Patients usually suffer acute pain after cardiac surgery. Numerous regional anesthetic techniques have been used for those patients under general anesthesia. The most effective regional anesthetic technique was still unclear.Five databases were searched, including PubMed, MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library. The efficiency outcomes were pain scores, cumulative morphine consumption, and the need for rescue analgesia in this Bayesian analysis. Postoperative nausea, vomiting and pruritus were safety outcomes. Functional outcomes included the time to tracheal extubation, ICU stay, hospital stay, and mortality.This meta-analysis included 65 randomized controlled trials involving 5,013 patients. Eight regional anesthetic techniques were involved, including thoracic epidural analgesia (TEA), erector spinae plane block, and transversus thoracic muscle plane block. Compared to controls , TEA reduced the pain scores at 6, 12, 24 and 48 h both at rest and cough, decreased the rate of need for rescue analgesia , shortened the time to tracheal extubation  and the duration of hospital stay . Erector spinae plane block reduced the pain score 6 h at rest and the risk of pruritus, shortened the duration of ICU stay compared to controls. Transversus thoracic muscle plane block reduced the pain scores 6 and 12 h at rest compared to controls. The cumulative morphine consumption of each technique was similar at 24, 48 h. Other outcomes were also similar among these regional anesthetic techniques.TEA seems the most effective regional postoperative anesthesia for patients after cardiac surgery by reducing the pain scores and decreasing the rate of need for rescue analgesia.https://www.crd.york.ac.uk/prospero/, ID: CRD42021276645 Patients usually suffer acute pain after coronary artery bypass graft or valve surgery: 78% of patients experienced pain during coughing, while 49% of patients experienced pain at rest . It is iAlthough intravenous opioid is the first-line postoperative analgesic, opioid-related adverse effects, such as postoperative nausea and vomiting (PONV), pruritus, ventilator-associated pneumonia, can lead to other problems including prolonged intubation, and higher mortality . NumerouNetwork meta-analysis (NMA) pools evidence from a large number of comparisons and patients to compare several interventions, allowing for indirect comparisons and ranking. Therefore, we conducted this NMA with the aim to compare regional anesthetic techniques efficacy and safety for pain relief after cardiac surgery.2.The pre-registered protocol was implemented in the PROSPERO database (CRD42021276645). This paper was reported in accordance with PRISMA guideline.2.1.On September 2, 2022, two investigators searched PubMed, MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library for relevant studies with the words “cardiac surgery/cardiac surgical procedures” and . Additionally, we read the references of articles in search for literature that met the criteria.2.2.Original studies were eligible if the following criteria were met: (i) RCT study in English; and (ii) assessed the efficacy and safety of regional postoperative anesthetic techniques after cardiac surgery under general anesthesia. Original studies were ineligible if the following criteria were met: (i) studies involving combination blocks  ; (ii) paThe first author, year of publication, country, surgery type, anesthesia technique, groups and number of participants in each group, drug and dose for regional anesthetics, block timing, postoperative analgesia, and outcomes were extracted in the involved eligible studies. When the data could not be gathered from tables and full text, GetData Graph Digitizer v 2.26) was used to obtain the numerical data from figures  for statistics , 7. Five2.4.P-value. The surface under the cumulative ranking curve (SUCRA) was calculated and ranked. Begg's and Egger's tests were performed to evaluate publication bias. All analyses were conducted using the “gemtc” package of R version 4.0.2 .Cochrane Collaboration's tool was used to evaluate the quality of involved studies. Mean difference (MD) and 95% confidence interval (CI) were used to report the cumulative morphine consumption, pain scores, the time to tracheal extubation, ICU stay, and hospital stay. Odds ratios (ORs) were used to report the risk of PONV, pruritus, mortality, and the need for rescue analgesia. In this Bayesian NMA, random-effects and consistency models were used to analyze data . Inconsistency was assessed by the node-splitting method with Bayesian 3.3.1.Finally, 65 RCTs were included using our search strategy  9–73). –73. 9–733.2.There was no difference in pain scores at 2–4 h both at rest and cough among these regional anesthetic techniques. Pain scores at 6, 12, 24, 48 h both at rest and cough were lower for TEA than for controls . Pain sc−25, 95% CI: 2.33 × 10−74–0.078; OR = 0.10, 95% CI: 0.016–0.55, respectively, There was no difference in the cumulative morphine consumption at 24, 48 h among these regional anesthetic techniques . SAPB an3.3.−10, 95% CI: 1.01 × 10−30–0.83; OR = 0.070, 95% CI: 0.0043–0.70, respectively, −11, 95% CI: 1.72 × 10−32–0.081, SAPB and PVB reduced the risk of PONV compared with the control group (OR = 6.65 × 103.4.TEA shortened the time to tracheal extubation compared with controls (MD = −181.55, 95% CI: −243.05 to −121.33, 3.5.P > 0.05 for all cases, indicating inconsistencies were not sufficient to influence the conclusions of our NMA (There was a significance level of  our NMA . The ran4.This paper is the first comprehensive NMA assessing the efficacy and safety of regional anesthetic techniques after cardiac surgery. Though none of the regional anesthetic techniques could reduce the cumulative morphine consumption compared with controls, our results revealed that TEA, ESPB, and TTMPB reduced pain scores at different time points. TEA also reduced the rate of need for rescue analgesia, the time to tracheal extubation, and duration of hospital stay. ESPB could reduce the risk of pruritus and shorten the duration of ICU stay.Pain is the most severe during the first 24 h following cardiac surgery, and it gradually decreases . IneffecIn 1954, TEA was first introduced in cardiac surgery . This reIt is likely that PVB is the most commonly administered paraxial nerve block . PONV inPINB, TTMPB, and PIFB complement the anteromedial chest wall by providing anesthesia confined to the parasternal region. According to the nuance of the injection position, they were divided into two categories: regional anesthetics was injected between the internal intercostal and pectoralis major muscles in PIFB and PINB; regional anesthetics was deeply injected between the internal intercostal and transverse thoracic muscles in TTMPB , 91, 92.On the anterolateral chest wall, a new method named “PECS” was reported to anesthetize the medial-lateral pectoral nerves, long thoracic nerve, and thoracodorsal nerve since 2011 . In the 4.1.First, the results regarding to the emerging techniques, including TTMPB, PIFB, ESPB, PECS, and SAPB, need to be confirmed in more RCTs. Several ongoing trials with regional anesthetic techniques for cardiac surgery were shown in 5.TEA seems the most effective regional postoperative anesthesia for patients after cardiac surgery by reducing pain scores and decreasing the rate of need for rescue analgesia.


The aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain.In the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up.Pain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with β -1.37 mm  per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) β (95% CI) arm 1: 0.13  and arm 2: 0.37  compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [β 0.44 ] and higher active joint count [0.77 ] were predictive of higher pain over time, whereas, low VAS physician [ -0.34 ], CHQ Physical [ -0.42 ] and Psychosocial summary Score [ -0.42 ] were predictive of lower pain.Treatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain.Dutch Trial Registry number 1574. Juvenile Idiopathic Arthritis (JIA) is the most common auto-immune disease in children, with an estimated prevalence of 33 per 100.000 children . Pain isIn JIA, treatment to target (T2T) with clinical remission as a treatment goal has been widely recommended , 20. TreThe aim of this subanalysis is to compare pain scores over two years in three treatment strategies in non-systemic JIA patients who were treated to target aimed at inactive disease . FurtherThe BeSt for Kids study (NTR 1574) is a Dutch multicenter randomized single-blinded trial. It was designed to investigate the effectiveness of three different treat to target strategies for non-systemic JIA patients. Newly diagnosed patients between 2 and 16 years old with JIA  were included. Exclusion criteria were a disease duration of more than 18 months, uveitis at enrolment and prior DMARD therapy.Patients were randomized between three strategy arms. Patients in arm 1 were initially treated with methotrexate(MTX) or sulfasalazine(SSZ) monotherapy. Patients in arm 2 initially received MTX and 6 weeks prednisolone bridging. Patients in arm 3 were initially treated with etanercept (ETN) and MTX. Patients were treated to target, with inactive disease  as treaThe BeSt for Kids study was approved by the Institutional Review Board at Leiden University Medical Center and written informed consent was obtained from all participants before enrolment.The primary outcome measure was pain intensity. This was assessed using a 100 mm visual analogue scale (VAS), where 0 mm is ‘no pain’ and 100 mm is ‘unbearable pain’. Patients were asked to rate their pain over the last 7 days. Under the age of 12, pain was estimated by the parents. A VAS pain of ≤ 35mm is considered ‘mild pain’, whereas ‘moderate pain’ is defined as 36–60 mm and ≥ 61mm as ‘severe pain’ .Inactive disease was defined by the adjusted Wallace criteria , where PDescriptive statistics were used with mean and standard deviations (SDs) for continuous variables and absolute frequency percentage for categorical variables. Potential differences in VAS pain scores over time between treatment arms were compared using linear mixed models with random intercept and random slope for visits clustered within patients. The third arm was treated as reference arm since we hypothesized that arm 3 would be superior compared with arm 1 or arm 2, based on earlier research . PossiblAdditionally, a third mixed model was used in an exploratory analysis to assess the ability of several baseline characteristics to predict the chance of high pain levels during follow-up. For this model multiple imputation was used to deal with missing values of variables with missing data from patients who were still in follow-up, as well as data from the 2 patients that were lost to follow-up and performed based on predictive mean matching . Imputation variables were treatment group, age at inclusion, sex, NSAID use, VAS pain, PGA, VAS patient/parent general wellbeing, VAS disease activity, symptom duration at diagnosis, Juvenile Arthritis Disease Activity Score 10 (JADAS10), number of active joints, number of limited joints, Child Health Assessment Questionnaire (CHAQ) score, CHQ- PhS, CHQ-PsS, JIA category, Erythrocyte Sedimentation Rate (ESR), baseline ESR and all baseline outcome measures. We first evaluated the possible predictive variables in a univariable model and subsequently added them to a multivariable model and evaluated its predictive value for reaching a lower VAS pain during follow-up.p-value < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS version 25  and Stata SE version 16 (StataCorp LP).For all statistical analyses Ninety-four patients were randomized between 2009 and 2014 into the three treatment arms: 32 patients were assigned initial monotherapy (arm 1), 32 patients received initial methotrexate (MTX) with 6 weeks prednisolone bridging therapy (arm 2) and 30 patients initial MTX and etanercept (ETN) (arm 3). Baseline demographics, including proportions of missing data, are summarized in Table Mean (SD) pain at 24 months was 17.3 (25.5) mm in arm 1, 25.6 (28.5) mm in arm 2 and 15.8 (21.0) mm in arm 3 ). When comparing pain scores over time per treatment arm, pain decreased significantly in every arm with β -1.37 mm  per month. No significant difference was found in pain over 24 months between treatment arms (interaction term treatment arm*time (months) in arm 1 with β (95% CI) 0.13  and in arm 2 with β 0.37  compared to arm 3). Correction for age and sex yielded similar results. Pain trajectories over time are depicted in Fig. When performing the model for the first three months separately, pain decreased at a similar rate in each treatment group with β(95% CI) -7.82 mm  per month. Arm 1 compared to arm 3 with β(95% CI) 1.45 and arm 2 with β(95% CI) 2.33.Over 24 months, more than 70 percent of patients reached inactive disease . The effSeveral baseline characteristics were selected beforehand and tested for predictive value for pain over time, first in a univariable and subsequently in a multivariable prediction model. In the multivariable model, higher VAS pain and number of active joints at baseline were significantly predictive of higher pain over time, whereas higher VAS physician, CHQ PhS and PsS were predictive of lower pain. Baseline symptom duration, NSAID use and VAS patient/parent were not predictive of pain during follow-up Table . VAS paiThe BeSt for Kids is one of the first treat-to-target studies in newly diagnosed, DMARD naïve, non-systemic JIA patients investigating pain as outcome measure. In the current subanalysis, three frequently used initial treatment strategies were compared for effectiveness in treating pain , 32. In Although few studies have addressed pain over time as an outcome, we know from cross sectional data and reports from trials and prospective observational studies that pain scores can remain high after treatment. These high pain levels are reported after treatment according to clinical practice before the availability of biologic treatment , 35, butEven though we saw a decrease of active disease and pain in the BeSt for kids study, still some of our patients who did achieve inactive disease continued to have pain. It is this group of patients that deserves additional attention , 37. CenIn addition to this, we could consider adding an extra patient reported outcome, to investigate whether the clinical improvement we find corresponds to what our patients regard as a satisfactory improvement in pain levels , 41, 42.We performed an exploratory analysis to identify baseline factors that predict pain over time. In univariable analyses we identified VAS pain, PGA, VAS patient/parent, number of active joints, PhS and PsS as significant predictors of pain over time. In a multivariable model including all previously tested variables, identified VAS pain, PGA, number of active joints, PhS and PsS remained predictive. This is in accordance with previous literature , 46–48.Counterintuitively and in contrast to previous studies, in our multivariable model, a lower PGA at baseline was associated with more pain during the two years follow up , 46. ThiContrary to previous studies we did not find symptom duration as a significant baseline predictor for more pain over time. This could be due to lack of power, as these studies included more patients and the effect that was found was very small , 46.In our previous publication , we repoThere are some limitations to our study. The sample size of our study was limited, therefore more subtle differences might have been found in a larger study cohort. Second, pain is multifactorial in nature and affected by many psychosocial patient factors . This stWe conclude that treat to target therapy is effective in reducing pain over time for DMARD-naïve non-systemic JIA patients, irrespective of initial treatment. On the other hand, some children still experience pain despite achieving clinically inactive disease. This emphasizes the necessity of addressing patient related outcomes in addition to targeted treatment to reduce disease activity. Several baseline predictors for pain over time were found, which could help to identify and support non-systemic JIA-patients with a high risk of pain in addition to a treat-to-target strategy treatment.


Two derivatives of the numeric rating scale (NRS) and visual analog scale (VAS), namely patient-reported percentage pain reduction (PRPPR) and calculated percentage pain reduction (CPPR), are commonly used when evaluating pain reduction. A small number of studies have attempted to assess the agreement between PRPPR and CPPR. However, they have been limited in their scope by a focus on specific types of pain, or by their focus on specific treatment modalities. As far as the authors of this article are aware, this is the first study to assess the agreement between PRPPR and CPPR in chronic pain patients, as well as the first to assess how the duration of treatment affects the correlations between PRPPR and CPPR. The aim of this retrospective analysis was to determine whether the duration of treatment affects CPPR and PRPPR, and the discrepancy and agreement between the two. Additionally, the study assessed whether individual treatment modalities, or the lack there of, impacted the discrepancy and correlation between PRPPR and CPPR. The mean PRPPR and CPPR for the entire patient population were 59.98 and 40.71, respectively. The mean discrepancy between the two parameters was 19.27. The agreement between PRPPR and CPPR, as measured by the concordance correlation coefficient, was 0.984 . Pain is commonly assessed clinically utilizing the numerical pain rating scale (NRS) or the visual analog scale (VAS). The treatment of pain is frequently evaluated using patient-reported percentage pain reduction (PRPPR), also referred to as the patient-reported percentage improvement in pain scale (PR-PIPS), and calculated percentage pain reduction (CPPR), also known as the calculated percentage improvement in pain scale (C-PIPS). A small number of studies have attempted to assess the agreement between PRPPR and CPPR. However, they have been limited in their scope by a focus on specific types of pain, or by their focus on specific treatment modalities. As far as the authors of this article are aware, this is the first study to assess the agreement between PRPPR and CPPR in chronic pain patients, as well as the first to assess how the duration of treatment affects the correlations between PRPPR and CPPR.Clinicians and researchers have had an interest in the clinical assessment of pain dating as far back as the 1950s  remains A systematic review by Hjermstad et al. in 2011 concluded that the commonly used unidimensional pain scales—numerical rating scales (NRSs), verbal rating scales (VRSs), and visual analogue scales (VASs)—are all adequate for evaluating pain . StatistNaturally, changes in pain scales are also used to evaluate the response to the treatment of pain. In 2020, Bahreini et al. found that the minimum clinically significant difference (MCSD) required for patients in an emergency department setting to report a difference in pain was 16.55 on the VAS and 1.65 points on the NRS. This finding was irrespective of whether the patients were experiencing a reduction in or exacerbation of pain .Additionally, a derivative of pain scales is often used when evaluating pain reduction, known as calculated percentage pain reduction (CPPR). CPPR is calculated by subtracting the post-treatment NRS score from the pretreatment NRS score and dividing the result by the pretreatment score—(pre-NRS—post-NRS)/pre-NRS . AnotherIntuitively, it would be expected that PRPPR and CPPR would reflect very similar—if not identical—results; however, the limited number of studies have demonstrated that there is in fact a statistically significant discrepancy between them as well as an imperfect agreement between the two ,12,13,14t-tests were utilized to calculate mean numerical variables, and the paired t-test was used to assess the difference between PRPPR and CPPR for the entire patient population and the stratified groups. The concordance correlation coefficient was used to assess the agreement between PRPPR and CPPR.Following approval from the Advocate Healthcare Institutional Review Board on 13 November 2018 as protocol number 6985, the authors of this article conducted a retrospective analysis of 1362 patients treated for various chronic pain conditions. In-depth chart reviews of patients at the Chicago Anesthesia Pain Specialists Clinic were utilized to collect demographics, treatments, and treatment responses. All patients were treated for at least 6 months and were seen in the clinic no less than 4 times. Patient health information was protected via utilization of secure computers. Race/ethnicity was recorded and categorized into White non-Hispanic, White-Hispanic, African American, Asian, or other. The demographic data of the patients’ studies are summarized in t-test was used, generating the mean PRPPR, mean CPPR, and the correlation between the two parameters.To assess how different treatments may impact the discrepancy and agreement between the PRPPR and CPPR, patients were categorized using medications or other interventions as categorical variables, namely, opioid pain medications, steroid injections, gabapentin, NSAIDs, muscle relaxants, tricyclic antidepressants, benzodiazepines, other psychiatric medications, and other interventions. Once stratified into groups, the paired-sample The mean PRPPR and CPPR for the entire patient population were 59.98 and 40.71, respectively. The mean discrepancy between the two parameters was 19.27. The agreement between PRPPR and CPPR, as measured by the concordance correlation coefficient, was 0.984 .When stratified into groups based on the duration of treatment, the PRPPR and CPPR were 56.7 and 37.94, respectively, amongst patients treated for less than 1 year. The mean discrepancy amongst this cohort was 18.75, while the correlation coefficient was 0.989 .The PRPPR and CPPR were 61.45 and 42.18, respectively, among patients treated for 1–2 years. The average difference among this group was 19.26, and the concordance correlation efficient was 0.989 .The PRPPR and CPPR for patients treated for 2–3 years were 54.54 and 35.94, respectively. The mean discrepancy for this cohort was 18.60, and the concordance correlation coefficient was found to be 0.976 .Among patients treated for 3–4 years, the PRPPR and CPPR were 48.87 and 30.37, respectively. The mean discrepancy within this group was 18.49 and the concordance correlation coefficient was 0.979 .The PRPPR and CPPR were recorded as 66.86 and 46.81, respectively, among patients treated for 4–5 years. The average difference among this group was 20.02, and the concordance correlation coefficient was calculated as 0.983 .For patients treated for longer than 5 years, the PRPPR and CPPR were found to be 81.66 and 60.14, respectively. The mean discrepancy within this cohort was 21.51, while the concordance correlation coefficient was determined to be 0.980 . The fluctuations in PRPPR and CPPR over time are depicted graphically in p < 0.001). Patients who did not receive opioid pain medication reported a mean PRPPR and mean CPPR of 68.96 and 48.71, respectively, providing for a discrepancy of 20.25, with a correlation of 0.985 (p < 0.001).When the patient population was restratified into groups based on the presence or absence of certain medications or treatment modalities in their therapeutic regimen, the following results were found. Patients utilizing opioid pain medications reported a PRPPR of 55.12 and a CPPR of 36.38, accounting for a mean discrepancy of 18.73. The correlation between PRPPR and CPPR was 0.982 (p < 0.001). Patients who did not receive steroid injections had a mean PRPPR and mean CPPR of 57.45 and 38.22 respectively, resulting in a difference of 19.23, with a correlation of 0.984 (p < 0.001).Individuals who received Steroid injections had a PRPPR of 60.26 and a CPPR of 40.99, with an average difference of 19.26. The correlation between PRPPR and CPPR was 0.984 (p < 0.001). Patients who did not use gabapentin had a mean PRPPR and mean CPPR of 60.62 and 31.30, respectively, leading to a difference of 19.32, with a correlation of 0.986 (p < 0.001).When using gabapentin, patients experienced a PRPPR of 59.11 and a CPPR of 39.95, producing a mean difference of 19.15. The correlation between the two measures was 0.981 (p < 0.001). Patients not using NSAIDs had a mean PRPPR and mean CPPR of 57.36 and 38.49, respectively, resulting in a difference of 18.86, with a correlation of 0.984 (p < 0.001).The PRPPR and CPPR were reported to be 62.32 and 42.73, respectively, by patients using NSAIDs, with a mean discrepancy of 19.58. The correlation between PRPPR and CPPR was 0.985 (p < 0.001). Conversely, patients who did not take Muscle relaxants had a mean PRPPR and mean CPPR of 60.76 and 41.37, resulting in a difference of 19.38, with a correlation of 0.983 (p < 0.001).Patients who received muscle relaxants had a mean PRPPR of 58.25 and a mean CPPR of 39.33, and thus a difference of 18.95. The correlation between the two measures was 0.987 (p < 0.001). Patients who did not utilize TCAs reported a PRPPR of 59.62 and a CPPR of 40.43, resulting in a discrepancy of 19.19 with a correlation of 0.984 as well (p < 0.001).Amongst patients utilizing TCAs, a mean PRPPR of 66.12 and a mean CPPR of 46.01 were reported, generating a discrepancy of 20.10 with a correlation of 0.984 (p < 0.001). Patients who did not receive benzodiazepines were found to have a PRPPR of 61.49, a CPPR of 42.03, a discrepancy of 19.46, and a correlation of 0.984 (p < 0.001).Benzodiazepine-receiving patients reported a PRPPR and CPPR of 55.02 and 36.48, respectively. The discrepancy was therefore found to be 18.85, while the correlation was found to be 0.987 (p < 0.001). Patients not receiving other psychiatric medications had a mean PRPPR and mean CPPR of 60.09 and 40,84, respectively, resulting in a difference of 19.24, with a correlation of 0.984 (p < 0.001).A PRPPR of 59.86 and CPPR of 40.57 were reported in patients using other psychiatric mediations. The discrepancy between the two parameters in this population was thus 19.28, and the correlation was found to be 0.987 (p < 0.001). Patients who did not receive other forms of intervention had a mean PRPPR and CPPR of 59.56 and 40.23, respectively, with a difference of 19.33 and correlation of 0.982 (p < 0.001).The subset of patients who were treated with other interventions reported a discrepancy between PRPPR and CPPR of 19.06, caused by a PRPPR of 60.96 and a CPPR of 41.90. The correlation between the parameters was 0.989 . The mean C-PIPS was 54 with a standard deviation of 28, while the mean PR-PIPS was 59 with a standard deviation of 25 .In 2017, Pratici et al. published an article detailing the differences in CPPR and PRPPR obtained from 97 patients who received epidural analgesia during labor and were asked to rate their pain just prior to the administration on analgesia and 30 min thereafter. The study reported a PRPPR of 79 with a standard deviation of 21.5 and a CPPR of 80 with a standard deviation of 21.2. The concordance correlation coefficient was calculated using both the VAR and NRS scores and yielded a coefficient of 0.76 (95% CI 0.6 to 0.8) and 0.77 , respectively. The authors concluded that moderate agreement existed between PRPPR and CPPR .The discrepancy between PRPPR and CPPR amongst 197 patients receiving first time fluoroscopic steroid injections for musculoskeletal or radicular pain was described by Cushman et al. in 2015. The patients in this study were stratified in several ways: patients with reported pain improvement vs. patients who reported no improvement of pain; male vs. female; and by age groups . The authors reported several noteworthy findings. First, there was a fair-to-moderate association between PRPPR and CPPR at 3 weeks follow-up. Second, patients reported a higher PRPPR in comparison to their CPPR more than twice as often, leading the authors to conclude that patients are unable to assess their PRPPR compared to their preintervention pain score with a high degree of accuracy. The mean difference between PRPP and CPPR was +16% . The concordance correlation coefficient was 0.44  .Seven-hundred and sixty-one patients with acute pain or cancer pain were included in a study published in 2003 by Cepeda et al. Patients’ CPPR and PRPPR were evaluated in the acute setting, while receiving analgesics every 10 min until their pain intensity fell below 4/10 using a verbal NRS scale. This study found the concordance correlation coefficient to be 0.56 , with the authors concluding that a good  agreemenThe current study found that PRPPR overestimates CPPR in keeping with the above publications, thus validating this phenomenon. However, in contrast to previous studies, the current study found much higher levels of agreement between PRPPR and CPPR. The levels of agreement previously described were moderate to strong, while this study found very strong levels  of agreeRegarding the first question, it is worth noting that when calculating  CPPR at In 1981, Linton et al. published a study that had recruited 12 chronic pain patients to evaluate the accuracy of memory for chronic pain. The mean duration of pain experienced by the patients was 2 years, with a minimum duration of 6 months. Ninety-two percent (11/12) of the patients recalled higher levels of pain than those originally recorded as a baseline, reporting levels 19% higher . This phSeveral later studies highlighted the inaccuracy of patient recollection of pain and identified factors that may play a role in distortion of pain recollection. Eich et al. found that current levels of pain intensity alter the recollection of pain. Patients who experience higher intensities of pain at the present time overestimate their baseline pain, and patients who experience lower pain intensities currently underestimate their initial pain . In addiAfter reviewing the body of work presented in this article, the authors suggest that the underlying cause of the discrepancy between PRPPR and CPPR is inaccurate patient recollection of pain, likely overestimating past levels. However, it remains unclear which metric, PRPPR or CPPR, is a better tool for evaluating pain reduction in chronic pain patients, and this requires further research.This predicament is best illustrated when observing the phenomena clearly illustrated in Regarding the effect that various medications and interventions may have on the discrepancy between PRPPR and CPPR, and the correlation between the two, this study found no significant impact.PRPPR overestimated CPPR in the patient population of this study. The mean discrepancy between the two fluctuated minimally when patients were stratified into groups based on the duration of their treatment despite large fluctuations in both PRPPR and CPPR. Furthermore, the agreement between the patients’ PRPPR and CPPR was very strong and fluctuated minimally with the duration of treatment. The lowest value for the concordance correlation coefficient was 0.976, found in the group of patients treated for 2–3 years.As the agreement between PRPPR and CPPR is very strong, it can be inferred that any increase or decrease in either of the parameters may be predicted in the other with a high degree of accuracy. However, it is not possible to deduce which of the parameters is a more accurate representation of actual improvement in a patient’s underling pain, and further research is required to gain insight into the mechanisms driving the discrepancy between PRPPR and CPPR.


Introduction: Posterior spinal fusion (PSF) is a commonly performed orthopedic procedure to correct scoliosis in children. Continuous epidural analgesia (CEA) is a proposed means of providing analgesia following PSF. Whether a single epidural catheter with the tip in the upper thorax can provide adequate analgesia for PSF, which often spans the upper thoracic to lower lumbar regions, is unresolved in the literature.Method: In this single-center, retrospective study, we reviewed 69 consecutive patients undergoing PSF for adolescent idiopathic scoliosis (AIS) with CEA at our institution from October 1, 2020 to May 26, 2022. Data for the entire cohort was divided into two time intervals before and after epidural removal, group epidural (Epi) and group no epidural (No Epi). Daily intravenous and oral opioid morphine equivalents per kilogram (OME/kg) plus mean and maximal visual analogue pain scores (VAS 0-10) were recorded from post-anesthesia care unit (PACU) discharge to the end of postoperative day (POD) three. Results: 57 patients were included in the study. Opioid usage was 4.5 times greater in the 19 hours following removal of the epidural catheter when compared to the entire period (mean 65 hours) the epidural was in place . 51% (29/57) of patients did not require opioids  while the epidural was in place, all patients required opioids after epidural removal. Mean opioid usage while the epidural was in place was 9.3 OME, equivalent to approximately 6 mg of oxycodone. Mean and maximum pain scores increased significantly after removal of the epidural on POD 3 (mean pain score: Epi 3.4 (1.8) vs No Epi 4.1 (1.7); p<0.001) (max pain score: Epi 4.9 (2.5) vs No Epi 6.3 (2.1); p<0.001). Conclusions: This is the first study we are aware of to report pain scores and cumulative opioid requirements for PSF patients receiving CEA with a single epidural catheter before and after epidural removal. Opioid usage increased over four times in the 19 hours after epidural removal compared to the total opioid requirements while the epidural was infusing. Mean and maximum pain scores increased significantly after removal of the epidural on POD 3. This study firmly establishes that CEA with a single epidural catheter can provide profound analgesia for patients having PSF for AIS. Posterior spinal fusion (PSF) is a commonly performed orthopedic procedure to correct scoliosis in children. It is associated with substantial pain and opioid use in the postoperative period. Continuous epidural analgesia (CEA) with local anesthetic delivered via a single epidural catheter was first proposed as a means of providing analgesia following PSF in 1996 . MultiplIn this single-center, observational, retrospective study, we reviewed 69 consecutive patients undergoing PSF for adolescent idiopathic scoliosis (AIS) at our institution from October 1, 2020 to May 26, 2022. Approval was obtained for all parts of the study by the Washington Institutional Review Board, Olympia, USA. Patients who had PSF for diagnoses other than AIS, underwent previous spine surgery, or did not have an epidural for postoperative analgesia were excluded from the study. We collected demographic data for all participants to include age, gender, weight, Cobb angle, surgical duration, and number of levels fused. Daily intravenous and oral opioid requirements plus mean and maximal visual analogue pain scores (VAS 0-10) were recorded from post anesthesia care unit (PACU) discharge to the end of postoperative day (POD) three. Opioid usage was converted into oral morphine equivalents per kilogram (OME/kg) because of the wide range of weights in our study population. Pain score measurements were taken a minimum of every four hours. The mean pain score for the day was determined by summing the pain scores and dividing by the number of observations. Pain scores recorded as zero during sleep were not included . Data for the entire cohort was separated into two time intervals. The first interval began after discharge from the PACU and ended with removal of the epidural catheter at 0500 on POD 3 (Group Epi). The second time interval began after removal of the epidural catheter and ended at midnight on POD 3 (Group No Epi). The primary outcome is the comparison of opioid usage while the epidural was in place and after epidural removal. Secondary outcomes include the number of patients not requiring opioids with the epidural in place and after epidural removal, pain scores in the two group, the number of patients reporting severe pain (VAS >7) all three PODs, and complications associated with the epidural catheter.All epidural catheters were placed intra-operatively by the surgeon with the tip of the catheter measured to reach the fifth thoracic vertebral level. The epidural space was identified under direct vision between vertebral levels T8 to L1. A 16 gauge, 5.25 inch angiocatheter was advanced superiorly into the epidural space through a small midline laminotomy and the epidural catheter threaded through the angiocatheter. The angiocatheter was then removed and the distal end of the catheter was tunneled through the paraspinal muscles and out through the skin lateral to the incision. An epidural test dose was performed prior to wound closure. Following confirmation of spontaneous movement of both lower extremities, the epidural was dosed with a bolus of local anesthetic determined by the attending anesthesiologist. All epidural infusions contained 0.1% bupivacaine with 5 mcg/mL hydromorphone or 0.1 % ropivicaine with 5 mcg/mL of fentanyl. The infusion was initiated upon arrival in the PACU. The rate of the epidural infusion was at the discretion of the attending anesthesiologist. The rate of infusion and any changes to the infusion rate were collected. Once satisfactory analgesia was achieved the patient was transferred to the inpatient unit.No changes in our analgesic protocol occurred during the study period. Patients received a multi-modal analgesia regimen with scheduled acetaminophen , a non-steroidal anti-inflammatory drug , and gabapentin . Diazepam (0.1 mg/kg intravenous q6 hours) or methocarbamol (750 mg intravenous q6 hours) were available as needed for the treatment of muscle spasm. Oxycodone  and morphine (0.1 mg/kg intravenous q hours) were used as needed after discharge from the PACU for breakthrough pain of four or greater. Patients who could not tolerate morphine or oxycodone were given intravenous or oral hydromorphone. All patients received similar postoperative standardized physical therapy and rehabilitation measures. All patients had their epidural infusions turned off at 0500 on POD 3 and routinely went home on POD 4.Midway through the study period, we transitioned from a flexible, radiolucent, nylon epidural catheter  to a radiopaque, wire-reinforced, styletted Arrow TheraCath epidural catheter . Subsequently, the vertebral level and the distance from the midline of the Theracath epidural tip was confirmed on the postoperative chest x-ray. We compared opioid usage and pain scores with both types of epidural catheters.All patients received a balanced general anesthetic with propofol and remifentanil infusions plus 2% desflurane. Fentanyl, morphine, and hydromorphone were used for analgesia intraoperatively and in the PACU as determined necessary by the attending anesthesiologist per their usual practice. Neuromonitoring was employed in all cases. Foley catheters were inserted intraoperatively and were discontinued at the time of epidural removal.Statistical analysisDemographics, pain scores and opioid requirements distributions are summarized with mean and standard deviation. Unpaired t-tests were used to compare demographics, pain scores and opioid requirements among epidural catheters. Paired t-tests were used to compare pain scores and opioid requirements across time. The chi-square test was used to compare the incidence of use of opioids (yes/no) between groups.Of the 69 patients reviewed, 12 were removed for meeting one of the exclusion criteria  growing rods, one anterior spinal fusion). Patient demographics and surgical parameters of the remaining 57 patients are presented in Table For the primary outcome, opioid usage was 4.5 times greater in the 19 hours following removal of the epidural catheter when compared to the entire period (mean 65 hours) the epidural was in place . Table In the entire cohort, 51% (29/57) of patients did not require opioids  while the epidural was in place. The mean total opioid usage while the epidural was in place was 9.3 OME, equivalent to approximately 6 mg of oxycodone for the 65 hours the epidural was infusing. Two patients required a total of 4 mg of intravenous morphine while the epidural was in place. The remainder of the opioids were oral while the epidural was in place. 88% of patients (50/57) did not require any opioids from after discharge from PACU to POD 1. 38% (22/57) of patients used opioids on POD 2. All patients (57/57) required opioids after epidural removal on POD 3. Two patients required intravenous morphine after epidural removal, the remainder were oral. Opioid usage showed evidence of an increasing trend across each POD. The largest increase in opioid use while the epidural was in place was between the DOS and POD 1. Patients received a mean of 870 mcg of opioid (hydromorphone or fentanyl) via the epidural for the duration the epidural was in place .Mean and maximum pain scores increased after removal of the epidural on POD 3 (mean pain score: Epi 3.7 (1.6) vs No Epi 4.1 (1.6); p=0.005) (max pain score: Epi 5.3 (2) vs No Epi 6.2 (2.1); p<0.001). Table Maximum pain scores were greatest on POD 3 after epidural removal. The mean pain score on POD 3 after epidural removal was significantly higher than POD 1 and POD 2, but did not reach statistical significance when compared to the mean pain score on the DOS. Pain scores were similar on POD 1 and POD 2, although opioid usage showed an increase on POD 2 (p=0.03).We found no evidence that the two catheter groups were unbalanced with respect to age, gender, magnitude of the curve, surgical duration or number of levels fused. We found no differences in pain scores and opioid usage when comparing the flexible (Perifix) and stiff, radiopaque (Theracath) epidural catheters Table . We did find suggestive evidence of a decrease in the incidence of breakthrough pain in the Theracath group with 63% (17/27) not requiring opioids while the epidural was in place compared to 40% (12/30) in the Perifix group (p = 0.08). 12% patients (7/57) reported at least one episode of severe pain (VAS >7) while the epidural was in place each of the three PODs, four in the Perifix group and three in the Theracath group. The three in the Theracath group reporting severe pain each POD had epidural catheters with the tip within one vertebral segment of the fifth thoracic vertebrae and within 6 mm of the midline. The mean distance of the Theracath epidural from the midline was 0.6 mm (range 0-12 mm). The mean distance of the catheter tip from T5 was 0.7 vertebral segments (range 0-3).67% patients 38/57) had a side effect that required treatment while the epidural was infusing  that resolved after the infusion was stopped. All three of these infusions were subsequently restarted. Seven patients required a rate reduction for excessive sedation or mild hypotension. There were no episodes of hypotension that required pharmacologic treatment. 14 patients required a rate increase for inadequate analgesia. 30% patients (17/57) developed a new side effect not present before epidural removal when an opioid was first initiated  of the entire cohort experienced at least one episode of severe pain (>7) all three PODs the epidural was in place. Sucato et al. reported 13% of their epidural catheter cohort had their epidural prematurely removed, inadequate analgesia the reason in 61% of cases that had to be terminated [/57 of thWe found that a wire-reinforced, styletted epidural catheter can reliably be placed at or near a specific vertebral level in the thoracic epidural space when placed under direct vision via an angiocatheter. Using a radiopaque epidural catheter allows identification of the catheter location and in cases where advancing the catheter is difficult, steering the catheter into position is possible. Further, we demonstrated that the Theracath catheter consistently does not deviate far from the midline in scoliotic patients. The Theracath epidural catheter has a spring wire tip to discourage intravascular and subarachnoid placement. There is a case report of a knot in the spring wire tip which occurred in 1988 . This coThe use of CEA was associated with a significant number of side-effects requiring treatment. These results are consistent with a previous report . All sidThis study has limitations inherent in an observational, retrospective study. It was performed in a single-center and requires a careful comparison with multiple centers. We lacked a control group that did not have an epidural infusion, making it impossible to make any conclusions on the effect of CEA compared to someone who did not receive an epidural. However, in comparing opioid usage and pain scores before and after epidural removal each patient served as their own control. There may have been other confounders but the observed differences in pain scores and opioid usage after epidural removal were highly significant.In conclusion, this study firmly establishes that CEA with a local anesthetic mixture via a single epidural catheter can provide profound analgesia in patients having PSF for AIS with low risk. We further demonstrate that a wire-reinforced, styletted epidural catheter can reliably be placed intraoperatively under direct vision to the desired position in the thoracic epidural space with radiologic confirmation of position. Future work will focus on studying the efficacy of CEA compared to intrathecal or parenteral only opioid-based protocols.


In the case of a score of 4 on the FLACC scale, the application of 0.2 mg/kg−1 of nalbuphine was ordered. Results: After the surgery, the patients received 15 mg/kg−1 IV paracetamol every 6 h to prevent rebound pain. The patient’s hemodynamic parameters were stable and within normal range. In the first 24 h period, the FLACC scores from all patients ranged from 0 to 3. One patient required metamizole 12 h after surgery. No evidence of block complications was observed. Conclusions: This case series showed that the PENG block assured opioid-free pain management and provided adequate postoperative analgesia. However, we are convinced that future randomized, controlled trials are needed in this field.Introduction: The Pericapsular Nerve Group (PENG) block is a novel technique that allows for analgesia of the anterior hip capsule via the articular branches of the accessory obturator nerve and femoral nerve, which have a significant role in the innervation of the hip capsule. A PENG (Pericapsular Nerves Group) blockade is effective in both adult and pediatric patients. However, no studies on patients under five are available in the literature. Herein, we describe our experience with two pediatric patients with hip dysplasia. Purpose: This study aimed to evaluate the analgesic effect of the pericapsular nerves group (PENG) in preschool children undergoing hip surgery. Patients and methods: This study included two patients, aged 4 and 2 years old, who were qualified for hip surgery. Spinal or general anesthesia with the addition of a PENG block was performed. During the procedure, the basic hemodynamic parameters were monitored. The pain was assessed using the FALCC  score. A dose of 15 mg/kg The use of local anesthesia for perioperative analgesia in hip surgery is a widespread practice that has been shown to reduce pain, perioperative complications, and postoperative opioid use . In pediNeural axis technology reduces pain scores in pediatric patients undergoing hip replacement surgery. However, positioning requirements, bilateral sensory and motor blocks, and urinary retention limit their use. Caudal and lumbar plexus blocks are the most common regional blocs, which are advanced techniques. However, many anesthesiologists are reluctant to use a lumbar plexus block because of the risk of complications such as hematoma, renal puncture, and high neuraxial anesthesia . ConversGirón-Arango et al.  first deUnfortunately, there are no studies on patients under five years of age in the available literature. Therefore, we present using the PENG block for perioperative pain management in two pediatric patients undergoing unilateral surgery for pediatric hip dysplasia.Written informed consent was obtained from the parents for this scientific contribution.Patients were admitted to W. Dega Orthopedic and Rehabilitation Clinical Hospital at Poznan University of Medical Sciences with a hip pathology as a part of a multidisciplinary care pathway. After discussion with the surgical team, treatment goals included 2 days of hospitalization in the PICU (Pediatric Intensive Care Unit) for postoperative pain relief and the complete removal of motor blockade. In addition, we suggested a PENG block for postoperative pain relief instead of an epidural catheter. In both cases, after the induction of anesthesia, the PENG block was performed . The patients were kept supine during the focal block. A low-frequency linear transducer (2–5 MHz) was put in a transverse plane along the left anterior inferior iliac spine (AIIS) to identify the iliopsoas muscle, femoral nerve, and femoral artery (FA). The probe was then rotated counterclockwise to align with the pubic ramus to visualize the AIIS, iliopsoas prominence (IPE), FA, iliopsoas, and iliopsoas notch. Under direct vision, a 22-gauge 50 mm echo needle was advanced in the lateral-medial plane between the psoas tendon and the pubic ramus until the needle tip touched the IPE. The needle was withdrawn, and after negative aspiration, 0.2% ropivacaine was injected in incremental doses. Preparation and surgical positioning allowed for maximal time for block onset. −1 IV paracetamol every 6 h to prevent rebound pain. The pain was measured every 2 h using a FLACC score. A dose of 15 mg/kg−1 of metamizole was administered if the FLACC score was 3. In the case of a FLACC score ≥ 4, an application of 0.2 mg/kg−1 of nalbuphine was ordered. The evidence of block complications, like mobility disorders, bleeding, neuropathy, or systemic toxicity from local anesthetic deposition, was observed. Muscle weakness or mobility of the hip joint was difficult to follow due to the plaster cast.The basic hemodynamic parameters were monitored postoperatively during the procedure and the first 24 h. After the surgery, the patients received 15 mg/kg1st Case Report2 mixture was used, under the control of SpO2 > 94% and pCO2, within the 35–45 mmHg range . After the induction of general anesthesia, the PENG block was performed with 7.5 mL of 0.2% Ropivacaine  was performed with 1.5 mL of 0.5% heavy spinal bupivacaine. After the spinal anesthesia, the PENG block was performed with 5 mL of 0.2% ropivacaine .−1 of metamizole was administered if the FLACC score was 3. In the FLACC score ≥ 4, the application of 0.2 mg/kg−1 of nalbuphine was ordered. There was no evidence of block complications, like mobility disorders, bleeding, neuropathy, or systemic toxicity from local anesthetic deposition. Muscle weakness or mobility of the hip joint was difficult to observe due to the plaster cast. However, parents and caregivers did not observe any mobility or sensory disturbances.In the first 24 h postoperative, the patient’s hemodynamic parameters  were stable and within the normal range. After the surgery, the pain was measured every 2 h using a FLACC score. A dose of 15 mg/kgThe patient’s hemodynamic parameters were stable and within normal range. During the surgery, neither patient required extra doses of opioids. The time of the procedure was 105 and 75 minutes; the difference was due to the surgical technique. Blood loss was 200 mL and 170 mL . Postoperatively, the patients appeared comfortable with numeric pain scores of 2/3 of 10. Paracetamol was administered every 6 h to prevent rebound pain. Overnight, both patients did not require breakthrough opioids or muscle relaxants. After 12 h postoperative, 200 mg of IV metamizole was administered to the male patient due to a FLACC score of 3. Later, FLACC and subjective pain scores were 0–1/10 for the next 24 h, and the parents did not report poor pain control . On the The patients were discharged on the first evening following surgery with an acetaminophen-opioid preparation for pain control and as-needed diazepam for muscle spasms. There was no proof of block complications, like mobility disorders, bleeding, neuropathy, or systemic toxicity from large-volume local anesthetic deposition .Effective management and control of intraoperative and postoperative pain are essential in perioperative hip disease to minimize opioid use and its side effects. In our facility, most pediatric hip surgeries are performed under spinal anesthesia and propofol sedation, with preserved spontaneous ventilation. However, the 4-year-old boy had general anesthesia due to the myelomeningocele ,13. In aOne of the difficulties in controlling hip pain using adequate regional analgesia is the complex innervation of the joint by multiple nerves. The most common local anesthesia and analgesia techniques for hip surgery are the lumbar plexus block, lumbar epidurals, femoral nerve blocks, sciatic nerve blocks, fascia iliac blocks, and pericapsular injections. However, they may provide only partial analgesia or lower extremity weakness, hypotension, and related side effects, especially in patients with congenital and acquired musculoskeletal system defects .The single-shot PENG block has lately been reported in the cadaveric study ,16 and iThe technical simplicity of imaging in traction-fixed patients and no need for multiple punctures made this blockage ideal for young pediatric patients . UnfortuThe PENG block has become a widely used ultra-sound guided regional technique for facilitated motion-preserving hip blocks. However, quadriceps weakness was observed after the PENG block . The preSimilar to our study, the pediatric case reports of older children showed the opioid-sparing effect of PENG block in the first 24 h postoperative ,17,18. IA significant disadvantage of single-shot regional nerve blocks is the restricted time window of the analgesic effect. In addition, the potential for rebound hyperalgesia after a single nerve block from 12 to 24 h has been described . In our Several additives, such as alpha-2-adrenergic receptor agonists and dexamethasone, have been shown to extend analgesia following single-dose regional nerve blocks . TherefoAlso, some studies ,30,31 haIn 2021, Morrison et al.  publisheCoherent with the literature, our experience established exercise-preserving and opioid-sparing pain management using PENG blocks in patients under five. Therefore, we settled on a safe and well-tolerated pediatric range of ropivacaine 0.3–0.5 mL of 0.2% ropivacaine [


A major cause of morbidity in lower limb amputees is phantom limb pain (PLP) and residual limb pain (RLP). This study aimed to determine whether a variation of the surgical technique of inserting nerve endings into adjacent muscle bellies at the time of lower limb amputation can decrease the incidence and severity of PLP and RLP.t scores.Data were retrospectively collected from January 2015 to January 2021, including eight patients that underwent nerve insertion (NI) and 36 that received standard treatment. Primary outcomes included the 11-point Numerical Rating Scale (NRS) for pain severity, and Patient-Reported Outcomes Measurement Information System (PROMIS) pain intensity, behaviour, and interference. Secondary outcome included Neuro-QoL Lower Extremity Function assessing mobility. Cumulative scores were transformed to standardised p = 0.298), and 2.6 out of 10 for RLP in the NI cohort, compared to 4.44 in the control cohort (p = 0.035). Mean ‘best pain’ and ‘current pain’ scores were also superior in the NI cohort for PLP , and RLP .Across all primary and secondary outcomes, NI patients had lower PLP and RLP. Mean ‘worst pain’ score was 3.5 out of 10 for PLP in the NI cohort, compared to 4.89 in the control cohort . Mean PROMIS t scores were also lower for the NI cohort for PLP ; 45.0 vs 51.5 for pain interference; p = 0.015, 46.3 vs 51.1 for pain behaviour; p = 0.569). Mean Neuro-QoL t score was lower in NI cohort .Mean PROMIS Surgical insertion of nerve endings into adjacent muscle bellies during lower limb amputation is a simple yet effective way of minimising PLP and RLP, improving patients’ subsequent quality of life. Additional comparisons with targeted muscle reinnervation should be performed to determine the optimal treatment option. Postamputation pain remains a common yet problematic complication following lower limb amputation. There are two main painful neurologic sequelae following an amputation: residual limb pain (RLP) and phantom limb pain (PLP), both of which are difficult to treat, lowers the patient’s quality of life and is a major factor for poor prosthetic function . PrevalePLP is an uncomfortable or painful sensation in the lost limb, either generalised to the whole limb, or one specific region of the lost limb . ReporteRLP, also known as ‘stump pain’, is localised to the remaining limb. Often described as an electric-like or burning pain, it can be perceived to be superficial at the amputation site, deep with the limb, or involving the whole limb. RLP is usually responsible for somatosensory discomfort in amputees immediately after amputation , whilst RLP is mainly caused by terminal neuromas that from at the end of cut nerve endings. Many treatment options exist, from the early strategies utilising neuroablation via neurotoxins, to surgical management involving neuroma excision and translocating the nerve ending to another more favourable microenvironment. A new technique, targeted muscle reinnervation, was pioneered in 2002 by Dumanian, initially for better usage of myoelectric-controlled prosthesis . This inThis study was approved by the Cambridge University Hospitals institutional review board (project number 10157). The electronic patient records was searched between January 2015 and January 2021 for patients who had a lower limb amputation. Patients with upper limb amputations, younger than 18, hemipelvectomies, and those that were using neuromodulator medications were excluded. In total, 102 patients were individually contacted to complete questionnaires either via phone call or email. Twelve patients with less than 12 months follow-up were excluded. 56 patients were excluded due to incomplete responses or no response. Eight patients with amputation of digits rather than major limbs were excluded. The final sample size of general amputees was 36.At the discretion of the surgical team, several patients with various indications for major lower limb amputation  who had an amputation between January 2015 and January 2021 were given the option to concurrently undergo intramuscular insertion of nerve endings. Patients younger than 18, those with open wounds, those involved in other pain studies, those undergoing radiotherapy were excluded. Eight patients were identified, and all underwent nerve ending insertion in the same operative session as the amputation.PLP and RLP pain severity were assessed using the numeric rating scale (NRS), which includes an eleven point Likert scale. Pain severity was assessed at its best, worst, and current level over a seven day period. NRS scores of ≤ 3 suggests mild pain, 4–6 suggests moderate pain, and ≥ 7 suggests severe pain. Ordinal logistic regression was performed to determine the odds of having worse pain in the nerve insertion (NI) group compared to the control group for both PLP and RLP.t score suggest a greater pain intensity, greater pain interference or increased outward expression of pain. The aforementioned four questionnaires were given to both the normative sample of lower limb amputees, and amputees treated with insertion of nerve endings, assessing both RLP and PLP.Pain was further investigated using the Patient-Reported Outcome Measurement Information System (PROMIS) pain intensity short-form 3a, PROMIS pain behaviour short-form 7a, and PROMIS pain interference short-form 8a. The pain intensity questionnaire evaluates the patients’ pain over the past seven days using a five-point Likert scale ranging from ‘very severe pain’ to ‘no pain’. Pain behaviour looked at any manifestations of pain that would become noticeable to others, and used a six-point Likert scale from ‘never’ to ‘always’, whilst also including the option of ‘had no pain’. Grimacing, low mood, shouting for help are examples of outward expression of pain. Pain interference evaluated the extent to which pain affected patients’ daily life activities, and used a five-point Likert scale ranging from not at all to very much. Areas assessed included spending time with family and friends, doing household chores, and enjoying hobbies. Standardised t scores were calculated from cumulative scores using Assessment CenterSM’s HealthMeasures Scoring Service , with a t scores, with a higher score indicating better function.Functional assessment was conducted using Neuro-Quality of Life (Neuro-QoL) Lower Extremity Function (Mobility) Short Form, which contains eight items on a five-point Likert scale ranging from ‘without any difficulty’ to ‘unable to do’. Simple activities such as getting in and out of a car, pushing open a heavy door, walking for 15 min were assessed. Likewise, cumulative scores were converted to standardised When a neurovascular bundle is identified, the vessels are ligated and divided just short to the tip of the bone stump. Nerves were left approximately 5–10 cm longer than the maximal bone stump length, as observed grossly. The main nerves  were then divided longitudinally in half by sharp dissection leaving the fascicles intact as much as possible. This then gave two main branches of the nerve. For smaller nerves , the nerves were left approximately 5–8 cm longer, but were not divided/split.After the nerves were divided and muscle bellies prepared for suturing to the bone stump, the nerve lengths were carefully trimmed so that they fit in the adjacent muscle belly and will not be kinked when the stump is formed. Just before the muscle bellies were sutured to form the stump, the nerve endings were secured with 2/0 absorbable suture, and a small slit was created in the muscle belly. The needle of the suture was then inserted into the muscle belly and exited on the opposite side, securely burying the nerve end inside the muscle. When the suture exits the muscle belly on the other side, the suture was secured to the muscle. For each separate nerve ending, the procedure was repeated. The purpose of this procedure is to allow nerve growth into the adjacent muscle belly to avoid (or limit) neuroma growth. A diagram is shown in Fig. After identifying a neurovascular bundle, the nerve endings were dissected proximally such that eventually, the resulting end would lie deep in the stump, away from the distal end of the residual limb. The nerves were then placed under some traction, but care was taken to avoid excessive traction which could cause proximal pain and neuropathy. Ligatures were placed on the nerve ends, carefully avoiding nearby vessels, as ligation with pulsing vessels can become a source of throbbing and pain. The nerve was then allowed to freely retract.n < 10) or Chi-squared test (n ≥ 10) were used for categorical values, and Mann–Whitney U test for nonparametric continuous variables. Bonferroni’s adjustment was applied to reduce the familywise error rate when performing multiple comparisons of primary outcomes. Statistical significance was set to p ≤ 0.05.Statistical analysis was performed using IBM SPSS Statistics version 27 . Fischer’s exact test , and 2.6 out of 10 for RLP in the NI cohort, compared to 4.44 in the control cohort (p = 0.035). Mean ‘best pain’ and ‘current pain’ scores were also superior in the NI cohort for PLP , and RLP , although the improvement in current pain NRS score did not reach statistical significance. At the very worst, 33.3% in the control cohort had severe PLP and 16.7% had severe RLP, compared with 0% and 12.5% in the NI cohort, respectively. Notably, no patients in the NI cohort reported any PLP or RLP at their best state. No patients in either the NI or control group suffer from severe PLP or RLP in their current state, and only mild PLP or RLP was reported from patients in the NI cohort in their current state. Ordinal logistic regression analysis determined that compared to NI patients, the control group patients had a 2.097 higher odds (95% CI: 0.534 to 8.245) and 5.742 higher odds (95% CI: 1.362 to 24.201) of increased PLP and RLP, respectively.Patient-reported NRS scores are presented in Table t scores were lower for the NI cohort for RLP . Mean PROMIS t scores were also lower for the NI cohort for PLP ; 45.0 vs 51.5 for pain interference; p = 0.015, 46.3 vs 51.1 for pain behaviour; p = 0.569). Table t score was higher in the NI cohort than control cohort . Those with p values ≤ 0.05 are shown in bold.As shown in Table There is mounting evidence that targeted muscle reinnervation (TMR) leads to reduced PLP and RLP, and improved lower limb function and mobility, when compared to amputees treated conventionally , 10–12. Another technique that has gained traction is regenerative peripheral nerve interface (RPNI), which involves the insertion of a proximally dissected end of a peripheral nerve into a free muscle graft . The theCompared to the control group, NI decreased PLP by an average of 1.39 points (28.4%) on the NRS scale and decreased RLP by 1.84 points (41.4%). Studies of both acute and chronic pain suggest that a reduction of 2 points on the NRS scale or a decrease in approximately 30% represents a clinically important difference and is associated with decreased need to take pain relieving medication . SignifiPROMIS pain intensity, behaviour, and interference scores further supports the efficacy of NI into adjacent muscle belly. Nevertheless, despite improvements in pain behaviour in the NI cohort, the difference with the control cohort was not statistically significant. As reported in a clinical validity study, PROMIS pain behaviour seems to be less sensitive to pain intervention than pain interference scores . This prThe surgical protocol of our nerve insertion cohort is a variation of previously described protocols that implanted proximal nerve endings into adjacent muscles , 29. OurOur study has several limitations. As with most studies of this format, the main limitation is the reliance of our results on patients’ active recall, judgement of one’s own condition, and understanding of the questionnaires. The 11-point NRS questionnaire, PROMIS measures, and Neuro-QoL assessment were chosen based on their widespread use and proven clinical validity across multiple specialties , 34–37. When performed in the same sitting as the amputation, nerve insertion into adjacent muscle bellies decreased PLP and RLP intensity, decreased pain interference and pain behaviour, and improved lower limb function and mobility. Given the increasing prevalence of PLP and RLP and the significant morbidity it causes, the simple and efficient technique of NI has the potential to have a major impact of many future amputees. TMR is undeniably an advancement for better myoelectric prosthesis control, however, NI is a simple and efficient technique for decreasing symptomatic neuroma formation in patients who do not urgently need TMR for myoelectric prosthesis.In light of our results, we recommend that future studies using larger multi-centre cohorts investigate whether the benefits of NI over conventional treatment is similar to that of TMR, and if so, whether the shorter operative time, decreased surgical insult, and reduced surgical complexity warrants NI to be the mainstay of multidisciplinary amputee care.


It remains a clinical challenge identifying when joint hypermobility (JH) is responsible for pain. Previous nomenclature utilized terms such as (benign) joint hypermobility syndrome (JHS) but this was updated in 2017 as advances in genetics provide a basis for nearly all variants of Ehlers-Danlos syndrome (EDS) with the exception of hypermobile EDS (hEDS). New terminology describes hypermobility spectrum disorders (HSDs) as the updated term for JHS. Diagnosis of a subtype of HSDs should be considered in patients who have JH coupled with the presence of secondary musculo-skeletal manifestations  and at the exclusion of hEDS. Extra-articular manifestations are common. Treatment relies on management strategies for other chronic pain syndromes with a multidisciplinary approach likely optimal. Lifestyle modifications focus on weight loss and exercise. Physical therapy helps strengthen periarticular muscles, improving mobility. Pharmacologic therapies focus on judicious use of non-steroidal anti-inflammatory drugs and acetaminophen. Serotonin and norepinephrine reuptake inhibitor may help widespread pain. Avoidance of opioids remains prudent. The purpose of this review is to provide clinicians the rationale for the update in nomenclature, understand the musculoskeletal and extra-articular manifestations of the subtypes of HSDs, considerations when making the diagnosis, and treatment. Initially pain related to join hypermobility was presumed isolated to the musculoskeletal system and affect otherwise healthy patients. It was also considered distinct from heritable disorders of connective tissue such as Ehlers-Danlos syndrome (EDS). Up until 2017 this clinical syndrome was called the joint hyper-mobility syndrome (JHS) or benign joint hypermobility syndrome (BJHS).,3 Over the last two decades, greater clinical awareness of the relationship between musculoskeletal pain and JH, coupled with identification of novel genes related to clinical variants of EDS, highlighted difficulty distinguishing patients with BJHS from those with heritable disorders of connective tissue, the most frequent being EDS, hypermobility type (type III prior to 2017) (EDS-HT).The relationship between joint hypermobility (JH) and pain was described in the mid-to-late 1960s. and a familial study demonstrating co-segregation of these two disorders in pedigrees with multiple affected members fitting criteria for both. Despite genetic testing more readily available to assist in the diagnosis of various EDS subtypes, the hypermobility EDS variant still has no known genetic marker. Thus, within the EDS nomenclature the term hypermobility EDS (hEDS) was introduced and a new set of diagnostic criteria provided. For other patients who have symptomatic JH, do not have a known subtype of EDS, and do not meet diagnostic criteria for hEDS, they now have a subtype within the hypermobility spectrum disorders (HSDs).In 2017 an update in nosology was published by the Ehlers-Danlos Society, replacing clinically overlapping and occasionally confusing terms of BJHS and EDS-HT. This work was the culmination of years of expert opinion The lack of clinician familiarity and experience with the disorders, a highly variable clinical presentation, and absence of a confirmatory test, lead to continued under recognition of these disorders. Adding to the challenge of identifying patients with HSDs is the high rate of extra-articular manifestations. The purpose of this review is to update clinicians across the spectrum of healthcare about the concept and clinical impact of HSDs, the reason for and significance of the update in nomenclature, the impact that these disorders have with regard to causing chronic musculoskeletal pain, the clinical manifestations observed beyond the joints, and how to identify, diagnose, and treat patients with HSDs. This review will specifically focus on patients 18 years of age or older.Historically the diagnosis of symptomatic JH, be it attributable to BJHS, EDS-HT, or now to hEDS or a subtype of HSDs, has been challenging. With a prevalence approaching 4% of the general populations, underdiagnosis has been common. The term JH is not diagnostic but instead a description of a clinically identifiable finding, either reported on history or observed on physical examination.At the core of all HSDs, along with other heritable disorders of connective tissue, is the presence of JH. JH  describes the capability of a joint (or group of joints) to move passively or actively beyond normal limits along physiologic axes.,10 It consists of 5 questions about JH, as shown in  Reported sensitivity and specificity for the 5PQ is 84% and 85% respectively.,10 Physical examination may also identify JH. This can be assessed using a goniometer, measuring observed maximal range of motion (ROM) and comparing results appropriate for the age and gender of the patient. Another way to identify JH is to use the Beighton scoring system. This technique utilizes 9 quick, easy to perform examination maneuvers and are listed in  The presence of an observed finding is 1 point and scores range from 0 to 9. For adults, a cut-point of at least 4 out of 9 points is suspicious for GJH.,9 Measurements obtained with the goniometer and BS may be influenced by age, gender, ethnicity, and physical fitness.,11If clinical suspicion exists that a patient has JH, several confirmatory assessments are available. A screening questionnaire is available, known as the 5-Part Questionnaire (5PQ). LJH typically affects a single small or large joint but may be bilateral, such as observed bilateral genu recurvatum. When multiple joints (5 or more) are involved, the term GJH applies, and should involved all limbs and the axial skeleton. The clinical decision making regarding whether or not a patient has GJH is not necessarily as straightforward as it would seem, especially when joint ROM changes over time and there is no standardized approach that remains valid and reproducible under diverse clinical circumstances. Other subtypes of JH may also exist based on clinical practice and the literature. Peripheral JH (PJH) is a potential form of JH appreciable in the hands and/or feet. It is distinct from LJH as it involves the four limbs but distinct from GJH as it spares the large joints and axial skeleton. It may be clue to vascular EDS. Historical JH is self-reported (through the 5PQ) GJH but with a negative Beighton score (BS).When JH is observed at one or a few types of joints, this is defined as localized JH (LJH). While JH is asymptomatic, there exist musculoskeletal symptoms and complications that may reasonably be considered secondary manifestations of JH. These secondary musculo-skeletal manifestations are listed in There are currently four different subtypes in the spectrum of HSDs. They share JH with other conditions, notably EDS, and these subtypes do not appear to be Mendelian disorders.The four currently described subtypes of HSDs, in line with the aforementioned subtypes of JH, are:Generalized (joint) HSD (G-HSD): GJH objectively assessed utilizing a clinical score such as the Beighton score plus one or more secondary musculoskeletal manifestations.a. Differential diagnosis for these patients, in the context of the pattern and severity of their symptoms and clinical findings, could be due to hEDS.Peripheral (joint) HSD (P-HSD): JH limited to hands and feet plus one or more secondary musculoskeletal manifestations.Localized (joint) HSD (L-HSD): JH at single joints or group of joints plus one or more secondary musculoskeletal manifestations regionally related to the hypermobile joint(s).Historical (joint) HSD (H-HSD): self-reported  GJH by the 5PQ with a negative BS plus one or more secondary musculoskeletal manifestations. The updated 2017 terminology substitutes all previous terms used to define patients with JH but without a molecularly proven condition. Terms now outdated are EDS type III, EDS-HT, hypermobility syndrome, JHS, and BJHS.vs. BS), and the specific group of people being studied. With the elimination of the term BJHS in 2017, figures are now used to describe the combined prevalence of HSD and hEDS. The combined prevalence of HSDs and hEDS is 1 in 600 to 1 in 900. Expert opinion is that HSDs are common and that hEDS is likely to be common. The current prevalence figures are also likely underestimates because many people with EDS or HSDs experience a delay in diagnosis. Prevalence of the BJHS was about 3%-4% of the general population, affecting 3.3% of women and 0.6% of men.,13 This data was obtained from a cross-sectional population survey in the United Kingdom. Twenty-eight percent returned a survey with complete data. Around 18.3% classified as being hypermobile and 16.3% having chronic widespread pain. Those with JH were more likely to report chronic widespread pain , and hypermobile participants were 40% more likely to report the most severe pain. Another study utilized a nationwide linked electronic cohort and nested case-control design. Described using BJHS, the study identified 6021 individuals, of whom 30% were men and 70% were women. A prevalence of 194.2 per 100,000 in 2016/2017 was noted with a sizeable gender difference of 8.5 years in the mean age at the time of diagnosis.Understanding the epidemiology of HSDs has been hampered by a variety of factors. These include the updated nosology but also whether JH, GJH, or BJHS were being studied, the instrument to measure JH  report a GJH prevalence between 11%-12.5%,17 and other between 12.5%-26%.,18,19 Among professional dancers, the prevalence ranges between 64.9% and 72%.,21 GJH also appears to be more likely in younger females and less likely in older males. A large community based study which examined the frequency of GJH and how it was related to osteoarthritis (OA) by ethnicity (African American vs. Caucasian) reviewed data collected in the Johnston County OA project database from 2003-2010. From this group, 8% of Caucasians were hypermobile vs. 5% of African Americans, a statistically significant difference.Incidence and prevalence estimates for GJH vary. The prevalence of GJH in children and young adults under the age of 19 is 32.5% for girls and 18.1% for boys, with a prevalence of JH around the world at 34.1% in this study.,23 For readers interested in the currently known genetic basis of various EDS variants, the author recommends the summary provided by Malfait et al. published in 2017. For environmental factors, current theories emphasize localized biomechanical overloading and chronic soft tissue injury due to joint laxity and instability. This likely leads to soft tissue injury manifesting as localized joint arthralgias (nociceptive pain) and in some, over time, diffuse musculoskeletal pain .,8,24,25 Patients with HSDs appear to lack proprioceptive acuity, which may increase risk of injury due to difficulty judging joint position. A 2010 meta-analysis of 18 studies concluded that there is an increased risk of knee injury but not of the ankle. Compounding the effects of altered loading on the joint is an observed decrease in muscle mass and muscle strength. Increased tendon laxity leads to difficulty transmitting power produced by muscles.,29 Two studies comparing patients with asymptomatic GJH with BJHS found patients with BJHS tended toward decreased joint momenta in the lower extremities, necessitating a greater force to maintain equilibrium.,31 Of note, these conclusions have been refuted by other studies, with a systematic review questioning the clinical relevance of differences in gait and the effect that it has in the musculoskeletal pain of BJHS.The specific underlying causes and mechanisms responsible for the musculoskeletal pain reported by patients in HSDs require further extensive investigation. With the evolution of the understanding of the molecular changes responsible for most variants of EDS as well as the nosology update in 2017, the genetic backgrounds of both HSDs and hEDS are currently unknown but seem to have a weak autosomal dominant pattern.,33 This has been found in high performance athletes with GJH, and it has been speculated that this serves as a compensatory mechanism to prevent joint instability. Cross-sectional studies suggest that chronic trauma reduces the pain threshold, and hyperalgesia may serve as a compensatory mechanism to minimize joint instability. Knowledge about the pathophysiologic mechanisms that link HSDs to extra-articular manifestations is even less clear. Previously described in BJHS, higher rates of anxiety and depression may be due to pain-related fear and fear avoidance, but studies are scarce to clarify this relationship.,35,36 Even less is understood about the autonomic dysfunction patients may experience potentially due to connective tissue abnormalities.,36Beyond biomechanical factors, patients with HSDs may have neurologic perturbations that contribute to diffuse musculoskeletal pain. Generalized hyperalgesia is common and believed to be mediated by central sensitization. Fear of provoking pain and sustaining injury potentially leads to decreased levels of physical activity, hastening deconditioning and exercise intolerance.th or 7th decade of life, the onset of pain typically starts in the early to mid-teenage years. Pain may be reported as a dull to moderate ache, limited to activities or constant in nature. Weight bearing joints may be more symptomatic and/or interfere with the ability to perform activities of daily living. The joint pain may be worse with physical activity or repetitive use, potentially improving with decreasing the intensity of the activity. Prolonged morning stiffness lasting more than 30 min is unusual, although with chronic widespread pain prolonged morning stiffness may last longer.Symptoms may have a highly variable presentation, with patients likely coming to the attention of the medical establishment because of their musculoskeletal symptoms. With a possible onset at any age, even as late as the 6 The strongest associations of HSDs are with orthostasis, a variety of functional gastrointestinal disorders, and pelvic and bladder dysfunction., 52, 53 though not exhaustive, summarizes the growing list of extra-articular manifestations associated with HSDs.The review of systems may capture information about the extra-articular manifestations of HSDs. Patients may have mental health, nervous system, and digestive system issues with a higher odds of receiving a prescription in other disease categories  within 12 months before and after the diagnosis. although sometimes with variable expression.Family history is also important to obtain. It is possible that a family history of JH or GJH will be reported by a patient using a term such as “double jointed”. Whether or not these family members have pain will vary, but some family members might have been diagnosed with BJHS classical EDS, vascular EDS, and hEDS have an autosomal dominant pattern of inheritance, Overt synovitis is unusual, but some patients may have small effusions as a consequence of meniscal or cartilaginous irritation. Some patients may have scoliosis, lordosis, pes planus, valgus deformities of the knees, or easy joint subluxation. Musculoskeletal findings that might be a clue that the patient has a heritable disorder of connective tissue would be arachnodactyly or an arm span-to-height ratio ≥ 1.05. Cutaneous findings inconsistent with HSDs are unusually soft or velvety skin, mild skin hyperextensibility, piezogenic papules of the heel, and atrophic scarring. The presence of mitral valve prolapse (MVP) or aortic root dilatation on echocardiograph may again point to a diagnosis other than a subtype of HSDs.Physical examination should utilize the BS, focus on a thorough musculoskeletal exam, and assess cutaneous findings that might point to a heritable disorder of connective tissue. Joints should be examined for tenderness, swelling, redness, and deformities in addition to assessing ROM. Patients may potentially transition through various HSDs as their symptoms evolve. It is paramount to exclude the possibility that a patient has hEDS. The process of excluding hEDS make require several visits and expert evaluation given the need for detailed history taking and observing subtle clinical findings. The author recommends using the 2017 International Classification of the Ehlers-Danlos Syndromes by Malfait et al. for the criteria to diagnose hEDS.For diagnosis, JH should be identified at some point during the evaluation of the patient coupled with the presence of secondary musculoskeletal manifestations, and with the exclusion of hEDS. Conceptually, asymptomatic JH, the HSDs, and hEDS fall on a spectrum ranging from isolated JH to hEDS. Treatment of dysautonomia in patients with HSD may improve both fatigue and pain. The majority of patient with a subtype of HSD may reasonably be managed at a primary care level, but access to physical therapists as well as mental health specialists skilled in biofeedback and cognitive behavioral therapy may also provide substantial supportive care.,55 Plausibly other specialists such as rheumatologists, pain managers, sport medicine specialists, or orthopedic surgeons may be needed. Extra-articular manifestations may also require subspecialist evaluation and management, for example, dysautonomia and postural orthostatic tachycardia syndrome (POTS) managed by a cardiologist.A multidisciplinary approach is presumed to be the best way to globally address symptoms. The focus should address the cause of the pain , reducing pain when possible, and maximizing functional capacity and quality of life. Training was cited as a significant issue, with most respondents citing a lack of access to external training (80%).  Second, patients with a subtype of the HSDs will likely have challenges establishing a meaningful relationship with health care providers. A lack of familiarity with the concept of HSDs , the debilitating effect of chronic pain, extra-articular manifestations that mimic a systemic autoimmune or inflammatory arthritis, and years of diagnostic delay make it challenging for a patient to place trust in health care providers when for months or years they have been diagnosed with other pain syndromes. Eleven patients with HSD/hEDS interviewed as part of a phenomenological hermeneutic study revealed that relationships among HSD/hEDS patients are adversely affected. These patients reported change in their social network and that various type of relationships were influenced by their disease.Two limitations exist with the management strategy noted. First, specialists with familiarity assisting the management of a subtype of HSD may not be readily accessible. A survey distributed to rheumatology occupational and physical therapists in Scotland found that they had expertise in the management of HSD/hEDS patients however, the expertise was concentrated in higher levels of care, making it a challenge for patients managed at a primary care level to access.  Modification or restriction of certain activities required by their employment might be needed stretching techniques should be focused on tight muscles, not lax joints.,8 Neuromuscular taping and bracing may help to prevent injury and improve gait. Patients with HSDs should consider strengthening programs for periarticular musculature in order to stabilize joints.,60 Some patients may be apprehensive of joint injury (or repeat joint injury), and for this cognitive behavioral therapy may be helpful.Lifestyle modification is potentially beneficial for patients with HSDs, although rigorous studies evaluating the efficacy of any particular intervention are lacking. Empiric strategies would include weight loss, incorporating anti-inflammatory foods and diet strategies , and participation in regular exercise. A randomized trial of 21 patients assessing multidirectional shoulder instability in HSD/hEDS patients found home-based exercise programs were beneficial for improving shoulder function using several different validated indices. Regarding intensity, some clinicians favor low-load strengthening exercises, concerned that high-load strengthening exercise may lead to joint injury, though this lacks support in the current literature. A randomized trial of 100 adult patients demonstrated that after 16 weeks of therapy, high-load shoulder strengthening exercise was statistically superior to low-load strengthening exercise for self-reported function. No serious adverse events were noted. A different study enrolled 14 HSD/ hEDS patients in a multidisciplinary rehabilitation regimen consisting of physical training to improve aerobic capacity, muscle strength and proprioception. At the end of 8 weeks patients showed a clinically relevant improvement in functional disability, muscle strength, perceived harmfulness, and pain intensity.Isometric exercises appear reasonable as they do not extend the muscle completely. An observational study of 27 female patients with HSDs/hEDS demonstrated isometric external rotation while holding a 2 kg dumbbell resulted in inferior translation whereas isometric shoulder flexion and shoulder/elbow extension respectively led to anterior-superior and superior translation. Muscle pain or spasm may be treated with antispasticity agents such as baclofen or tizanidine, although patients with exercise intolerance or orthostatic symptoms may not tolerate TCAs or tizanidine. Patients with comorbid fibromyalgia may benefit from gabapentin or pregabalin. Patients surveyed through the Ehlers-Danlos Society diagnosed with EDS or HSD reported that the most commonly used therapies were NSAIDs, acetaminophen, opioids, and physical therapy (70%-92% of patients). Therapies rated as most efficacious were opioids, physical therapy, and marijuana. Patient-initiated complementary therapy use was widespread (56%) and mainly utilized by patients with higher reported levels of pain. Vitamin C may be useful in addressing some cutaneous features, and vitamin D supplementation may be required in those with reduced bone mineral density and hypovitaminosis D.,66Pharmacologic treatment strategies are similar to that for other chronic pain conditions with avoidance of opioids and a deference toward non-steroidal anti-inflammatory drugs (NSAIDs)/acetaminophen, topical NSAIDs, and antidepressants (particularly serotonin and norepinephrine reuptake inhibitors (SNRIs) or low-dose tricyclic antidepressants (TCAs).While the relationship between JH and pain has been known for decades, it remains a challenge identifying when JH is responsible for pain. Variability in patient symptoms and clinical presentation, clinician inexperience identifying pain attributable to hypermobility, and recent changes in nomenclature make diagnosing patients with a subtype of HSD fraught with difficulty. In addition to joint and regional pain attributable to muscle/tendon involvement, extra-articular manifestations are common. The current treatment of pain borrows from studies using older nomenclature as well as management of other chronic pain syndromes. A multidisciplinary approach is likely optimal, incorporating specialists such as physical therapist and mental health specialists to address the regional and chronic pain that patients with subtypes of HSD experience. Lifestyle modifications focused on weight loss and exercise create the foundation for therapeutic interventions for HSDs. Isometric exercises appear reasonably safe and effective but data is limited to regional management (shoulder). Pharmacologic therapies focus on judicious use of NSAIDs, acetaminophen, and use of SNRIs and TCAs for more widespread pain.