit were also derived from the analysis. Factors that predicted an inpatient hospitalization from the observation unit included patients’ pain scores and the need for consult service recommendations while in the observation unit. Indeed, this research showed that patients in an observation unit for pain management received appropriate consultations and admissions when necessary. However, most were discharged home safely and without a quick return to the acute care setting. p < 0.001) and supportive care  or pain service  consultations. We concluded that an EDOU appears to be the appropriate venue to care for a subsegment of patients presenting to an emergency department with cancer pain, with patients receiving safe care as well as appropriate consultation and admission when indicated.Pain remains an undertreated complication of cancer, with poor pain control decreasing patients’ quality of life. Traditionally, patients presenting to an emergency department with pain have only had two dispositions available to them: hospitalization or discharge. A third emerging healthcare environment, the emergency department observation unit (EDOU), affords patients access to a hospital’s resources without hospitalization. To define the role of an EDOU in the management of cancer pain, we conducted a retrospective study analyzing patients placed in an EDOU with uncontrolled cancer pain for one year. Patient characteristics were summarized using descriptive statistics and predictors of disposition from the EDOU and were identified with univariate and multivariate analyses. Most patients were discharged home, and discharged patients had low 72-hour revisit and 30-day mortality rates. Significant predictors of hospitalization were initial EDOU pain score (odds ratio (OR) = 1.12; 95% CI 1.06–1.19;  Pain is a common concern among patients with cancer, and poor pain control is associated with sleep disturbances and mood disorders . The goaRecommended strategies to improve pain management in patients with cancer have included more frequent reassessments, earlier initiation of pain control with morphine, and appropriate dosing of morphine when administered ,7,8,9. HObservation medicine is an emerging mode of healthcare delivery that can offer patients with cancer pain access to a hospital’s pain management solutions and specialists without an inpatient hospitalization. In cancer-related care, observation medicine is novel; only two ED observation units (EDOUs) have been established in the United States specifically in the service of cancer patients. Previously, however, protocol-driven general EDOUs have been found to be successful in managing other types of pain, specifically chest pain and abdominal pain ,10,11. DA single-center retrospective study was conducted at The University of Texas MD Anderson Cancer Center, Houston, Texas, and included all patients who were placed in the EDOU for pain after visiting the ED between 1 March 2019 and 29 February 2020. Patients were placed in the EDOU during the study’s timeframe only when medically necessary. Patients were placed in observation as opposed to hospitalized inpatient based on the two-midnight rule for Medicare patients and Millman care guidelines for managed care or commercial payers. Screening using these criteria was achieved at the time of treating physician documentation with the assistance of case managers, as was standard during the study period at The University of Texas MD Anderson Cancer Center. Primary oncologists were notified about all placements in the EDOU and, thereby, had an opportunity to change their patients’ plan of care. When the EDOU no longer had bed capacity, patients were placed in observation on their primary service—these patients were not included in this study’s analysis.Excluded were patients aged <18 years, non-cancer patients, patients placed on observation under a primary service outside of the EDOU, and patients for who pain was not the primary reason for observation. Data, including patients’ demographics, clinical and cancer-related data, pharmacy data, and EDOU-related data, were collected from the institution’s data warehouse using Epic SlicerDicer and manual review.Pain was identified as the primary reason for observation based on treating physician documentation. Pain scores were documented on nursing assessments using a verbal rating scale between 0 and 10, where 0 represents an absence of pain and 10 represents the worst pain a patient can imagine. Analyzed data included scores obtained on presentation to the ED and EDOU placement as well as during a patient’s stay in these care areas. The primary outcomes of interest were various patient characteristics and ultimate disposition from the EDOU. We also compared 30-day mortality and 72-hour ED revisit rates for those admitted and discharged from the EDOU. Patients were considered to be established with our supportive care and/or pain service if they had completed at least one appointment with either of those services within 90 days prior to the indexed ED presentation.Patients’ characteristics were summarized using descriptive statistics: counts and percentages were derived for categorical variables; means, standard deviations or medians, and interquartile ranges (IQR) were derived as appropriate for continuous variables. Statistical inference was used to compare different groups, with the chi-squared test or the Fisher exact test used in the analysis of categorical variables as appropriate. Mann–Whitney U tests were used in the analysis of continuous variables, as all the continuous variables failed the normality test. Univariate logistic regression analysis was performed to determine the association between each clinical variable and hospital admission. Relevant variables and statistically significant clinical variables from the univariate analysis were further analyzed using a multiple logistic regression model reporting the odds ratio (OR) with 95% confidence interval (95% CI).http://www.r-project.org, version 4.0.3, accessed on 2 February 2021).The institutional review board of The University of Texas MD Anderson Cancer Center approved this study and granted waivers of informed consent (Protocol DR08-0666). All statistical analyses were performed using R software for Windows  were eventually placed in the EDOU. After application of further exclusion criteria (including pain not being the primary reason for observation), 668 (47.0%) out of the 1420 visits were identified as eligible for analysis . For theThe median age of the final cohort was 59 years (IQR 48–68 years), and the majority were either White (58.5%) or Black (20.0%). Most of the patients in the cohort were women (60.8%). Breast, colorectal, and lung cancer were the most common cancer types, and a few patients (2.7%) had more than one cancer type .Almost half of the patients had a history of hypertension (46.8%). Other frequent comorbidities were diabetes (24.0%) and renal failure (21.0%). Chemotherapy within 30 days prior to the ED presentation was identified in 198 (30.0%) patients, and 89 (13.2%) visits were for patients who had had immunotherapy within 1 year prior to presentation. Almost one-third (30.2%) of the visits analyzed were for patients who were actively receiving radiotherapy, defined as radiotherapy within 30 days prior to the ED presentation. Only 96 (16.0%) and 97 (16.2%) of the patients were found to be established with pain and supportive care services, respectively. In addition, opioids were prescribed within 45 days prior to the ED presentation in more than half of the patients (56.5%).The abdomen (29.0%), back (17.3%), and extremities (15.8%) were the most common locations of identified pain . Chest pp < 0.001). Similarly, 36.7% of patients requiring inpatient admission had a supportive care consultation, in contrast to 25.9% of discharged patients (p = 0.005).Significantly higher proportions of patients who were ultimately admitted to the hospital had received pain service or supportive care consultations compared to those who were ultimately discharged . Specifip = 0.006), and 1.6% of discharged patients died within 30 days of discharge . Though 72 h ED revisit rates were higher in discharged patients compared to admitted patients, they remained low, with only 2.2% of the patients who were discharged after pain management in the EDOU revisiting the ED within 72 h , higher median pain scores during the ED stay (p < 0.001), and higher initial EDOU pain scores (p < 0.001) compared to the patients who were discharged , pain/chronic pain consultation , palliative/supportive care consultation , and prescription of opioids prior to ED presentation  were all associated with hospital admission, after controlling for other clinical variables.Univariate analysis showed that the initial ED triage pain score and the initial EDOU pain score were both associated with hospital admission after EDOU placement. In addition, pain/chronic pain consultation, palliative/supportive care consultation, and prescription of opioids prior to ED presentation were also associated with hospital admission . SimilarThe EDOU appears to be an appropriate venue for the management of uncontrolled cancer pain. Our results showed that most patients suffering from cancer pain who are placed in an EDOU for pain management can be safely discharged. Discharged patients have low ED revisit rates within 72 h as well as low 14-day and 30-day mortality rates after discharge from an EDOU. In fact, the 72 h rate of return found in this study (1.3%) is notably lower than what was observed in a study examining revisit rates in a general EDOU . The lowThough the authors were unable to find another descriptive analysis of patients placed in an EDOU for pain as a primary concern, this study’s results were in line with several other publications exploring the characteristics associated with cancer-related pain. One such chart review of mostly gastrointestinal and lung cancer patients found that factors associated with more difficult-to-control pain included having a gastrointestinal tumor and severe baseline pain . SimilarWe also demonstrated that patients who were admitted to the hospital from the EDOU were more likely to have had supportive care or pain service consultations during their EDOU stay, indicating that their pain may have remained more intense or been more intractable than that experienced by patients who would eventually be discharged. Indeed, patients who were ultimately hospitalized had higher median pain scores during their ED visit and higher median pain scores during their EDOU stay compared to those who were discharged. Initial pain scores in both the ED and EDOU were also higher among patients who were eventually admitted to the hospital compared to those who were discharged. Multiple other studies similarly demonstrate that initial pain intensity is the most important domain in predicting successful pain management, with increased intensity being associated with a longer time to adequate pain control ,16. It iIn a large study by Knudsen et al., initial pain control was an important predictor of improved pain relief in patients with breakthrough cancer pain , indicatOur study’s data reflected the wide range of cancers that patients presenting to an emergency department with pain are often diagnosed with and distinguished between various cancers in its analyses. Unlike a study by Wang et al., which showed that gastrointestinal cancer was an independent risk factor for poor treatment outcomes in 3 days, our study found that the type of cancer a patient was diagnosed with did not have a significant impact on whether they were admitted or discharged from an EDOU, a decision generally made in approximately 1 day after placement in our EDOU . WhereasThis difference in findings may be related to differences between the populations analyzed in our study vs. the study conducted by Wang et al. While Wang et al. reviewed the charts of patients with an inpatient hospitalization for cancer pain, our study reviewed the 13.6% of patients presenting to the ED with pain as a primary concern who were placed in an EDOU . Though Pain-related ED visits have historically been and continue to be common among patients with breakthrough oncologic pain ,17. As eMany patients in our study population who were placed in an EDOU for pain management required this placement despite outpatient management, as almost one-third of the patients analyzed were already seeing supportive care and pain service specialists outside of the hospital . Given tAs there are only two cancer-specific EDOUs in the world, our study was limited to a single-center trial. However, as our study site routinely treats a large number of patients with a wide variety of cancers who have received a diverse range of treatments, the external validity of our study’s findings may only be minimally affected by the single-center cohort we analyzed. Our study bears the same limitations that other retrospective chart reviews bear, with the data being limited by real-time record-keeping practices. For example, we were not able to confirm the performance status of every patient in the study, instead relying on a patient’s need for supportive care or chronic pain service involvement to infer the impact of their disease on quality of life. However, our data about morbidity and mortality were robust, as patients presenting to our ED were likely to also be followed by MD Anderson Cancer Center specialists in the outpatient setting. This is supported by the fact that many of the patients in our study were followed by our supportive care and pain services prior to presentation.The scope of this study was defined by data from patients who were already placed in an EDOU, limiting our analyses to patients who were selected by treating physicians for observation as opposed to admission or discharge. It is, thereby, outside this study’s scope to delineate if patients with specific cancers, comorbidities, or other characteristics are more likely to be directly admitted or observed upon initial presentation to the ED. Further research comparing these factors for patients who were directly admitted to the hospital from the ED when presenting with pain with the same factors for those who were placed in an EDOU may help inform predictive decision-making for physicians and hospital systems deciding which patients with oncologic pain should be placed in an EDOU. Social factors were also outside the scope of this study, as socioeconomic well-being and a patient’s ability to follow up were not parsed out in our analysis. Further study on the effect these factors have on cancer-related care is important because a patient’s socioeconomic well-being may affect their ability to get outpatient follow-up and advanced care. This, in turn may have an effect on the rate of ED revisits within 72 h of discharge from an EDOU as well as the 30-day mortality rate in patients with fewer financial resources.EDOUs are capable of successfully managing a subsegment of patients presenting to an emergency department for acute oncologic pain, with low 72-hour ED revisit and 30-day mortality rates. Though the most frequent types of cancer among patients presenting with pain are gastrointestinal, breast, and lung cancers, the type of cancer a patient has is not significantly associated with the patient’s disposition from an EDOU. A majority of patients cared for in an EDOU are successfully discharged, with hospitalized patients more often requiring supportive care or pain service consultations prior to admission. Our findings suggest that EDOUs offer a more appropriate care environment than immediate admission or discharge for patients who require significant cancer pain management but may not require inpatient hospitalization for their therapy.


Open hemorrhoidectomy is one of the standard procedures for grade IV hemorrhoids. Postsurgical pain is a common problem for patients. We aim to prospectively evaluate potential factors affecting postoperative pain among hemorrhoidectomy patients.An observational study was conducted on 360 patients who had undergone Milligan-Morgan open hemorrhoidectomy. Details of the surgery and baseline information were recorded. Preoperative anxiety and depression were analyzed via the self-rating anxiety scale 20 (SAS-20) and self-rating depression scales 20 (SDS-20), respectively. Postoperative pain score was performed daily after surgery until the patient was discharged. The numerical pain score was evaluated by the visual analogue scale (VAS). The association between preoperative psychological states (anxiety or depression) and postoperative pain was analyzed using a generalized additive mixed model.p = 0.025).A total of 340 patients eventually provided complete data and were included in our study. The average age was 43.3 ± 14.4 years, and 62.1% of patients were women. In total, 14.9% of patients had presurgical anxiety and 47.1% had presurgical depression. Postsurgical pain reached a peak point 1–2 days after surgery and went down to a very low level around 4–5 days after surgery. More excision of hemorrhoids could lead to more pain experience after surgery. Presurgical depression was associated with postsurgical pain. Patients who had presurgical depression had higher pain scores after surgery (2.3 ± 1.9 vs. 3.3 ± 1.9, Preoperative depression and the amount of excisional hemorrhoids are positively related to postsurgical pain. Hemorrhoid disease is one of the most frequent complaints affecting a large population. In China, the prevalence rates were around 18% in the elderly population . AccordiPrevious studies have shown that emotional distress, such as presurgical anxiety and depression, is positively correlated with postsurgical outcomes , 13. In We initiated this observational study to analyze which factors could affect subjective pain after surgery. Both the subjective and objective factors were taken into consideration. We aimed to figure out factors related to the degree of postsurgical pain. With the findings, we could predict the degree of pain after hemorrhoidectomy for everyone. Personalized pain management could then be adopted.This is a prospective study. From January 2019 to December 2021, 740 patients with a symptomatic fourth degree of hemorrhoids underwent Milligan-Morgan open hemorrhoidectomy. Patients who did not reach fourth-degree hemorrhoids were excluded. All patients had signed written informed consent. The local ethics committee and departmental internal review board approved this study. Patients who could not cooperate with data collection or had other postsurgical complications were excluded. Patients who had used opioids before admission to the hospital were excluded. Incidences of complications during the hospital stay period were recorded. Patients with serious complications shortly after surgery were excluded. Finally, 360 patients finished the study and provided eligible scales. Details are shown in This is an observational study. Symptom onset, pain score, analgesic consumption, duration of hospital stay, and complications were recorded. A detailed preoperative consultation with a comprehensive information booklet for hemorrhoidectomy was provided to all the patients. The same surgeon performed all surgery. We did not use local anesthesia before surgery. The number of removed packs is listed in To assess whether psychological factors play a role, all patients were asked to finish the anxiety and depression questionnaire before surgery. Self-rating anxiety scale 20 (SAS 20) and self-rating depression scale 20 (SDS 20) were used to quantify the psychological status. High score values indicate high levels of anxiety or depression. By referring to the Chinese national norm, an SAS score <50 was considered normal for anxiety . An SDS Postsurgical pain was assessed every day after surgery. The visual analogue pain score system was used . Every dhttp://www.R-project.org; The R Foundation) and EmpowerStats version 2.20 . A P-value <0.05 was considered statistically significant (two-sided tests).Baseline characteristics are presented as means ± SDs for normally distributed variables, medians (interquartile ranges) for non-normally distributed variables, and frequencies and percentages for categorical variables. Analysis of variance, the Kruskal–Wallis rank test, and the chi-square test were used to compare characteristics, clinical data, and postoperative pain scores where appropriate. In this study, longitudinal data were postoperative pain scores over time. The longitudinal changes in postoperative pain scores were analyzed using the generalized additive mixed model (GAMM), which is ideal for longitudinal data analysis because it is easy to accommodate unbalanced and unevenly spaced observations , 21. In Finally, 340 patients provided qualified VAS scores and SAS/SDS questionnaires without any postsurgical complications. The VAS system was used to quantify the pain degree. Pain score was the highest on the first day after surgery and slowly decreased afterward. On days 4–5, the degree of pain returned to a very low level. Patients were usually discharged on the fifth day after surgery. Details are shown in p = 0.006; day 3: 1.5 ± 4.4 vs. 2.5 ± 1.2, p = 0.03). Details are shown in The total amount of oral analgesic consumed by the patients after surgery was recorded. Patients with anxiety took a higher amount of pain killer 2–3 days after surgery . There were no significant differences in terms of pain scores between patients with and without anxiety. On the third day after surgery, patients with depression had significantly higher pain scores .The preoperative feeling of anxiety and depression was evaluated by SAS 20 and SDS 20. Before surgery, in 340 patients, 51 patients (14.9%) had abnormal levels of anxiety. A total of 160 patients (47.05%) were assessed to have depression. Details are shown in We recorded the number of excisional hemorrhoids. We also studied the educational background, alcohol/tobacco consumption, and clinical symptoms such as prolapsus and hematochezia. Patients who underwent more hemorrhoid excision had higher pain scores after surgery. No differences were found in terms of other factors. Details are shown in β: −0.52; 95% CI: −0.63 to −0.41; p < 0.001) and fully adjusted model . In the crude model (model 1), compared with patients without depression, those with depression have higher postoperative pain. However, it was not statistically significant . In model 2 adjusted for age, sex, education, and patients with depression were independently and significantly associated with postoperative pain . In the full model (model 3), further adjusted fo the number of excisional haemorrhoids, the association between depression and postoperative pain was close to the margin of statistical significance . However, we did not observe significant anxiety and postoperative pain in all models. Details are shown in The GAMM model showed that the postoperative pain score decreased significantly with time in the crude model  were excluded. We found that the pain score was highest on the first day after surgery and slowly decreased afterward. The GAMM model showed that the postoperative pain score decreased significantly with time in the crude model. There are no significant differences in terms of pain scores between patients with and without anxiety. However, patients with anxiety took higher amounts of pain killer 2–3 days after surgery. On the other hand, patients with depression had significantly higher pain scores on the third day after surgery than others. In the fully adjusted model adjusted for age, sex, education, and the number of excisional hemorrhoids, we still found that patients with depression were independently and significantly associated with postoperative pain. Together, our data suggested that depression could promote postsurgical pain after Milligan-Morgan open hemorrhoidectomy.https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower.html). Considered an effect size (f) of 0.30, error probability alpha of 0.05, power (1 – error probability beta) of 0.90, the number of groups of 2, the number of measurements of 5, a correlation among repeated measures of 0.5 for F tests (ANOVA: repeated measures), the calculated total sample size was 74. We finally had 340 patients. In addition, a post hoc power analysis was conducted by using the same statistical software. Considering an effect size (f) of 0.30, error probability alpha of 0.05, the total sample size of 340, the number of groups of 2, the number of measurements of 5, a correlation among repeated measures of 0.5 for F tests (ANOVA: repeated measures), the calculated power (1 – error probability beta) was 0.95. Thus, based on the results of priori power analyses and posthoc power analyses, we believe that this study has an adequate sample size.Before we started this research, we analyzed the sample size using statistical Software G*Power 3.1.7 for Windows . This finding was not surprising because more excisional hemorrhoids would lead to more surgical trauma in the local site. Also, this would cause postoperative spasm of the anal sphincter and leave the inflammation reaction around the anal. Thus, unlike malignant diseases, the surgical concept for hemorrhoids should be as less as possible. Also, we validated the affection of pre-surgical symptoms, such as hematochezia and prolapsus. Moreover, the results were negative.We found that patients with fewer excisional hemorrhoids had less pain 1 and 2 days after surgery  was usually 4–5 days after surgery. The LOS varied very much due to the different situations in different countries. Some surgeons even showed that the LOS could be nearly a month . Other rThere are several limitations to our study. First, we only record the pain score of hospitalized patients. Thus, we lack the related data when patients were discharged. Second, this is an observational study, and there is no additional intervention treatment. More study is required to figure out advanced therapies. Also, patients with different expectations of the operation may have different readouts in terms of pain degree. As a result, the pain score from the patients may not be very accurate. To weaken the affection, we only recorded the data on patients with symptomatic fourth-degree hemorrhoids. Still, this is not objective enough and advanced methods are required for further study. In addition, there are now advanced devices to help reduce postsurgical pain and there are many reports. In our study, due to the restriction of medical insurance and Diagnosis-Related Groups (DRGs), we only use the normal high-frequency elytrotomy. The results may change when an advanced device is adopted.In conclusion, our study suggested that the amount of excisional hemorrhoids correlates with the pain of postsurgical pain. In addition, psychological states could also affect the complaints of postsurgical pain. Presurgical depression could increase the degree of postsurgical pain.


Arthritis of the basal thumb is a relatively common condition also affecting younger patients. Wilson et al. described a 20°–30° closing wedge osteotomy of the first metacarpal bone to unload the trapeziometacarpal joint. It was the purpose of this study to analyze the clinical and radiographic outcome of patients who underwent proximal extension osteotomy of the first metacarpal bone using patient-specific planning and instruments (PSI).All patients who underwent proximal metacarpal osteotomy for basal thumb arthritis at our tertiary referral center were retrospectively included. The patients underwent preoperative planning using computed tomography and 3D segmentation to build patient-specific guides and instruments for the operative treatment. Stable fixation of the osteotomy was achieved by internal plating. The inclusion criterion was a minimum follow-up of 1 year with clinical examination, including the Michigan Hand Outcomes Questionnaire (MHQ), and computed tomography to validate the correction. Complications and reinterventions were recorded.A total of eight Wilson osteotomies in six patients could be included at a mean follow-up duration of 33±16 months . The patients were 49±8 years  at the surgery and 88% were female. The postoperative MHQ for general hand function was 77±8  and the MHQ for satisfaction was 77±28 . The working status was unchanged in 7/8 hands (6/7 patients). Radiographic analysis revealed successful correction in all cases with unchanged Eaton–Littler stage in 7/8 hands. No complications were recorded.The combined extending and ulnar adducting osteotomy using patient-specific guides and instrumentation provides an accurate treatment for early-stage thumb arthritis.Type IV—retrospective, therapeutic study.The online version contains supplementary material available at 10.1007/s00402-022-04430-4. Arthritis of the basal thumb is a relatively common condition also affecting younger patients . A prevaWilson et al. described a 20°–30° closing wedge osteotomy of the first metacarpal bone to unload the trapeziometacarpal joint . The autDespite the promising outcome data reported, no study analyzed the achieved osteotomy using computed tomography. All existing studies have planned the osteotomy to be performed only indirectly based on the thickness of the wedge to be removed. Further, no studies using patient-specific planning and instruments (PSI) exist so far. We always performed a 20° extending and 5° ulnar adducting osteotomy according to a former 3D analysis of the first carpometacarpal joint, aiming to achieve an optimal joint surface contact in pinch grip position without disturbing ROM in Flexion.Therefore, this study aimed to describe and analyze the accuracy of utilizing PSI to achieve the planned amount of correction and orientation of the closing wedge osteotomy and report clinical and radiographic outcome measures. We hypothesized that the planned osteotomy could be achieved using PSI with satisfying patient-reported outcomes measures following surgery.This study was approved by the cantonal ethics committee of the University of Zurich (Switzerland) (ID 2020-01888) and conducted following the Helsinki Declaration.All patients who underwent dorsal extension/ulnar adduction osteotomy of the first metacarpal bone for basal thumb arthritis between 2016 and 2018 at our tertiary referral hospital were retrospectively included in the analyses. The inclusion criteria were early-stage basilar osteoarthritis graded as Eaton and Littler  stage 1 The patients underwent computed tomography  of the hand in 0.5 mm slice increments before surgery. All hand scans were three-dimensionally segmented using a standard segmentation software and algorithm . Consecutively, a dedicated planning software  was used to plan the osteotomy and create the PSI guides as previously described in the literature . Those gAll patients underwent surgery by a senior consultant in hand surgery in a standardized manner. The first metacarpal bone was approached dorsally to position the PSI osteotomy guides Fig. . K-wiresPostoperative care consisted of wearing a cast for 4–6 weeks before functional training. Return to sports was allowed from 8 weeks postsurgically.The patients underwent a standardized clinical and radiographic evaluation at a minimum follow-up period of 1 year. One senior hand surgeon (L.R.) conducted a clinical assessment evaluating the overall outcome using the Michigan Hand Outcomes Questionnaire (MHQ) , the ranThe MHQ is a self-reported questionnaire evaluating the six main categories of overall hand function, activities of daily living, pain, work performance, aesthetics, and patient satisfaction. Each item ranged from 0 to 100, with higher values indicating better results, except for pain. On the pain scale, higher values described more pain.All patients received a second computed tomography  postoperatively and three-dimensional (3D) models were segmented as described above. Consecutively, the segmented bone models were compared to preoperative models using a recently published 3D displacement description method . This mep < 0.05.Descriptive statistics are given as mean ± standard deviation . Preoperative and postoperative ordinal ranked data were compared using Wilcoxon rank sum testing. The significance level was set to Eight osteotomies in six patients were performed. Postsurgery, the mean follow-up period was 33 ± 16 months . The basic demographic data are presented in Table All eight cases could be clinically analyzed postoperatively. The detailed data are displayed in Table Radiographic outcome analysis is displayed in Table p = 0.317).  experienced a relapse of pain 10 months postoperatively without any traumatic event. He was further unable to continue his work as a heavy manual laborer. Nevertheless, a subjective pain reduction of 40% compared to preoperative could be achieved. Further injections to the joint could not improve the pain, neither could a resection of a symptomatic os sesamoideum. Interestingly, the patient was rated as Eaton-Littler-Stage I without progression.Four reintervention surgeries were performed, of which three were the removal of the plate and one resection of symptomatic os sesamoideum in the patient with the lowest postoperative MHQ score.The proximal closing wedge osteotomy for basal thumb arthritis was described by Wilson et al.  to unloaWe report the clinical and radiographic outcome of 8 extension osteotomies of the first metacarpal bone using PSI to treat basal thumb arthritis. The osteotomies were performed in 20° extension and 5° ulnar adduction to achieve an optimal joint surface contact in pinch grip position without disturbing the range of motion in flexion. The patients reported satisfying results with substantial improvement comparing the preoperative to postoperative state at a mean follow-up duration of 33 ± 16 months . The mean postoperative overall MHQ was 77 ± 18 and the MHQ pain score 24 ± 23 or VAS 2 ± 2. MHQ patient satisfaction reached 77 ± 28. The radiographic analysis of the osteotomy using computed tomography and three-dimensional analysis revealed an average osteotomy angle of 17°, deviating 4.2° from the plan. The mean height of the osteotomy was 4.1 mm with a deviation of 0.9 mm from the plan.We demonstrated the achievement of the planned osteotomy using PSI to carry out the desired osteotomy. No study in the current literature analyzed the outcome of the osteotomy using computed tomography. A previously published study  for corrThe clinical results of our study are comparable to the current literature, which is heterogeneous regarding surgical techniques and outcome analyses. The satisfaction mainly reached 70% to 90% according to the respective study , 7, 9–12The basal thumb joint's osteoarthritis stage progressed very slowly. According to the Eaton and Littler stage, only 1/8 (13%) went from stage 1 to stage 2. This fact may be explained by the short follow-up period of our cohort with 2.8 ± 1.3 years. Other authors described progression rates ranging from 38% at 9 years  and 10 yThe complication rate in our cohort was very low. These results might be related to the surgical technique of internal fixation using a plate. Most authors , 11, 12 The corrective osteotomy of the first metacarpal bone has to be discussed in comparison to other surgical techniques, especially the trapezium resection arthroplasty with or without tendon interposition. This technique is described as standard procedure in late-stage basilar thumb arthritis (Eaton-Littler III/IV) with satisfying long-term results , 22. ComOur study has several limitations. First, the study had a retrospective design with all the inherent biases. Secondly, no preoperative scores were available for comparison with the achieved results. Thirdly, we only reported on a small group of eight osteotomies with a minimum follow-up of 1 year. That might be explained by the new PSI technology, which we started using roughly 3 years ago for this relatively rare indication. Nevertheless, we decided to analyze these data with a minimum follow-up of 1 year to provide this knowledge and draw attention to the technique's strengths. Most of the studies in the current literature provide similar small patient numbers.The proposed modification of the Wilson osteotomy using patient-specific guides and instrumentation provides a safe and successful treatment for early-stage arthritis of the thumb with low complication and reintervention rates. The combined dorsal extending and ulnar adducting osteotomy was performed with high accuracy in all patients and resulted in satisfying patient-reported outcome measures.Supplementary file1. Table S1: Individual Michigan Hand Outcomes Questionnaire (MHQ) for each hand.Supplementary file2. Figure S2: Presents the computer tomography of patient number 8 preoperatively and postoperatively.Below is the link to the electronic supplementary material.


Pediatric patients with cancer experience significant distress from both treatment and cancer-related pain. Careful selection of an analgesic regimen should be based upon individual patient factors, including the level of pain, response to therapy, and physiologic profile. Refractory pain is a therapeutic dilemma frequently encountered in the pediatric cancer setting. Systemic lidocaine infusions have been described as both safe and efficacious, as prior studies show patients reporting decreased pain scores and improved quality of life after lidocaine treatment. Given the favorable side effect profile of lidocaine, it has the potential to be considered for analgesia in the setting of refractory pain. This review discusses the use of systemic lidocaine infusions for analgesia in pediatric oncology patients with cancer-related pain. Among pediatric patients with cancer, pain carries significant morbidity before, during, and after treatment into survivorship . In addiTreatment for cancer-related pain in pediatrics is based upon three important considerations and goals published by the World Health Organization. These include preventing pain, maximizing ease of administration of pain control, and the ability of treatment options to be tailored to the patient ,7,8,9. OGabapentinoids are frequently used to treat neuropathic cancer pain; however, these drugs are only available by mouth, which precludes their use in cases of severe mucositis following chemotherapy ,13. SimiIn the pediatric oncology population, ketamine is a useful analgesic adjunct that acts as an NMDA-receptor antagonist. While its side effect profile does not include respiratory depression or physical dependency that is associated with opioids, ketamine is associated with other adverse effects, including hallucinations, anxiety, stimulation of the cardiovascular system, and vomiting ,18. AddiLidocaine is an amide local anesthetic that is approved for use as an intravenous injection . It workThe practical application of intravenous lidocaine has been described in previous literature ,25. In tThe careful selection of an analgesic regimen should be based on individual patient factors, including the level of pain, response to therapy, and physiologic profile. Therefore, it is equally important to recognize the contraindications for the administration of systemic lidocaine infusion. The safety and efficacy of systemic lidocaine infusions in pediatrics have mainly been evaluated using retrospective reviews and case studies. However, one prospective, randomized, double-blinded study in children was performed by Batko et al. . Forty-oA retrospective study by Mooney et al., evaluating 15 adolescent and young adult patients with chronic and refractory pain, established the wide range of analgesic indications for intravenous lidocaine infusions . The indIn another single-center retrospective observational study by Ayulo et al., the safety and efficacy of intravenous lidocaine were evaluated in pediatric patients with status migraines . Twenty-Additionally, neuropathic pain is a common effect of both the cancer diagnosis itself and the side effects of chemotherapy and surgery. Achieving neuropathic pain relief can be difficult. Subcutaneous and intravenous lidocaine administration has been shown to help alleviate cancer-related neuropathy in some cases ,30. In aDosing for systemic lidocaine infusions has varied among reporting institutions in the literature, and there is no established standard dose in pediatrics. As noted above, lidocaine does seem to be well-tolerated, with minimal adverse events and minimal correlation between dose and occurrence of side effects. In some institutions, lidocaine was first administered as a bolus (2.9 ± 0.18 mg/kg), followed by an infusion at a mean rate of 1.29 ± 0.2 mg/kg/h . In the A common dilemma when administering a medication to pediatric patients without a well-established dose recommendation is serious adverse effects. Fortunately, few serious side effects have been reported, and most patients who experienced them had other confounding characteristics. One patient experienced orthostatic hypotension requiring a fluid bolus and brief epinephrine infusion in the intensive care unit . In thisBased on animal studies and adult patient trials, there is a known risk for seizures in pediatric patients receiving lidocaine infusions; however, the dose that lowers the seizure threshold is unknown. Berde et al. extrapolated from previous data that an infusion rate > 2 mg/kg/h or plasma concentrations of lidocaine > 6 μg/mL could result in an elevated risk of seizures . In the Cardiotoxic effects have been described at higher levels (10–30 μg/mL) and include cardiac arrhythmias, heart block, myocardial depression, and cardiovascular collapse ,34. In oN-deethylation of lidocaine, which is mediated by cytochrome P-450 (CYP) enzymes CYP1A2 and CYP3A4 [Lipid emulsions have been used to lower lidocaine plasma levels in the event of toxicity . The stud CYP3A4 ,41. ThisCancer-related pain can manifest in many ways and is frequently chronic. When opioids no longer have the desired effect or contribute to serious unwanted effects, other pain relief options to pursue include sedatives, ketamine infusions, and a regional anesthetic of a neural blockade, as described previously. Acknowledging that refractory pain is distressing for many reasons, including psychological well-being and quality of life, appropriate care may include the use of these other options for cancer-related pain. Apart from these adjuvants, bolus and continuous infusions of intravenous lidocaine have also been demonstrated to be efficacious in pediatric patients with cancer .A retrospective study at St. Jude Children’s Research Hospital by Anghelescu et al. reviewed 29 hematology and oncology patients who received a total of 78 intravenous lidocaine infusions over a 10-year period . Pain scOne case series described four pediatric patients with advanced-stage solid tumors with histories of multi-modal pain treatments who were given intravenous lidocaine . Three oIn pediatric oncology, new therapies can present new side effects—patients with high-risk neuroblastoma now have the benefit of being treated with anti-GD2 targeted therapies. However, due to the nature of the drug’s target—nervous tissue—adequate pain control can be difficult to achieve. A known side effect of this antibody is pain, typically in the extremities, back, and abdomen ,46. CommA recent review was published evaluating articles with a combined seventy-three total patients who were treated with lidocaine parenterally for their complex, cancer-related pain . Among tFor many patients with a cancer diagnosis, surgical procedures are a guaranteed part of their treatment plan and a common cause of pain. Pain management in the postoperative period is typically multi-modal and dependent on the type of surgery, patient characteristics, and patient goals. Systemic lidocaine has been used in a multi-modal approach in adults post-operatively with promising results ,50,51. TLastly, advanced-stage cancer can cause considerable, refractory pain. In one case report of a young girl with end-stage, metastatic, recurrent retinoblastoma, the providers found that despite intravenous opioid rotation, the patient had refractory bone pain . She wasRefractory pain is a therapeutic dilemma frequently encountered in the pediatric cancer setting. The existing literature suggests that the use of intravenous lidocaine infusions in pediatric patients is safe and effective in treating cancer-related pain—particularly as an opioid-sparing adjuvant.There were several limitations to the review of the existing literature on children. Most of the studies were either case reports or retrospective studies, and only one prospective, randomized, double-blinded study was performed among pediatric patients. Another challenge is the lack of a standardized and unified way to measure pain. One review of the literature recognized that none of the articles analyzed used a validated measure of pain . While eRandomized, controlled clinical trials would also help establish an official recommended dose in pediatric patients to assess the analgesic effect and the safety of lidocaine. The primary outcome measure of paramount importance is a validated measure of pain. Secondary outcomes important to capture include adverse events and the change in the quality of life after the use of lidocaine infusions. Multicenter studies could increase the power of statistical analysis to effectively measure and analyze pain reduction and adverse effects.Refractory pain is a therapeutic dilemma frequently encountered in the pediatric cancer setting. The careful selection of an analgesic regimen should be based on individual patient factors, including the level of pain, response to therapy, and physiologic profile. The existing literature suggests that the use of intravenous lidocaine infusions in pediatric patients is safe and effective in treating cancer-related pain—particularly as an opioid-sparing adjuvant. Future prospective studies and randomized controlled trials comparing current practices with lidocaine infusions as adjuvant analgesic therapy in the pediatric oncology population would further elucidate the role of systemic lidocaine in this setting.


All children were anesthetized with sevoflurane, propofol (2–4 mg/kg), and fentanyl (2 mcg/kg). Postoperative pain was assessed using the Visual Analogue Scale (VAS), the Wong–Baker Faces Pain Rating Scale, and the Face, Legs, Activity, Cry, and Consolability (FLACC) scale. The postoperative pain was measured 1, 2, 4, and 6 h after the surgery. Results: The clinical trial reported a statistically significant correlation between administering pre-emptive analgesia (acetaminophen) and reducing pain in children after otolaryngological procedures compared to placebo. The ratio of boys to girls and age were similar among the groups (p > 0.05), so the groups of children were not divided by gender or age. Conclusions: Standard pre-emptive analgesia reduced the severity of pain in the postoperative period after otolaryngological procedures in children. Acetaminophen given before surgery reduces postoperative pain in children undergoing otolaryngological procedures.The aim of this randomized, controlled trial was to determine whether children undergoing otolaryngological procedures  benefit from pre-emptive analgesia in the postoperative period. Methods: Fifty-five children were assessed for eligibility for the research. Four children refused to participate during the first stage of the study, leaving fifty-one ( Adenoidectomy, tonsillectomy, or adenotonsillotomy are some of the most commonly performed surgeries in children all around the world. Tonsillectomy consists of the complete removal of the tonsils , but it Postoperative analgesia in pediatric patients undergoing tonsil surgery is a subject that has been widely discussed by ENT  specialists for years. The basic goals for surgical centers are painless hospitalization with a focus on a short hospital stay, an early home discharge and return to normal activities, and the prevention of re-hospitalization due to complications. Appropriate analgesic therapy requires standard protocols. Increasing awareness and effort to improve the pain management peri- and postoperatively in children have resulted in the development of guidelines in 2018 by the European Society for Paediatric Anaesthesiology (ESPA) Pain Committee . These gApproval was obtained from the Ethical Committee of the Medical University of Wrocław to perform the study under the number KB–459/2018. The authors confirm that all procedures comprising this research conformed to ethical standards and institutional guidelines for human experimentation. The study was registered in the ISRCTN registry under the number ISRCTN77862744 and was performed from July 2019 to February 2022. Trial registration: 26 April 2021—retrospectively registered.p < 0.05 and a test power (1—beta) > 0.80 and the expected treatment effect: for the significance test for related variables, the required group size is N = 45.The primary outcome of the study was to determine the effect of pre-emptive analgesia on postoperative pain in pediatric otolaryngology. The secondary outcome provides the correlation between pain scores measured with the Visual Analogue Scale (VAS), the Wong–Baker Faces Pain Rating Scale (WB), and the Face, Legs, Activity, Cry, and Consolability (FLACC) scale after surgery. Assuming a probability of first type error  at The clinical trial initially included a total of 55 children from the Department of Otolaryngology of the University Clinical Hospital in Wrocław. Four children who refused to participate at the very beginning of the study, with a subsequent lack of parental formal consent, were excluded, resulting in an overall number of 51 children . The incTo randomly allocate a patient to a study or control group, permuted block randomization was used. The patient, parent, anesthetist, and surgeon were all blinded to the study. Only the nurse delivering the premedication to the child was not blinded. Once the child received their premedication, the group allocation sheet was concealed in an envelope. The exact dose of postoperative analgesics was prescribed every 6 h, based on the child’s weight.Postoperative pain was assessed using the Visual Analogue Scale (VAS), the Wong–Baker Faces Pain Rating Scale (WB), and the Face, Legs, Activity, Cry, and Consolability (FLACC) scale. The FLAAC scale  is an asn = 26) or a placebo (n = 25), in addition to midazolam  at the dose of 0.5 mg/kg (N = 51) as premedication. Only the nurse delivering the premedication to the child was not blinded; the group allocation sheet was concealed in an envelope after the premedication liquid was administered to the child orally. The research documents were stored in a locker at the hospital, which only the investigators had access to.Fifty-one children were randomized to receive either pre-emptive analgesic acetaminophen  at the dose of 15 mg/kg  at the dose of 2–4 mg/kg iv, sevoflurane  as inhalation agent and fentanyl  at the dose of 2 mcg/kg iv. Sevoflurane was used to maintain anesthesia. At the end of surgical procedures, all patients received intravenous dexamethasone  at the dose of 0.2 mg/kg and nalbuphine  at the dose of 0.2 mg/kg as standard perioperative analgesia. Postoperatively the patients were transferred to the postop room and then to the otolaryngology ward, which took approximately 45 min.Postoperative pain was assessed using the Wong–Baker Faces Pain Rating Scale, the VAS, and the FLACC scale. The postoperative pain was measured 1, 2, 4, and 6 h after the surgery. The children were asked to score their pain on the VAS and Wong–Baker scale, while the FLACC scale was used by the research team to assess pain. During the evaluation, the research team and the parent or guardian were present. Only throat pain was included in the pain score analysis. All children in this study received postoperative analgesia. The patients were administered intravenous acetaminophen  at the dose of 15 mg/kg every 6 h after the previous dose was given. In case of severe pain, additional intravenous metamizole  at the dose of 15 mg/kg was administered.p < 0.05.Statistical analysis was performed using the STATISTICA v.13.3 software . Qualitative variables are presented in the contingency tables as numbers and proportions. The independence of the two qualitative variables was verified using the Chi-square test. For quantitative variables, mean values, median standard deviations, quartile ranges, and extreme values were calculated. The Shapiro–Wilk test was used to assess the normality of the distribution. As the empirical distributions deviated from the normal distribution, non-parametric tests were used in further analysis. The Mann–Whitney U test was used to estimate the statistical significance of the difference between independent groups. The relationship between pain scales was checked by calculating Spearman’s Rho correlation coefficient. The values of the intra-class correlation coefficients (ICC) and Bland–Altman plots were used to assess the compliance of the results of pain level measurements on the WB, VAS, and FLACC scales. The results were considered statistically significant at Data were collected on 51 children (23 girls and 28 boys). The children were divided into two groups. The first one consisted of twenty-six children (51%) who received acetaminophen prior to surgery. The second one consisted of twenty-five children (49%) who received a placebo. The mean age was 5.6 years  . Both grp > 0.05). There was no need to provide rescue analgesia for any patients during this trial.The study showed a statistically significant difference in postoperative pain between the two study groups. The level of pain in children after otolaryngological procedures, who received acetaminophen as pre-emptive analgesia, was significantly lower compared to those who received placebo, when using Wong–Baker Faces Pain Rating Scale and the VAS, except for the second hour after surgery . HoweverA statistically significant correlation was found between pain scores measured by WB, VAS, and FLACC scales at the first, second, fourth, and sixth hours after surgery .The highest rate of agreement between pain level assessment scales was between the WB and VAS scales . The BlaPostoperative pain management in children is challenging, especially after tonsillectomy, which is a painful procedure for most children—much more painful than an adenoidectomy . In receThis study showed that acetaminophen administered as a part of oral premedication effectively reduced the level of postoperative pain in children and thus demonstrated the effectiveness of pre-emptive analgesia. In order to exclude the influence of other potentially analgesic agents in this study, a uniform anesthetic protocol common to all participating children was established. The use of local anesthesia or other drugs outside the protocol was excluded. The surgery times were similar, and all procedures were performed without complications.The selection of acetaminophen, among other analgetic drugs commonly used in pain management in the otolaryngological ward, such as ibuprofen, opioids, and steroids for pre-emptive analgesia, was due to its limited side-effect profile. Acetaminophen has been shown to be very safe for use in children . It is aAnother analgesic drug considered was dexamethasone steroid. A single intraoperative dose of intravenous dexamethasone reduces postoperative nausea and pain . It is rOpioids were excluded because special precautions should be taken when prescribing opioids in patients with obstructive sleep apnea due to the increased risk of ventilation disorders in the postoperative period . HoweverThe idea of preemptive analgesia before tonsillectomy is not new. Still, our work advantage and novelty are the use of several pain scales, including those designed especially for children. In work published by El-Fattah and Ramzy , the parAssessing the pain children experience can be problematic because children are unwilling or unable to verbalize. Current standard pain assessment tools mostly rely on self-reporting and behavioral analysis of children, and a wide range of studies have developed methods to accurately assess the intensity of pain in children in the postoperative period. The pain scales most often used in the literature are the FLACC scale, the Wong–Baker FACES Pain Rating Scale, and the VAS . In this clinical trial, the research team concluded that postoperative pain in children should be assessed using the most popular and widely validated scales. Explaining the Wong–Baker and the VAS to the children in the preoperative period improved their understanding and informed pain scale marking in the postoperative period. In addition, children were asked to locate the site of pain in postoperative assessment—which was throat pain, excluding the intravenous cannula or other reasons. It was easier for both the patient and the research team and led to a better relationship with the child in the postoperative period.A standard anesthesia protocol was used in this study, including sevoflurane, intravenous propofol (2–4 mg/kg), and fentanyl (2 mcg/kg) induction. During the surgery, all patients received a single intravenous dose of dexamethasone (0.2 mg/kg) and nalbuphine (0.2 mg/kg) as standard perioperative analgesia. Postoperatively, the patient was transferred to the postop room and then to the otolaryngology ward, which took approximately 45 min. Sevoflurane is the most popular gas induction agent; it is tolerated well by patients and is known for its beneficial pharmacokinetic and pharmacodynamic properties . HoweverThe limitations of the present study rest on the fact that it is a single-center study with a small number of patients. The reason for this was the fact that the time implementation of the study coincided with the COVID-19 pandemic, and thus, the number of planned procedures performed during that period was limited. The observation and pain recording period was limited to 6 h after the surgery; therefore, it would be worth extending it to 24 h in future studies. This would give an answer to the question of whether pre-emptive analgesia influences the pain level at a later period than only a few hours after the surgery. It is therefore uncertain whether the results can be replicated in other larger centers, with variable experience and standardization in their practices.The clinical trial reported a statistically significant correlation between administering pre-emptive analgesia (acetaminophen) and reducing pain in children after otolaryngological procedures compared to placebo. The majority of children in both study groups did not experience severe postoperative pain regardless of whether or not they received acetaminophen before the procedure. However, the positive effect of pre-emptive analgesia was statistically significant in reducing pain to an absolute minimum. For this reason, it seems that pre-emptive analgesia should be routinely used in children undergoing otolaryngological procedures.


Pain symptoms were assessed with a diary  and questionnaires. Investigations included quantitative sensory testing (QST) and distal calf skin biopsies, at baseline and 3 months after baseline visit; subsequent options were 3-monthly visits over 1 year. 25 participants with NPDPN had tests at baseline, and 3 months after all received Capsaicin 8% patch treatment.p = 0.0001), but not PDPN SOC group. Short-Form McGill Pain Questionnaire (SF-MPQ) showed significant reductions in scores for overall and other pain descriptors only in the PDPN Q+SOC group. Warm perception thresholds were significantly improved only in the PDPN Q+SOC group (p = 0.02), and correlated with reduction in SF-MPQ overall pain score (p = 0.04). NPDPN Q+SOC group did not report pain during the entire study. Density of intra-epidermal nerve fibers (IENF) with PGP9.5 was increased at 3 months in PDPN Q+SOC (p = 0.0002) and NPDPN Q+SOC (p = 0.002) groups, but not in the PDPN SOC group. Increased sub-epidermal nerve fibers (SENF) were observed with GAP43 (marker of regenerating nerve fibers) only in PDPN Q+SOC (p = 0.003) and NPDPN Q+SOC (p = 0.0005) groups. Pain relief in the PDPN Q+SOC group was correlated with the increased PGP9.5 IENF (p = 0.0008) and GAP43 (p = 0.004), whereas those with lack of pain relief showed no such increase; in some subjects pain relief and increased nerve fibers persisted over months. PGP9.5 IENF increase correlated with axon-reflex vasodilatation in a NPDPN Q+SOC subset (p = 0.006).At 3 months after baseline, PDPN Q+SOC group had reduction in NPRS score (via nerve regeneration and restoration of function in DPN (disease modification). It may thereby potentially prevent diabetic foot complications, including ulcers.Capsaicin 8% patch can provide pain relief  Painful diabetic peripheral neuropathy (PDPN) may be defined as pain caused by a lesion of the peripheral somatosensory system attributable to diabetes mellitus (DM). Chronic pain can be a severe clinical manifestation of diabetic peripheral neuropathy, with a prevalence ranging from 8–30% reported in several studies of long-standing DM . The undCurrent treatments for treating neuropathic pain in patients with PDPN have limited efficacy and significant side effects . These iCapsaicin 8% patch (Qutenza) is a TRPV1 receptor agonist therapy, with several advantages over the alternative traditional low-dose topical formulations. It has been used to treat peripheral neuropathic pain as licensed in the EU, including PDPN, and for treating post-herpetic neuralgia (PHN) and PDPN, as licensed in the USA. The evidence and mechanisms for pain relief by capsaicin 8% patch (Qutenza) have been reviewed , 10–13. There is little data regarding the effect of topical treatment with capsaicin 8% patch (Qutenza) in skin biopsies. The time-course of nerve fibers degeneration and then regeneration over weeks following high dose topical capsaicin in skin biopsies have been reported by us in a human volunteer study , and by In clinical treatment combined with tissue studies, capsaicin 8% patch (Qutenza) application for post-herniorrhaphy neuropathic pain did not lead to significant pain relief or change of IENFs in skin biopsies from the site of surgery . In painThe aim of this study was to assess the mechanisms of pain relief following application(s) of the capsaicin 8% patch (Qutenza) in patients with Painful Diabetic Peripheral Neuropathy (PDPN). Patients with PDPN were randomized to receive capsaicin 8% patch (Qutenza) with Standard of Care, or Standard of Care alone. The patients were assessed at baseline and 3 months after baseline . The investigations included pain diary, questionnaires, quantitative sensory testing (QST), and skin biopsies studied with a range of biomarkers. Our findings led us to extend these assessments to patients with Non-Painful Diabetic Peripheral Neuropathy (NPDPN), in an open label single treatment study with capsaicin 8% patch.We have reported progressive loss of nerve fibers over 6 months in skin biopsies collected from patients with longstanding DPN, in a natural history study . In thisn = 50 with Painful Diabetic Peripheral Neuropathy, and n = 25 with Non-Painful Diabetic Peripheral Neuropathy) participated in this study. Study approval was obtained from the East of England, Cambridgeshire and Hertfordshire Research Ethics Committee (Ethics reference number: 17/EE/0498), the European Union Drug Regulating Authorities (EudraCT Number: 2017-004746-17), and registered in the ISRCTN registry (https://doi.org/10.1186/ISRCTN14254122). The study was monitored by the Joint Research Compliance Office, Imperial College London and Imperial College Healthcare NHS Trust, in accord with Good Clinical Practice (GCP) guidelines.This was a single-center study on the effects of Capsaicin 8% patch treatment. Seventy-five subjects  enrolled in the study were randomly allocated to either receive 30-min Capsaicin 8% patch application to both feet up to the distal calf, while continuing to take medication as part of their standard of care . An 11-point numerical rating scale (NPRS) with the 0-anchor point being “no pain” and the 10-anchor point being “pain as bad as you can imagine,” to describe “pain on average in the last 24 h” was used for both spontaneous and evoked pain.After completing this diary for 7 days, the result of their NPRS was used to determine eligibility for the study.Patients with PDPN were enrolled only when the average pain intensity was equal to or > 4 /10 for spontaneous pain. The participants were unaware of this criterion.Patients with NPDPN were enrolled only if the pain score was equal to 0.Patients with PDPN considered eligible were advised to continue completing the diary daily for the entire duration of the study until the end-of-study follow up visit. Capsaicin 8% patch treatment was within 1 month after the baseline visit.In the group of patients with PDPN, pain was described mostly as burning pain (64%) and less commonly as cramping pain (6%), sharp pain (11%), shooting pain (6%); throbbing/ stabbing pain (6%) or aching pain (3%).29 out of 37 subjects were taking treatments for neuropathic pain at the start of the study , but not topical treatments. The mean (SEM) of the numeric pain rating score (NPRS) at the first visit was 7.1 (0.31) for PDPN Q+SOC group and 8.1 (0.46) for PDPN SOC alone group. The mean ± SEM of the SF-McGill Questionnaire overall pain score at the first visit was 106 (9.5) for PDPN Q+SOC group and 126 (15.2) for PDPN SOC alone group. Pain characteristics for patients with PDPN are reported in Patients with NPDPN did not report pain in the extremities; some described their symptoms as lack of sensation or numbness.Clinical examination and tests were performed in both lower and upper limbs, and the right lower limb values were used for analyses.Neurological deficits were recorded using the Neuropathy Impairment Score Lower Limbs  (NIS-LL)The mean ± SEM NIS-LL at the baseline visit was 10.7 (1.1) for PDPN Q+SOC group; 12 (0.8) PDPN SOC alone group and 9.6 (1.4) for patients with Non-Painful Diabetic neuropathy (NPDPN Q+SOC).Symptoms were recorded using the Short-Form McGill Pain Questionnaire  with maxPatients were asked to complete the Clinical Global Impression of Change; this was completed at the baseline visit (for over the previous 3 months) and at 3 months follow-up visit. The Questionnaire is composed of a 7-point scale, enabling the patient to indicate no change, improvement or worsening of their condition.Nerve conduction studies were performed only on visit 1 by a senior consultant neurophysiologist. Nerve conduction studies of the common peroneal (including F wave studies) and sural nerves in the right leg were performed with a Medtronic Keypoint device . Nerve conduction studies were performed once at the baseline visit for all patients. Sural antidromic sensory action potentials of <5 μV amplitude and <40 m/s conduction velocity, and common peroneal nerve  values <3 mV amplitude, <40 m/s conduction velocity, were considered abnormal .For quantitative sensory testing (QST), thresholds for light touch were measured using Semmes–Weinstein hairs ; No. 1 (0.0174 g) to No. 20 (263.0 g). The hair with the lowest force reliably detected by the patient on the dorsum of the toe was recorded. Values > 0.0479 g were considered abnormal .Vibration perception thresholds were measured using a biothesiometer  placed on the metatarsophalangeal joint of the big toe. Three ascending and three descending trials were carried out, and the mean value obtained. Values >12 V were considered abnormal .Thermal perception thresholds were performed as described , 37 usin2 capsaicin 8% patch on the dorsum foot skin for 10 min. The increase of capillary flux (peak minus baseline) was measured adjacently using a laser-Doppler , and recorded in flux units  before capsaicin 8% patch (Qutenza) application and repeated 3 months after the initial visit or treatment, within the area of capsaicin 8% patch treatment. Skin biopsies collected from age and gender-matched healthy volunteers were analyzed alongside the patient‘s biopsies, as controls.The immunohistochemical methods and antibodies used have been reported previously , 38–40. The primary antibodies were to the structural nerve marker PGP 9.5 , the nerve regeneration marker, growth associated protein GAP-43 , von Willebrand factor vWF . 50-μm sections were also studied with PGP 9.5 antibody.Briefly, fixed sections were floated onto PBS in 12-well plates, dehydrated with alcohol/hydrogen peroxide solution for 30 min, washed with PBS and incubated with PGP 9.5 overnight, washed and incubated with the second antibody for 1 h, and then washed and incubated with ABC as above. After washing, the nickel developer solution was added, and staining allowed to develop. The reaction was stopped by adding 0.1 M sodium acetate pH 6.0, washed again in PBS, counterstained and free floated onto PPL slides, allowed to dry and incubated in xylene, and finally mounted using DPX mountant.via video link to an Olympus BX50 microscope. The gray-shade detection threshold was set at a constant level to allow detection of positive immuno-staining and the area of highlighted immuno-reactivity was expressed as a percentage (% area) of the field scanned. Images were captured (x40 objective magnification) along the entire length, and the mean values were used for statistical analysis. Quantification was performed by two independent blinded observers, and there was no significant difference between observers. IENF density for PGP 9.5 in 50 μm thickness sections were quantified according to the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines  and results expressed as fibers/mm length of the section. Sub-epidermal nerve immunoreactivity was obtained as a percentage (% area) measured by image analysis of digital photomicrographs captured idelines . Validatidelines , 43. Theidelines ].t-test, two-way ANOVA analysis, and Spearman's correlation test. For all statistical tests, p-values < 0.05 were considered significant.Data were analyzed using GraphPad Prism version 5.0 for Windows . The statistical tests used were paired two-tailed Mann-Whitney test, Student's n = 25; PDPN SOC alone, n = 12; NPDPN Q+SOC, n = 24). Few participants had further visits, mainly on account of the Covid-19 pandemic (data not shown). The control of diabetes was not significantly different at baseline across the study groups, or after patch treatment—in the PDPN Q+SOC group, pre-treatment Mean [range] HbA1c (mmol/mol), 55.0 (38–75), post-treatment 59.5 (42–90), p = 0.93; in the NPDPN Q+SOC group, pre-treatment 60 (41–77), and post-treatment 57 (45–69), p = 0.31.Data are presented for participants who completed all tests at the 3-month follow up visit  did not show significant difference in the NIS-LL score before and after the treatment of Capsaicin 8% patch.Patients with Painful Diabetic Neuropathy  and for patients with non-Painful Diabetic Neuropathy  had at least one abnormality on nerve conduction studies; 54% (33/61) had both motor and sensory abnormalities. The peroneal conduction motor response was absent in 4 patients in the PDPN Q+SOC group, 4 patients in the PDPN SOC alone group and 11 patients in the NPDPN Q+SOC group. The sural nerve response was absent in 6 patients in PDPN Q+SOC group, 5 patients in PDPN SOC alone group and 14 patients in the NPDPN Q+SOC group.***p = 0.0001 (p = 0.11).There was a significant reduction in the average daily NPRS 3 months after capsaicin 8% patch application for the PDPN Q+SOC group , with a = 0.0001 . The cha**p = 0.002), intermittent descriptors , neuropathic descriptors  and affective descriptors . There was no significant difference in these scores in the PDPN SOC alone group.At the follow-up visit 3 months after the treatment for PDPN Q+SOC group, SF-MPQ-2 showed a significant reduction in the overall pain score  did not report pain in the feet or distal calf for the entire duration of the study.**p = 0.007), or in the PDPN SOC alone group .Patient's Global Impression of Change (PGIC) was not significantly improved in the PDPN Q+SOC group .The PGIC in patents with non-painful Diabetic Neuropathy (NPDPN Q+SOC) was recorded as improvement of sensation at 3 months after the treatment  from baseline 13.1 (0.8) at 3 months after Capsaicin 8% patch application (mean ± SEM (range) 11.4 (0.9); n = 7, **p = 0.006, Axon-reflex vasodilatation was assessed in a subset of participants with non-painful diabetic neuropathy (NPDPN Q+SOC). Axon-reflex vasodilatation in skin was significantly increased between baseline and 3-month follow-up visit (n = 25), a statistically significant increase of IENFs with PGP9.5 in 15 μm sections (***p = 0.0005) and 50-μm sections  between baseline and biopsies after 3 months , a statistically significant increase of PGP9.5 marker for IENFs in 15 μm sections (*p = 0.02) and 50-μm sections , and 50-μm calf skin sections , and 50-μm calf skin sections . In contrast, a significant decrease was observed over 3 months in the PDPN SOC alone group; *p = 0.04  were observed in the PDPN Q+SOC group after treatment , 11. No No changes in von Willebrand Factor (vWF) were observed after treatment with capsaicin 8% patch in patients with non-Painful Diabetic Neuropathy .Thermal thresholds for warm perception in the PDPN Q + SOC group were significantly improved 3 months after capsaicin 8% patch treatment and were positively correlated with the improvement in the overall pain score , PGP9.5 SENF (***p = 0.0001) in 50 μm thick sections, and GAP43 (*p = 0.004), whereas those who reported no pain reduction did not show any increase of PGP9.5 IENF (p = 0.24), PGP9.5 SENF (p = 0.15) or GAP43 (p = 0.39)  .**p = 0.009). There was no significant change in the PDPN + SOC alone group (p = 0.81).PDPN + Q group showed a positive correlation between the increase of GAP43 regenerating nerve fibers after treatment and the GAP43 nerve fiber density at baseline i.e., before treatment (p = 0.03).Axon-reflex vasodilatation was assessed before and after capsaicin 8% patch application in seven NPDPN + Q group subjects, who showed a positive correlation between the increase of axon-reflex vasodilatation and the increase of PGP9.5 IENF  in patients with Painful Diabetic Peripheral Neuropathy (PDPN). We aimed to relate any skin biopsy and sensory test changes to the reduction of pain. In view of our initial findings, we then also assessed the efficacy of capsaicin 8% patch (Qutenza) application in improving nerve regeneration in patients with Non-Painful Diabetic Neuropathy (NPDPN).Reduction of spontaneous (on-going) pain in the PDPN Q+SOC group was significant, and showed a similar time-course, effect-size and responder rates to previous studies , 44. As p = 0.02), and were positively correlated with the improvement in the overall pain score for the Short-Form McGill Pain Questionnaire (p = 0.04). Axon-reflex vasodilatation in skin was significantly increased between baseline and 3-month follow-up visit in a subset of subjects tested in the NPDPN Q+SOC group (p = 0.006); there was a positive correlation between the increase of axon-reflex vasodilatation and the increase of PGP9.5 IENF (p = 0.03).This increase of nerve fibers was also shown overall in the PDPN Q+SOC group and NPDPN Q+SOC groups at 3 months after capsaicin 8% patch (Qutenza) treatment, for both intra-epidermal (IENFs) and sub-epidermal nerve fibers (SENFs) with the pan-neuronal marker PGP9.5. Sub-epidermal nerve fibers (SENF) assessed with GAP43, a selective marker of regenerating nerve fibers, were also significantly higher 3 months after treatment, and indeed higher than controls. In contrast, these were decreased in the PDPN SOC alone group after 3 months, in comparison with their baseline biopsies. Thermal thresholds for warm perception in the PDPN Q + SOC group were significantly improved 3 months after treatment  in affected DPN skin may explain why at 3 months post-treatment the average density is higher than at baseline. It may also explain why in healthy volunteer  thigh skin, the relative lack of this on-going regenerative process pre-treatment may lead to incomplete though overall more robust recovery toward normal values 3 months later (80% of baseline)  . FurtherIn patients with painful CIPN and NFCI, a 30-min application of capsaicin 8% patch (Qutenza) to the feet and distal calf led to a significant reduction of pain scores, along with a significant increase of intra-epidermal and sub-epidermal nerve fibers. This was accompanied, as studied in CIPN, by an improvement in a range of other mechanistic biomarkers i.e., epidermal levels of Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), and Langerhans cells . CapsaicIn support of the proposed disease modification mechanism of action: (1) thermal thresholds for warm perception in the PDPN Q + SOC group were significantly improved after 3 months and were positively correlated with the improvement in the overall pain score; (2) PDPN Q + SOC subjects with pain reduction at 3 months had a statistically significant increase in PGP9.5 IENF, SENF and GAP43, whereas those who reported no pain reduction did not; (3) PDPN Q+SOC group showed a positive correlation between the increase of GAP43 regenerating nerve fibers after treatment and the GAP43 nerve fiber density at baseline i.e., propensity for nerve regeneration; (4) NPDPN Q+SOC subjects showed a positive correlation between the increase of axon-reflex vasodilatation and the increase of PGP9.5 IENF; and (5) there was no significant improvement in the PDPN + SOC alone group; on the contrary, there was a decrease of regenerating nerve fibers marked by GAP43.In future clinical trials, the systematic study of factors that may contribute to or prevent the reported effects of the Capsaicin 8% patch on nerve regeneration would be useful, including concomitant drug regimens. This would require stratification of sufficient numbers of participants e.g., by age, duration and severity of diabetes/neuropathy, concomitant treatments, etc. We have reported here that the density of regenerating nerve fibers at baseline, marked by GAP43, were related to increased nerve regeneration following Capsaicin 8% patch treatment; this marker may thus identify “responders” for nerve regeneration. Other non-invasive markers to identify “responders” would be particularly useful. Future clinical trials should also include systematic studies of the cellular and molecular constituents of the milieu for nerve regeneration, and effect of treatments that that may synergize with Capsaicin 8% patch to enhance nerve regeneration e.g., neurotrophic factors.Regeneration of sensory nerve fibers and improvement in function in patients with DPN is important clinically, as dysfunction or loss of small sensory nerve fibers including nociceptors are associated with loss of protective sensation, axon-reflex vasodilatation, and trophic changes. These are the major factors for the development and non-healing of foot ulcers, leading to amputations , 29. In As in this study, we have previously reported and discussed an increase of sub-epidermal blood vessels with the same marker vWF in a different cohort of patients with PDPN , consideDiabetic foot syndrome is a major global burden to patients, their careers, and financial resources; better clinical tools and trials will help to improve current treatments outcomes , 46. OneThe findings of this study provide an exciting new prospect for the treatment of both painful and non-painful diabetic peripheral neuropathy. It has implications for the prevention of foot ulcers and amputations in patients with DPN, which are an important and increasing complication globally. Loss of sensory nerve fibers or their protective function are the major contributors to the development, recurrence, or non-healing of diabetic foot ulcers, leading to amputations. The capsaicin 8% patch (Qutenza) may provide preventative treatment for the diabetic foot syndrome.The original contributions presented in the study are included in the article/supplementary files, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by East of England—Cambridgeshire and Hertfordshire Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.PA conceived the study. RP and HF helped with clinical assessments. VM performed the nerve conduction studies. PD analyzed the skin biopsies. VB organized patient referrals and coordination of assessments. All authors contributed to drafting the manuscript and approved the final manuscript.The authors thank Diabetes UK for funding this study. The authors are grateful to Grünenthal GmbH, Germany, who provided supplementary funding for Capsaicin 8% patch Qutenza studies.This study received supplementary funding from Grünenthal GmbH. The funder had the following involvement with the study: interpretation of data. PA has received symposia speaker fees and advisory board honoraria from Grunenthal, but no personal remuneration for conducting this study.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.