Background and Objectives: To assess the effect of continuous cold flow (CCF) therapy on pain reduction, opioid consumption, fast recovery, less perioperative bleeding and patient satisfaction in patients undergoing a total knee arthroplasty. Materials and Methods: Patients affected by knee osteoarthritis between September 2020 and February 2022 were enrolled in this case-control study. Patients were randomly divided into two groups : the study group received postoperative CCF therapy while the control group was treated by cold pack (gel ice). The CCF device is a computer-assisted therapy with continuous cold fluid, allowing a selective distribution, constant and uniform, of cold or hot on the areas to be treated. In both groups, pre- and postoperative evaluations at 6, 24, 72 h and at the fifth day were conducted using Visual Analogic Scale (VAS), opioid consumption, passive range of motion, preoperative hematocrit, total blood loss by Gross formula, transfusion requirement and patient satisfaction questionnaire. Results: One hundred patients, 52 women (52%), were included in the study. Reduction of pain, opioid consumption and increase in passive range of movement were statistically significantly demonstrated in the study group on the first and third days. Patients were satisfied with adequate postoperative pain management due to CCF therapy (p = 0.01) and they would recommend this treatment to others (p = 0.01). Conclusions: A continuous cold flow device in the acute postoperative setting after total knee arthroplasty is associated with pain reduction and improving early movement. Patients were almost satisfied with the procedure. The management of perioperative pain control could improve participation in the early rehabilitation program as demonstrated by the increase in ROM, psychological satisfaction and reduction in opioid use. Total knee arthroplasty (TKA) is a widely accepted and successful procedure for end-stage arthritis. However, being a major orthopedic intervention, it is accompanied by tissue damage and an inflammatory response, manifesting as local swelling and edema ,2, reducPain is often severe in the early postoperative period, impeding rehabilitation . MultimoCold therapy for pain reduction is an accepted and frequently used treatment in daily practice after trauma or surgery. It involves the application of cold to the skin surrounding the injured soft tissues and in joint surgery is supposed to reduce the intraarticular temperature  Figure . It is sSeveral cold therapeutic options are available, including first generation cold therapy, such as crushed ice in a plastic bag; second generation cold therapy with circulating ice water with or without compression; and third generation advanced computer-assisted devices with continuous controlled cold therapy. The advantage of these latter devices is the possibility of temperature modulation with cooling at a specific and continuous temperature  for a prolonged time. These devices also allow a progressive increase in the temperature before stopping the treatment to avoid secondary cold-induced vasodilatation, and they are not needed to be periodically filled with cold water or ice .Even though some studies show excellent results regarding computer-assisted continuous cold flow therapy, the quality of the available literature is not convincing and level I evidence is still missing .The main aim of this study is to assess the effect of continuous cold flow therapy on pain reduction, opioid consumption, ROM recovery, less perioperative bleeding and patient satisfaction in patients undergoing a TKA.This is a prospective, case-control, monocenter study, validated by the Ethics Committee (protocol number: 10/CE/2020—1 June 2020) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All the patients involved in the study gave their informed consent prior to their inclusion in the study. The patients who were scheduled to undergo primary TKA replacement for grade IV gonarthrosis due to a proven painful knee osteoarthritis, who need to obtain pain relief and improve function, who were able and willing to follow instructions, were enrolled and treated at the Di Venere Hospital of Bari between September 2020 and February 2022.http://www.randomization.com, accessed on 1 September 2020). After surgery, the circulating nurse reviewed the random numbers list. The study group was represented by patients who were treated with postoperative continuous cold flow (CCF) therapy; the control group included patients treated with a cold pack (gel ice) postoperatively.The patients were divided into two groups using a predefined program  between 20 and 29.9 and chronic history (for at least 4 months) of knee joint pain.The exclusion criteria were inflammatory diseases, infection, coagulopathy, previous knee surgery, history of deep vein thrombosis or pulmonary embolism, rheumatoid arthritis, pregnancy and patients who were not able to understand and complete the procedure due to cognitive dysfunction or language barrier.The sample size as a prospective study was calculated using a pain score tested by visual analogic scale (VAS), referring to previous paper values on the same treatment protocol  as primaBetween September 2020 and February 2022, one hundred and twelve patients with grade IV gonarthrosis were evaluated for eligibility for the present study. Four patients had previous surgery of the knee, four patients participated in another study, two were living in another country, one declined to participate, and one other patient had reprieved the operation. Therefore, they were excluded from the study. Subsequently, 100 patients were included. An overview of the number of patients recruited, enrolled and analyzed in this work is presented in For each patient, the following data were recorded: age; sex; BMI; side of surgery; American Society of Anesthesiologists score (ASA) , surgicaData were recorded at the following times: T0 ; T1 (six-hours post-surgery); T2 (24 h post-surgery); T3 (72 h post-surgery) and T4 (fifth day post-surgery).Opioid consumption was measured as number of tablets, tramadol (50 mg), used in the postoperative days. All patients received standard pain therapy with acetaminophen 1 g every 12 h, ketorolac tromethamine 30 mg and daily low molecular heparin injections  as thrombosis prophylaxis up to 4 weeks after surgery.Passive range of motion as functional recovery was measured by the same operator for each patient using an orthopedic protractor.Blood loss was evaluated only at T2 using the formula described by Gross.Transfusion requirement was evaluated as the number of blood transfusions during hospitalization (transfusion trigger was set at 8.0 g/dL of hemoglobin).Patient satisfaction was assessed via questionnaire. Participants reported their overall satisfaction by placing an X on a 10-cm line (from 0 (extremely unsatisfied) to 10 (extremely satisfied)). The distance was measured in centimeters from the beginning of the line to the center of the patient’s X, using a ruler with 1-mm increments. Participants were also asked to recommend the method of cooling, answering “yes” or “not”.® Surgical, ConvaTec Inc., Reading, UK) for 7 days and a compressive dressing was applied in the operating room. A strict urinary nurse-led bladder scan management protocol was used for the prevention of postoperative urinary retention [According to a standardized protocol, patients received antibiotic prophylaxis with cefazolin 2 g and premedication 2 h before operation with acetaminophen 1 g. Patients were operated under spinal anesthetic treatment by one experienced knee surgeon (VC), performing a minimum of 150 TKA procedures annually. Patients were operated on using a midline anterior incision with a medial parapatellar arthrotomy and with the use of dedicated instruments for the implantation of a cemented Postero-Stabilized (PS) TKA   was dedicated to each patient during the entire period of hospital stay. It is a computer-assisted continuous cold flow therapy allowing a selective distribution, constant and uniform of cold or hot, on the areas to be treated. Patients cooled the affected knee according to a fixed protocol.The application started the day before surgery for 3 h and repeated within 6 h post-operation for 3 h. Then it was applied for 3 h respectively in the morning and in the afternoon, during the five postoperative days.Temperature was set at 5° as efficient CCF therapy requires cooling the skin and achieving reduction in pain according to Chesterton et al. . CompresIn the control group patients received 15 min cold pack (conserved at −17°) treatment with two cold packs anterior and one posterior to the knee within 6 h post-operation and then repeated at 2 and 4 h after surgery. The following days patients received the same cold pack 15 min after each physiotherapy session (10 am and 3 pm). Cold packs were also permitted as requested during the night. No compression was applied.Thereafter the same rehabilitation program was employed for all patients, consisting of full weight bearing and active range of motion exercises at day of surgery. A continuous passive motion device was used twice a day. As a primary endpoint, pain was quantified using the VAS scale with scores ranging from 0 (no pain) to 10 (worst imaginable pain).The functional recovery, pain management, blood loss and patient satisfaction were assessed as a secondary endpoint.® Inc., Armonk, NY, USA). Descriptive statistics were calculated for the overall sample and for follow-up. Categorical variables were presented as numbers or percentages. Continuous variables were presented as mean and standard deviation. Due to the non-homogeneous distribution of the values using the Kolmogorov–Smirnov test (p > 0.05), non-parametric tests were considered. To compare the average values between the groups at the same times, the U Mann–Whitney test or Fischer’s test were used, when appropriate. To compare the value within the same group at different times, the Wilcoxon test or Related-Samples Friedman’s test Two-Way Analysis of Variance were used. To demonstrate the correlation between the CCF device and variables, a multiple regression model was then fitted. For all the tests, a p-value of less than 0.05 was considered to be statistically significant.A prospective clinical study was conducted. The data were collected and analyzed using SPSS  and the differences between the groups were changed one- and three-day postoperative.Descriptive values and comparison results of passive knee range of motion values are given in No statistically significant difference was found between the groups regarding blood loss and transfusion number .Patients treated with CCF therapy were more satisfied than the control group .The multiple linear regression models showed postoperative VAS score and opioid consumption were influenced by CCF therapy rather than other preoperative variables .After a major orthopedic surgical procedure, such as TKA, pain control is imperative to promote rapid recovery and collaboration to the rehabilitation program. Nowadays, specific pathways of care, including enhanced recovery after surgery (ERAS), have been introduced. It has been proposed these pathways, along with multimodal analgesia, have reduced the length of hospital stay (LOS) for patients undergoing TKA . AnalgesThe most important finding in our study is that postoperative computer assisted CCF therapy is effective in pain control after TKA and associated with reduction in analgesic use during the early postoperative period. It is also associated with a major passive ROM during the first two days and with a great grade of patient satisfaction. We enrolled a larger study population if compared to power analysis due to the possibility of patient refusal and to strengthen the results.Significant reduction in VAS was observed only at T2 (24 h), however there was a reduction in VAS after every cooling session in the study group. Similar to these findings, pain reductions in the acute postoperative phase were reported ,28,29. IConsumption of analgesic was also investigated in this study. In our paper the consumption of additional opioids as rescue medication was up to two times greater in the control group than in the study group. However, this trend was significant only in the first two postoperative days, with these days being the worst period for pain management.The incremented use of opioids can slow a patient’s rehabilitation program due to side effects . A slower rehabilitation can be associated with retarded discharge and increased costs .Su et al.  showed aThe CCF therapy is crucial and ensures that the knee ROM movements start in the early postoperative period. There were studies reporting that the CCF therapy affects the knee movement gap in a positive way in the early postoperative period ,35,36. IPatients reported high satisfaction rate with postoperative cooling and were likely to recommend icing device. Less pain could substantiate this validation. The high level of satisfaction may also be associated to greater patient contact with the staff conduction device function and periodic skin and dressing check. The psychological aspect plays a key role in rehabilitation . Only twBlood loss evaluation is a key point to justify routine use of a cold flow device, considering its additional costs. Reduction in blood loss and blood transfusion may reduce costs associated with TKA. Additionally, blood transfusion is associated with an increased rate of periprosthetic infection. In our study we found that the total blood loss measured by Gross formula in the postoperative period in the study group was lower than in the control group; however, non-statistically significant values were observed in total blood loss. Kuyucu et al.  also didThe evaluation method of blood loss could explain the difference in results in the literature. We decided to use the formula described by Gross et al.  for blooThe novelty of this study is the careful analysis of the patient’s outcomes combined with their satisfaction. Psychological well-being improves clinical outcomes and makes the patient prone to better physiotherapy .Our study has several strengths. This was performed in one single center, one single experienced surgeon performed all surgeries using the same surgical approach, one type of anesthesia, implant, pain and rehabilitation program. The self-reported patient satisfaction questionnaire is an additional element considering the importance of a fast-track recovery plan in replacement surgery.However, some limitations must be considered. The sample size could be increased. Better evaluation of blood loss throughout alternative formula, including Hb values, should be adopted. Another limitation is that patients were evaluated only during the hospital stay so it cannot draw definitive long-term conclusions about CCF therapy efficacy.Continuous cold flow devices in the acute postoperative setting after TKA are associated with pain reduction and improving early ROM. Although reduction in blood loss throughout the Gross formula was observed, no significant differences were found. Patients were almost satisfied with the procedure and should recommend it to improve perioperative pain control and participation to the early rehabilitation program due to lower opioid consumption and higher passive ROM.


Under carbamazepine (daily dose 254 ± 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale . Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of Aδ-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects (n = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement (n = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional Aδ-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic ( Carbamazepine is an approved treatment option for neuropathic pain, e.g., in diabetic neuropathies  or trigeMuscle pain is a common symptom experienced by patients with neuromuscular diseases ,6,7 thatLike mexiletine, carbamazepine blocks voltage-gated sodium channels that are mainly expressed in peripheral C and Aδ nerve fibers . DysfuncIn this study, we screened a cohort of 560 myopathy patients for reported muscle pain. In 54 of these, carbamazepine had been prescribed to control chronic muscle pain within the past four years. We describe the etiological heterogeneity of muscle pain, characterize these patients, and assess both treatment response  and sideWe enrolled adult patients (>18 years) with chronic muscle pain that had been diagnosed with a hereditary or acquired muscle disease and received at least one prescription of carbamazepine as a symptomatic pain medication. Patients with carbamazepine treatment due to epilepsy, trigeminal neuralgia, or diabetic neuropathy were excluded, as were patients that were treated with oxcarbazepine. The underlying muscle disease had been diagnosed following standard procedures, including clinical examinations , electroWe screened clinical records belonging to 1683 patients overall and 3168 visits from 2016 to 2018. Out of these, 560 patients had an underlying myopathy and 54 of them were treated with carbamazepine a,b. TwenAll clinical examinations were conducted by the same, trained personnel  at the Neuromuscular Outpatient Clinic, Department of Neurology of the RWTH Aachen University Hospital, Aachen, Germany. We additionally evaluated records from previous visits. The study complied with the Declaration of Helsinki and was approved by the local ethics committee (EK00418).Within the frame of a standardized clinical interview, we assessed the patients’ history including symptoms, medical and family history, as well as previous and current medications, focusing on pain characteristics, influencing factors, localization, dynamics, radiation, and intensity. Additionally, we assessed potential sources of bias including the intake of statins ,33,34 orTo assess the pain type and character, we used the painDETECT questionnaire, which is designed to distinguish between nociceptive and neuropathic pain. With an overall score of fewer than 13 points, a neuropathic pain component is unlikely (<15%), whereas a score higher than 18 points indicates the presence of neuropathic with a probability above 90%. The overall sensitivity and specificity of the painDETECT questionnaire account for 84%, each .patient − meancontrol)/SDcontrol. This enabled the distinction between loss and gain of fiber function [Detailed sensory phenotypes were evaluated by quantitative sensory testing (QST) in order to (1) identify the most prominently involved nerve fibers correlating with muscle pain and (2) draw conclusions on potentially co-existent neuropathy. The QST uses calibrated stimuli on defined skin areas. As a test area, we chose the right foot in 22 patients, the left foot in 1 patient, and the right hand in 1 patient. In our protocol, we used the standardized test battery and reference values from the German Research Network on Neuropathic Pain (DFNS) ,37, consfunction ,37. For Pathological values in cold detection threshold (CDT), cold pain threshold (CPT), heat pain threshold (HPT), mechanical pain threshold (MPT), PHS, or pressure pain threshold (PPT) suggest malfunctioning of Aδ fibers whereas differences in HPT, warmth detection threshold (WDT), and also PPT, or CPT show a C fiber dysfunction. Deviations in mechanical detection threshold (MDT) and vibration detection threshold (VDT) point towards the involvement of Aβ fibers. Central sensitization is assumed if there are deviations in dynamic mechanical allodynia (DMA), HPT, or mechanical pain sensitivity (MPS). A positive wind-up ratio (WUR) suggests temporal summation ,37,39.Laboratory analyses were performed in peripheral blood in order to exclude potentially interfering causes of peripheral nerve dysfunction, for example, alcoholism, or diabetes mellitus, as well as to assess carbamazepine side effects.t-test if data followed a Gaussian distribution. Otherwise, we used the Mann–Whitney U test. To compare the same subgroup before and under carbamazepine treatment, we used the paired/dependent t-test. For group comparisons, we used one-way ANOVA or the Kruskal–Wallis test if non-parametric. The level of significance was defined as p < 0.05. For α-error correction, we used the Dunn’s test. Correlation analyses were performed with the Pearson or Spearman test.We imported the original dataset into GraphPad Prism 5. We tested Gaussian distribution using the D’Agostino and Pearson omnibus, Kolmogorow–Smirnow, and Shapiro–Wilk normality tests. To compare two subgroups within our study, we used the Student’s Our study represents a real-life cohort of individuals with muscle pain examined at a specialized rare disease and neuromuscular center a. MuscleMuscle diseases were assigned as myopathy of unknown origin (30%), benign cramp-fasciculation syndrome (20%), (suspected) neuromyotonia (14%), mitochondrial myopathy (6%), myofibrillar myopathy (4%), central core myopathy (4%), paramyotonia congenita (4%), FSH dystrophy type I (4%), centronuclear myopathy (4%), metabolic myopathy (2%), myotonia congenita type Becker (2%), phosphorylase deficiency type McArdle (2%), autoimmune necrotizing myopathy (2%), proximal myotonic dystrophy type II (2%), nemaline myopathy (2%), and myositic overlap syndrome (2%).Independent of the underlying muscle pathology, myalgia was reported as the first symptom in 89% of the patients, followed by muscle cramps in 46%, fasciculations in 31%, muscle weakness in 22%, muscle stiffness in 11%, and atrophies in 2% .In 91% of the patients, no special incident was described prior to symptom onset. In the remaining 9%, the following triggers were subjectively attributed to the manifestation of muscle pain : mononucleosis, hepatitis C, statin intake, physical stress/ sleep deprivation, and a fall. Patients described the disease course to be progressive (72%), stable (22%), or fluctuating (2%). Assessing the current symptoms, myalgia was the most common one found in 85%, followed by muscle weakness and cramps in 35%, fasciculations in 22%, muscle stiffness in 6%, joint pain in 4%, and hyperflexible joints, atrophies, headaches, and recurrent subluxations in 2% each .We obtained 90 CK values from 50 patients. Of these, 26 patients had an elevated CK level  at least once and 24 patients were within the normal range at all times. CK levels were most elevated in three patients with McArdle disease (2639 U/L), proximal myotonic dystrophy type II (2888 U/L), and centronuclear myopathy (1054 U/L). Previous rhabdomyolyses were reported by one patient with myopathy of unknown origin .In 78%, the family history was not informative regarding neuromuscular disorders. Six percent reported first-degree relatives with comparable symptoms, although not being systematically assessed by a specialized physician. There was a positive family history for polyneuropathies, rheumatism, and Parkinson’s disease in 4% and for myotubular myopathies, amyotrophic lateral sclerosis, or spinal muscular atrophy (SMA) in 2%. Other diseases in the family history were gouty arthritis and fibromyalgia.On average, the study participants had already been suffering from muscle pain for 14.2 ± 14.5 years  at the time of examination. The mean NRS during the study visit was 4.2 ± 2.7 . The pain dynamics were described as pain attacks (50%), persistent pain with pain attacks (38%), and persistent pain with slight fluctuations (13%). In addition to these pain qualities, 63% suffered from muscle cramps. Whole body pain was reported in 43%, followed by more localized manifestations at the limbs, including upper and lower leg muscles evenly in 39%, only the lower limbs in 13%, and 6% did not specify the localization of pain. Forty-three percent described their muscle pain to be generalized, and 6% did not clarify the exact localization. To describe the character of pain, the following attributes were most commonly used: soreness (62%), burning (21%), pricking (21%), pulling (21%), pressing (7%), cramping (7%), piercing (6%), heat-like (3%), and pulsing (3%). Pain radiation was reported in 14 patients (58%). A potential trigger of pain exacerbation was physical stress (57%). One patient reported an intensification of pain in the evening, while another patient experienced pain peaks in the morning. As mitigating factors, study participants reported warmth (15%) and physiotherapy (4%) including relaxation techniques, massages, and acupuncture, whereas others described moderate physical activity to be soothing. Fourteen patients (26%) had limited their professional situation either by changing from a mostly standing to a seated activity (2%) or by early retirement (24%).n ≥ 18) of patients rated the frequency of occurrence as “never”, “hardly noticed”, “slightly”, or “moderate” (0–3 points). Only the two items “tingling sensations” (67%) and “numbness” (71%) were rated less often by two and one individual(s) in the range from 0 to 3 points. Out of the eight patients that described more severe (4–5 points) tingling sensations (19%) and numbness (11%), two had a mild sensory deficit in the lower extremities.In the painDETECT questionnaire completed by 44%, the mean score (±SD) was 7.6 ± 6.6  points. A neuropathic pain pattern (≥19 points) was found in two patients (8%), whereas three were classified in the borderline range (13–18 points). More than 80% of our cohort did not show any neuropathic pain component (≤12 points). For each designated neuropathic pain item, the majority  affected hip flexors in 41%, hip extensors in 26%, knee extensors in 24%, knee flexors in 24%, arm extension in 11%, arm abduction in 9%, and finger spreaders in 6%. Furthermore, we observed atrophies , scoliosis (11%), scapular winging (11%), fasciculations (7%), myotonia (8%), myoclonus and rippling (2%), ptosis (5%), and a signe des cils (5%).Compared to healthy controls, the QST profiles in patients with chronic muscle pain showed a significantly lower Z-Score for CDT, WDT, and TSL, showing hypoesthesia for both cold and warmth perception. A significantly elevated Z-Score for MPT indicated mechanical hyperalgesia, and a significantly lower Z-Score in VDT showed vibrotactile hypoesthesia. We observed significantly more paradoxical heat sensations (PHS), and the significantly elevated DMA indicated allodynia in our muscle pain cohort .In this study, the only indication for carbamazepine treatment was chronic muscle pain. With a mean duration of carbamazepine intake of 13.4 ± 22 months (range 0–120 months), the average daily dosage was 253.7 ± 138.3 mg (range 100–900 mg). We observed continuation in 17%, and 15% did not report any side effects. Seven percent of patients received a carbamazepine prescription but decided not to take it. Forty-four percent stopped taking carbamazepine due to side effects. The most commonly reported side effects leading to drug discontinuation were elevated liver enzymes, nausea, or fatigue  (p = 0.0359) in patients with a nociceptive painDETECT-score compared to patients with an unclear or neuropathic result (p < 0.01), meaning that patients with higher NRS levels reported a greater pain reduction under treatment.In a standardized retrospective assessment, 48% of patients reported a relevant improvement of muscle pain under therapy, while 15% did not observe any effect, and 7,5% were unsure. The average NRS before carbamazepine treatment was 6.8 ± 1.6  while being 4.77 ± 1.99  under treatment. The pain reduction  was highly significant in this cohort (< 0.001) a. There c result b,c. RespWe herein describe a representative real-life cohort examined at a German neuromuscular reference center, showing that the range of underlying conditions associated with muscle pain is broad, making it even more challenging to address this type of pain in clinical practice.To date, there is no approved drug available specifically for the symptomatic treatment of muscle pain. Ours and other studies ,41,42 shIn our study, carbamazepine treatment significantly lowered the reported pain levels. The mechanism of action might therefore be less specific for neuropathic, but also apply for nociceptive pain. It is known that carbamazepine blocks voltage-gated sodium channels, such as Nav1.7, and nociceptors that are highly expressed in peripheral nerve endings . The genPatients with myopathy show small fiber dysfunction on QST when examined over the skin of mainly foot dorm. It is possible that nociceptive fibers in the muscles themselves are also affected, in which case carbamazepine would co-treat a possible neuropathic pain component. However, this was hardly the case, as shown in Sensory profiles can, however, vary between tissues—there is, unfortunately, no method available to directly examine the nerve fiber function in muscles. Interestingly, myopathy patients showed sensory plus signs such as pinprick hyperalgesia and dynamic mechanic allodynia as well as paradoxical heat sensations upon cooling. These measures are consistent with the concept of a possible secondary central sensitization of the nociceptive system  either tMuscle pain is a complex pain syndrome that has mostly been considered nociceptive. In this work, we show that patients with nociceptive pain may still have small fiber dysfunction, which adds to the complexity of pain and might complicate therapeutic choices. In accordance with our results, other studies on nociceptive pain syndromes suggest that central sensitization might likewise play a role in non-neuropathic pain syndromes ,45.Despite an apparently good treatment response, 25 out of 54 patients discontinued carbamazepine treatment within six months (mean). This was mostly related to fatigue 15%), no improvement (11%), and liver enzyme elevation (7%). These side effects have previously been reported in association with carbamazepine, independent from its indication . Compare5%, no imCarbamazepine has a long-term tradition as an anti-seizure drug, and its indication was extended for neuropathic pain syndromes, including diabetic neuropathy  and trigCLCN1) and skeletal muscle voltage-gated sodium (SCN4A) channels [In 2018, mexiletine was approved for the symptomatic treatment of non-dystrophic myotonia (paramyotonia congenita and myotonia congenita)  caused bchannels . Mexiletchannels  previouschannels . In 2020channels  in the aAs a potential limitation of this study, the examined cohort was heterogeneous, including various underlying conditions b. It is Acknowledging that randomized, placebo-controlled, and double-blinded studies are necessary for high-level evidence, we admit that our retrospective study design comes with certain limitations: The time point, duration, and dosage of carbamazepine treatment were not standardized. The evaluation of treatment response was based on the subjective evaluation of pain intensity reported by patients, coming with a potential recall bias, a problem that is, however, difficult to overcome in any type of pain condition, especially in a retrospective study design. A selection bias might have arisen from the fact that we only received feedback from patients who were motivated to participate in the study.We conclude that carbamazepine can be a useful medication and improve quality of life in patients with neuromuscular disorders. Due to the high rate of side effects leading to discontinuation, the expected beneficial effects of carbamazepine should be carefully weighed up against the potential risks.


Sternocostoclavicular hyperostosis (SCCH), the main clinical manifestation of chronic non-bacterial osteomyelitis (CNO) in adults, is associated with various degrees of chronic pain and restricted shoulder girdle function. We evaluated the impact of CNO/SCCH on quality of life (QoL) and its determinants in 136 adult patients with this rare auto-inflammatory bone disorder using the Short Form 36, Brief Pain Inventory, Brief Illness Perception, Utrecht Coping List, and Shoulder Rating questionnaires. Data were compared with those of the general Dutch population, patients with chronic pain, fibrous dysplasia, or osteoarthritis. Eighty-six (64%) predominantly female (85%) patients with completed questionnaires were included in the study. Sixty-four (75%) had isolated CNO/SCCH. Mean delay in diagnosis was 3.0 ± 5.5 (SD) years, 90% had variable pain, and 84% limited shoulder function. Compared to healthy and chronically diseased reference populations, CNO/SCCH patients demonstrated significant impairments in almost all aspects of QoL, maladaptive illness perceptions, and ineffective coping strategies. For patients with >5-year delay in diagnosis, higher pain scores and limited shoulder function were identified as determinants for impaired QoL. Patients with CNO/SCCH reported significant impairments in QoL associated with clinical and psychological determinants. Clinical measures such as shortening delay in diagnosis, effective pain management, and psychosocial interventions targeting these factors should help minimize the negative impact of CNO/SCCH on QoL. Chronic non-bacterial osteomyelitis (CNO) is a rare auto-inflammatory bone disorder of unknown origin. In adults, the lesions affect the axial skeleton, with a predilection for the medial end of the clavicles, sternum, and first ribs, which led to coining the term sternocostoclavicular hyperostosis (SCCH) to the disorder. Other areas of the axial skeleton such as the spine, sacrum, and mandible may also be affected. The skeletal lesions are associated with the characteristic dermatosis palmoplantar pustulosis (PPP) in about 30% of cases. The disorder most commonly presents in young adulthood, predominantly in women, with lesions most commonly isolated to the sternocostoclavicular region . The natQuality of life (QoL) is defined as “the functional effect of an illness and its consequent therapy upon a patient, as perceived by the individual patient” , and shoA decade ago, our group conducted a study addressing QoL in a cohort of 52 adult CNO/SCCH patients, using structured interviews and validated QoL questionnaires, with findings demonstrating significant impairments in QoL compared to healthy controls. Our data identified a delay in diagnosis to be the major determinant of impairment in QoL due to its association with a higher prevalence of physical and psychosocial sequelae, such as higher emotional distress expressed as illness-induced anger, fear, distress, and dejection, and with more health-related impairment in social activities and to perceptions of more negative disease consequences .However, available data on QoL remains scarce in CNO/SCCH, and the primary aim of our study was to further evaluate in depth various aspects of QoL and its determinants in our now larger cohort of adult CNO/SCCH patients and to compare these data with data from healthy and diseased reference populations. The second aim of our study was to evaluate the impact of identified clinical and psychological determinants in addition to diagnostic delays, such as pain severity, limitation in shoulder function, illness perceptions, and coping strategies on QoL in CNO/SCCH patients, as we hypothesized these determinants may also significantly impact on their QoL.One hundred and thirty-six adult patients with an established diagnosis of CNO/SCCH based on characteristic clinical and radiographic features, who attended the outpatient clinic of the Leiden University Medical Center between 2017–2020, were invited to participate in this cross-sectional study by letters posted to their registered home address, including twelve who had participated in the study we conducted a decade previously . The onlPatients could complete the questionnaires online or by hand, returning them by post. Online data entry and control were performed through an online survey platform . Up to two phone calls were placed to contact patients who failed to respond to the invitation sent by regular land mail.Sociodemographic, clinical, and radiographic data were retrieved from the electronic medical records. Data on delay in diagnosis, follow-up years and level of education, localization and extent of skeletal lesions, and presence of extraskeletal manifestations such as palmoplantar pustulosis was also specifically collected. Level of education was categorized using the International Standard Classification of Education (ISCED), with a low level of education defined as a primary to lower secondary education; medium level of education as an upper secondary to post-secondary non-tertiary education; and high level of education as the first and second stage of tertiary education.The Short Form 36 (SF-36) questionnaire is a validated widely used instrument for the evaluation of various domains of QoL in individuals older than 14 years. SF-36 consists of nine domains: “physical function”, “role physical function”, “bodily pain”, ”general health” perceptions, “vitality”, “social function”, “role emotional”, and “mental health”. Higher scores indicate better QoL .The Brief Pain Inventory (BPI) questionnaire is an assessment tool originally designed to assess pain in patients with cancer  but alsoThe Brief Illness Perception questionnaire (BIPQ) was designed to evaluate the cognitive and emotional perception of illness in patients with chronic or acute conditions  and consThe Utrecht Coping List (UCL) is a validated questionnaire widely used to evaluate coping strategies, based on the assumption that individuals prefer a certain way of coping, regardless of the situation—the coping strategy . The UCLThe Shoulder Rating Questionnaire (SRQ) is a validated questionnaire used in the assessment of the severity of shoulder symptoms and degree of impairment of shoulder function ,22,23. Tn = 1742) [n = 162) [CNO/SCCH SF-36 data were compared with reference data from the general Dutch population ( = 1742) ; from a n = 162) , and witn = 162) ,26. CNO/BPI scores were compared between patients with isolated vs. additional axial localizations and between patients with shorter and longer delays in diagnosis. The impact of two BPI pain index scores, pain severity, and pain interference on QoL domains, was also evaluated. BIPQ data were compared with reference data from patients with two chronic disorders: asthma and diabetes mellitus type 2 .n = 107, with median age 55 years (range 45–65)) [n = 59, median age 64 years (range 55–74)) [CNO/SCCH coping strategies data were compared with those of two reference populations: a randomly selected group of Dutch women combined with a group of Dutch female nurses ( 45–65)) , and a g 55–74)) .Statistical analysis was performed using SPSS for Windows, Version 23.0  Results are presented as means (±SD) or as median (range) and categorical variables were summarized with frequency counts and percentages.T-test or Mann-Whitney U test. The final analysis included correlation analyses between the SF-36, BPI, SRQ, BIPQ, and UCL domain scores using Pearson’s and Spearman’s correlations for normally and non-normally distributed variables, respectively. The level of significance was set at p < 0.01 for all tests in order to correct for multiple testing.The primary analysis included the comparison of SF-36, BPI, and BIPQ’s CNO/SCCH data with reference data using a pooled sample T-test. Secondary analysis included comparison SF-36, BPI, and BIPQ data between CNO/SCCH and FD/MAS subgroups based on the extent of skeletal lesions, and between CNO/SCCH subgroups based on the delay in diagnosis, by also using an unpaired n = 59 (69%) by hand and n = 41 (31%) online. Respondents were predominantly women . The median age was 52 years (range 23–79 years), the median age at diagnosis was 43 years (range 22–69) years. Mean delay in diagnosis was 3.0 ± 5.5 years, and the median duration of follow-up after diagnosis was 5 years (range 0–26 years). A diagnostic delay of <3 years was observed in 36 patients (41%), 3–5 years in 23 patients (26%), and >5 years in 29 patients (33%). The level of education was ’low’ in 19 patients (20%), ‘medium’ in 37 patients (42%), and ‘high’ in 29 patients (33%). Patients had predominantly isolated CNO/SCCH . Twenty-two patients (25%) had additional affected sites of the axial skeleton such as spine , mandible , or both . Palmoplantar pustulosis was present in 27 patients (30%). Delay in diagnosis was shorter in patients with additional axial localizations compared to those with isolated CNO/SCCH (mean 3.5 ± 2.4 years) vs. 5.5 ± 6.2 years) (Questionnaires were >90% completed by 86 patients (64%), 2 years) .Twenty-six of the 56 working patients (46%) were unable to perform their work adequately and 17(21%) stopped working because of shoulder complaints.p = 0.029). Other QoL domain scores were respectively: “physical function” , “role physical” , “bodily pain” , “general health” , “ vitality” , “social functioning” , and for “role emotional” .CNO/SCCH patients had significantly lower QoL outcome scores compared to healthy individuals from the general Dutch population in all SF-36 domains, except for “mental ealth” , “bodily pain” (p < 0.001), “social functioning” (p < 0.001), and “role emotional” (p = 0.007). In contrast, CNO/SCCH patients had significantly better scores compared to patients with osteoarthritis in the domains “physical function” , “role physical” , “vitality” , “social functioning” , “role emotional” , and “mental health”   .p < 0.001) and “role emotional” (p = 0.002), with intriguingly lower QoL scores observed in patients with isolated SCCH compared to those with more extensive lesions. Isolated CNO/SCCH patients also had significantly lower outcomes in all QoL domains (p < 0.001), except again for the domain “mental health”, compared to patients with similarly localized lesions in monostotic FD. However, there was no significant difference in QoL between patients with polyostotic FD and CNO/SCCH patients with additional axial localisations. There was no significant difference in SF-36 outcome scores, between patients with or without extra-skeletal manifestations, except for lower “general health” scores in the latter   .p > 0.05), patients with a delay in diagnosis >5 years had significantly more impairment in QoL compared to patients with a delay in diagnosis <3 years in the domains “physical function” , “role physical” , “bodily pain” , “general health” , and “social function” . Patients with a delay of >5 years had significantly worse outcomes in “physical function”  and also more impairment in “general health”  compared to patients with a delay of 3–5 years (Whereas there was no significant difference in QoL domains outcomes between patients with a delay in diagnosis <3 years and those with a delay of 3–5 years (–5 years .p < 0.01) compared to patients with a delay <3 years (p < 0.01) (p > 0.05).Subgroup analyses of BPI outcome scores showed that pain scores did not significantly differ between isolated and non-isolated CNO/SCCH, and between patients with a delay <3 years and 3–5 years, although patients with isolated CNO/SCCH and a longer delay in diagnosis had consistently worse scores than patients with additional axial localisations and a shorter delay in diagnosis, albeit non-statistically significant. Patients with a delay in diagnosis >5 years had significantly worse pain outcome scores in all domains ( < 0.01) . There wThirty-two patients (36%) had severe to very severe limitations in shoulder function during daily personal and household activities, and 39 patients (47%) had the same limitations only during recreational or sporting activities .p = 0.001). Higher pain interference scores were also associated with perceiving more limitations in the domains “physical function”, “role physical function”, “general health”, “vitality”, “social function”, “mental health” , and “role emotional” (p = 0.002). However, neither of the BPI pain domains “pain severity” and “pain interference” were significantly associated with impairment in the SF-36 “bodily pain” domain, although higher BPI severity and interference index scores did show a trend for poorer QoL outcome scores in this domain , “social function”, and “mental health” (p < 0.01). Limited shoulder function was also significantly associated with higher scores in all BPI pain domains (p < 0.001)  .n = 309), patients with CNO/SCCH perceived more consequences of their disease, experienced less personal and treatment control, and attributed more of their symptoms to their disease . Compared to a reference group of patients with another chronic disease diabetes mellitus type II (n = 119), patients with CNO/SCCH also experienced less personal and treatment control of their illness, attributed more of their symptoms to their disease, had less concern about their illness, and had a worse personal understanding of their disease  (Compared to a reference group of patients with the chronic disease asthma (< 0.001) .p < 0.01). Although patients with extra-skeletal manifestations had generally less favorable outcomes, there was no significant difference in the subscales of BIPQ between patients with or without extra-skeletal manifestations. Patients with shorter delays in diagnosis had a better personal understanding of their disease compared to patients with a delay >3 years .Subgroup analysis of patients with isolated CNO/SCCH compared to those with additional axial localizations showed that patients with isolated CNO/SCCH experienced less personal control of their illness (p < 0.001) except for “bodily pain” (p = 0.103). Attributing more symptoms to the disease was associated with perceiving more limitations in “physical function”, “role physical function” and “general health” , and “social functioning” (p = 0.007). Perception of more “personal control” was associated with better “mental health” (p < 0.01). Less illness concern was associated with better SF-36 scores in all domains except for “bodily pain” . Compared to patients with chronic pain due to other pathologies, patients with CNO/SCCH reported using more active coping strategies (19.0 (3.5) vs. 16.4 (4.0), p < 0.001), seeking more distraction (18. (3.1) vs. 16.8 (4.0), p < 0.01) and social support (12.8 (3.3) vs. 13.5 (3.7), p < 0.001), with no significant differences in other coping strategies  vs. 6.8 (3.6), rategies .Subgroup analyses showed that there was also no significant difference in coping strategies between patients with isolated CNO/SCCH compared to those with more extensive axial involvement, or between patients with shorter or longer delays in diagnosis.p < 0.001) and with worse SF-36 “general health” scores   .To our knowledge, this is the first study fully evaluating various aspects of quality of life and its clinical and psychological determinants in patients with the rare autoinflammatory disorder CNO/SCCH. Our findings demonstrate that adult patients with CNO/SCCH have significant impairments in nearly all aspects of QoL compared to a reference general Dutch population. Our data identify delay in diagnosis of >5 years, chronic pain of moderate to high severity, negative or maladaptive illness perceptions, and less effective coping strategies as the major determinants of QoL in CNO/SCCH, further consolidating previously published findings from our group .Experiencing pain of variable severity is one of the major clinical manifestations of CNO/SCCH, and data from our study demonstrate that pain has a significant impact on various aspects of QoL, as reflected by the significant correlation between BPI outcome scores, especially those of “pain severity” and “pain interference” domains and most SF-36 QoL domains, surprisingly except for the “bodily pain” domain. This surprising outcome was further supported by a similar significant correlation between the SRQ shoulder function scores and all BPI pain scores and SF-36 domain scores, again except for “bodily pain”. These findings are of relevance in clinical practice, as they suggest that using SF-36 “bodily pain” domain outcome scores may not be sufficiently reliable for the evaluation of the impact of pain on QoL in patients with CNO/SCCH. A more complete evaluation of pain using additional BPI and SRQ outcome scores is thus recommended in the clinic for a full picture of the potentially significant contribution of pain to impairment of QoL in CNO/SCCH patients.Interestingly, our data show that the main significant determinant of pain in CNO/SCCH is a delay in diagnosis rather than the extent of the axial lesions. Our data also show that a delay in diagnosis of >5 years is associated with significant impairment in all physical, social function, and general health domains, suggesting a likely contributory role of this delay in the development of irreversible structural changes, potentially leading to secondary degenerative changes, and chronic debilitating limitation of shoulder function and pain symptoms both having a significant impact on various aspects of QoL.Our data further show a significant relationship between nearly all SF-36 domain scores and a number of illness perceptions domains such as “consequences”, “illness concern”, “emotional control’, and “identity”, the modulation of which may be potentially achieved by individually-tailored psychological therapy, which may, in turn, minimize the negative impact of maladaptive illness perceptions on QoL.This is to our knowledge, the first study evaluating coping strategies in a relatively large cohort of adult patients with CNO/SCCH. Although active coping strategies were frequently reported, these were associated with generally worse SF-36 “general health” domain scores, suggesting that active coping and more personal control and understanding may not significantly influence QoL in adult CNO/SCCH. Seeking social support was also more frequently reported by patients with CNO/SCCH than in those with chronic pain of unknown etiology, possibly indicating that establishment of a diagnosis of CNO/SCCH as the source of the chronic pain may be associated with a greater sense of social acceptance and greater tendency to ask family and friends for help. More palliative coping, defined as seeking distraction with other occupations, such as smoking or drinking alcohol, was also more prevalent in CNO/SCCH patients, which is of particular relevance as smoking is a known trigger for an auto-inflammatory reaction, which may exacerbate disease activity, thus potentially inducing higher levels of pain and more limitations in shoulder girdle function .We put our findings in perspective by comparing the impact of the identified clinical and psychological determinants of QoL in CNO/SCCH to the impact of these factors in other pathologies with similar characteristics as CNO/SCCH, such as chronicity in reference populations with asthma and diabetes mellitus type II, chronic pain in osteoarthritis, or similar pathological subtypes in FD/MAS, with lesions affecting one  or more skeletal sites ).Another reason to perform this comparison was that as yet, there are no disease-specific questionnaires for CNO/SCCH so it may be difficult to judge whether an observed outcome is related to the disease itself, or to one of its symptoms such as pain. This provided the rationale for the comparison of CNO/SCH data with those of another chronic osteoarticular disease associated with pain such as OA. Since OA mostly affects older patients, the observed differences may be age-related, which was the rationale for using another reference population of patients with a rare chronic bone disease also associated with pain, but affecting younger patients such as FD/MAS.Compared to a reference population of patients with chronic pain due to osteoarthritis, SF-36 QoL outcome scores were significantly less impaired in a number of domains in CNO/SCCH patients despite the fact that an inflammatory component is clearly involved in the pathophysiology of both disorders. Osteoarthritis is, however, a primarily generalized process of progressive degradation of cartilage matrix, associated with inefficient attempts at repairing, whereas adult CNO/SCCH is a rare auto-inflammatory bone disorder of the axial skeleton, with an abnormal osteogenic response to inflammation, eventually leading to irreversible structural changes in adjacent joints.In contrast, patients with CNO/SCCH fared significantly less favorably compared to patients with FD/MAS in the QoL domains: “Role physical”, “bodily pain”, “social function” and “role emotional”, suggesting less adequate emotional adaptation for their disorder, possibly because the diagnosis of CNO/SCCH is usually established in adulthood, whereas FD/MAS is most commonly established during childhood, especially its more severe polyostotic/McCune Albright types. In contrast to patients with FD/MAS, in whom impairment in QoL was more pronounced in the presence of higher skeletal burden (polyostotic vs. monostotic disease), patients with isolated CNO/SCCH intriguingly demonstrated significantly worse scores in the physical and emotional domains of QoL than those with additional axial localizations. This discrepancy in the impact of the extent of skeletal involvement on QoL between the two pathologies may be due to the significantly longer delay in diagnosis observed in patients with isolated CNO/SCCH, which may allow the development of irreversible changes in affected bones and secondarily adjacent joints, and also due to the documented impact of mineralization defects and increased skeletal burden on an increased risk for pain, deformities and fractures in FD/MAS ,28.p < 0.001). This probably reflects the fact that there is as yet no standard treatment for CNO/SCCH, and that various applied treatments are still often partially or not effective in controlling symptoms or disease progression. Finally, CNO/SCCH patients also had a worse personal understanding of their disease, and had less concern about their illness than those with diabetes , but did not differ in those aspects from patients with asthma. This may be due to the fact that diabetes is a much better-understood disease, its treatment is well-established, and patients are well aware of its possible serious (long-term) consequences if left untreated.Comparing illness perceptions between patients with CNO/SCCH and those with type 2 diabetes or asthma, showed that all three groups were equally aware of the chronic nature of their disease. However, CNO/SCCH patients perceived more consequences of their disease than asthma patients but did not differ from patients with diabetes. A possible explanation for this is that diabetes and CNO/SCCH are conditions that are continuously present, whereas asthma usually manifests itself in acute exacerbations spaced in time. CNO/SCCH patients also experienced less personal and treatment control and attributed more of their symptoms to their disease than patients with asthma or diabetes (all This comparison analysis provides valuable information about different ways by which similar physical and psychological determinants may impact QoL in CNO/SCCH patients compared to reference populations with other chronic diseases.Our study has strengths as well as limitations. Of its main strengths is the inclusion of a relatively large number of well-characterized patients across the clinical spectrum of the distinctive adult CNO/SCCH phenotype, the prerequisite availability of near-complete sets of data from five validated questionnaires covering several aspects of QoL and pain, shoulder limitations, illness perceptions, and coping strategies, and the opportunity to compare CNO/SCCH QoL data with data from healthy and diseased reference populations. Put together, these data allowed us to identify the main determinants of impaired QoL in adult CNO/SCCH patients.The main limitations of our study are that all questionnaires used were not CNO/SCCH disease-specific, although validated generic and domain-specific questionnaires, and that SRQ outcomes were not validated by objective clinical evaluation of shoulder girdle function at the time of completion of the questionnaire.In conclusion, findings from our cross-sectional study demonstrate that adult patients with CNO/SCCH have significant impairment in almost all aspects of QoL, maladaptive illness perceptions, and ineffective coping strategies, compared to healthy and chronically diseased reference populations. The main identified determinants of impaired QoL in adult CNO/SCCH were delay in diagnosis, chronic pain of moderate to high severity, and restricted shoulder girdle function. We believe findings from this study may hold significant clinical implications in the management of CNO/SCCH patients, such as shortening delay in diagnosis, effective pain management, early institution of adequate therapies to decrease disease activity, and appropriate psychological measures to address altered illness perceptions and inadequate coping strategies may help to minimize the negative impact of CNO/SCCH on various aspects of quality of life in patients with this rare chronic auto-inflammatory bone disorder.


To determine the effect of local infiltration anesthesia (LIA) at the donor site combined with a femoral nerve block (FNB) on short-term postoperative pain, functional outcomes, and rehabilitation after arthroscopic hamstring tendon autograft anterior cruciate ligament reconstruction (ACLR).This study was a single center, randomized controlled trial. Seventy-three subjects with ACL rupture were enrolled. Participants were randomly allocated to two groups, 47 in the experimental group (Group A) and 26 in the control group (Group B). All operations were performed under FNB. In Group A, 10 ml of 1% ropivacaine was injected precisely at the hamstring donor site. Patients in Group B were treated with the same amount of saline. Preoperatively and postoperatively, pain scores based on the numerical rating scale (NRS) and consumption of opioids were recorded. In addition, knee functions were assessed by the International Knee Documentation Committee Subjective Knee Form (IKDC), the Lysholm score, and the Knee injury and Osteoarthritis Outcome Score (KOOS) preoperatively and postoperatively at 1 and 3 months. In addition, we applied the KNEELAX3 arthrometer to evaluate the stability of the knee preoperatively and postoperatively so that subjective and objective knee conditions were obtained to help us assess knee recovery in a comprehensive manner.The hamstring donor-site block reduced pain within the first 12 postoperative hours. There were no significant differences between two groups in pain intensity preoperatively and equal to or greater than 24 hours postoperatively. Furthermore, there were no differences between the groups concerning knee functions preoperatively or in the short-term follow-up at 1 and 3 months.LIA at the donor site can effectively improve the early postoperative pain of patients after ACLR and reduce the use of opioids without affecting the functional outcomes of the surgery. ACL injuries may account for 50% of sports-related injuries in high school athletes . AlthougWith the progress of modern medicine, the patient's comfort during the treatment process has been continuously considered. The pain has been recognized the fifth vital sign and it has received increasing attention in clinical diagnosis and treatment practice . Pain isA reasonable perioperative analgesia approach is necessary for faster rehabilitation and satisfaction. Currently, intravenous or oral opioids are frequently prescribed for postoperative pain control following ACLR . HoweverAccording to our clinical experience, the main sources of pain after ACLR include the following three points: the skin incision, the graft fixation positions, and the graft donor site. The former two cannot be avoided, so we focused on relieving the pain at the donor site. FNB has been shown to be an effective method for relieving postoperative pain . We beliPain assessment is usually derived from subjective statements rather than objective measurements . Thus, iWe aimed to determine the effect of LIA at the donor site combined with a FNB on short-term postoperative pain and the functional outcomes and rehabilitation after arthroscopic hamstring tendon autograft ACLR. We hypothesized that the combination of FNB and LIA can achieve better analgesic effect, but it is not enough to directly impact the postoperative rehabilitation speed.This research was designed as a randomized controlled trial. Patients were designed to be randomized to undergo either a hamstring donor-site block or isotonic sterile water of equal volume, in an around 2:1 ratio. A permuted block randomization scheme was used with block sizes of 3. All operations were performed by the same experienced orthopedic surgeon in our hospital. The study protocol was approved by the institutional ethics committee. Informed consent for participation in the study was obtained from all patients before randomization.Patients 15–50 years of age who were diagnosed with ACL rupture, usually confirmed by means of history, physical examination, and magnetic resonance imaging, were screened for eligibility. Participants were randomly allocated to two groups . Baselin2; ASA physical class greater than 4; allergy to local anesthetics; preexisting neurologic deficit; undergoing revision surgery; any opioid use within the previous 3 months; inability to understand the NRS; or suffering from serious or chronic conditions that may have an impact on surgical treatment, postoperative recovery or regular follow-up. After returning to the ward after surgery, tramadol was orally administered if the pain at rest exceeded 3 on NRS. A unified analgesic scheme and postoperative rehabilitation plan were adopted during the perioperative period.The inclusion criteria were primary ACLR and a healthy contralateral knee. Exclusion criteria included refusal of surgical treatment; severe concomitant injuries; concurrently performed other different surgical procedures; weight less than 35 kg; body mass index (BMI) greater than 45 kg/mThe IKDC, the Lysholm score, and the KOOS were used to examine the functional outcomes preoperatively, at the 1-month follow-up, and at the 3-month follow-up. In addition, the degree of anterior tibial translocation was measured with a KNEELAX3 arthrometer   preoperaPain management success was assessed by the consumption of opioids (tramadol) during the patient's hospitalization and pain scores on an NRS, an 11-point scale where 0 indicates no pain and 10 indicates the worst imaginable pain , which iAIT for ACLR is becoming increasingly popular and it has been described extensively in previous papers , 24. HerAll patients received a preoperative FNB using an ultrasound-guided technique. One of the highlights of this study is the process of harvesting the hamstring tendon and subsequent local anesthesia. The medial tibial tuberosity incision was made where the hamstring tendon is removed with our self-developed tendon retriever. The surgeon initially obtained the tendon, while not moving the retriever, and slowly inject the 10 ml of ropivacaine. Then, the analgesic continued to be injected while withdrawing the retriever, and finally, the ropivacaine would fill the entire donor site .We designed a novel tendon retriever capable of precisely injecting local anesthetics, as shown in The CPT was first created and utilized as a tool by Edgar A. Hines, Jr. to study blood pressure variability . During The general flow of this test is as follows. A bucket full of cold water with ice should be prepared to keep the temperature constant. The water temperature was monitored (maintained at 4°C), as a 2°C difference in temperature can affect tolerance time and pain intensity . In addiWithin 1 week after surgery, complete knee extension was required during bed rest, quadriceps contraction and straight leg raising training were performed, ankle flexion and extension activities were performed, and passive knee flexion was performed. Partial weight-bearing with crutches when walking on the ground; passive flexion of the knee joint to 90 degrees was started on the 8th day, and full weight-bearing standing and walking with detached crutches were trained; at the end of the 2nd week, passive flexion of the knee joint to 120 degrees and full weight-bearing walking were required; fixed bicycle exercises, terminal extension and balance exercises were performed at 3–6 weeks; at 7–12 weeks, active and passive knee flexion, range of motion consistent with the unaffected side, knee extension and resistance knee extension, and full squatting were performed. Full return to full activities of daily living started 3 months and gradual return to sports started 9 months.α = 0.05, a sample size of at least 25 patients per group was obtained. SPSS 26.0 software was used for statistical analysis of the data. Measures were tested for normality using the D'Agostino test, and normally distributed indicators are expressed as the mean ± standard deviation (SD) and compared between groups using the independent samples t-test; nonnormally distributed indicators are expressed as the median and interquartile range (IQR) and compared between groups using the Mann–Whitney U test. Multifactorial logistic regression analysis was performed to assess the correlation between NRS scores and local anesthesia or not within 48 h preoperatively and postoperatively after adjusting for confounders. Statistical data are expressed as percentages (%), and comparisons between groups were made by the chi-square test or Fisher's exact probability method. P < 0.05 was considered a statistically significant difference.Calculation of the sample size was based on an expected difference of two points on the NRS score between the groups. With a power of 0.80 and P < 0.001). Within the first 12 h after surgery, pain level was significantly lower in Group A than in Group B (P < 0.05). There was no difference in pain scores preoperatively and at the time point greater than or equal to 24 h postoperatively (P < 0.05)  . Since w < 0.05) . This st < 0.05) –7. No coThe most important finding of this study was a statistically significant reduction in postoperative pain scores with the additional use of donor-site block. The significant complications of ACLR consist of infection, hematoma or hemarthrosis, failure of the surgery, etc. . HoweverTo date, few studies have been conducted on the effect of LIA at the donor site combined with FNB on short-term postoperative pain and functional outcomes after arthroscopic hamstring tendon autograft ACLR. The reduction of pain level was obvious within 12 hours after ACLR but this effect was no longer working beyond the period. In addition, the additional donor site block after FNB did not affect any other subjective or objective outcomes. However, an assumption should not be made arbitrarily that donor-site LIA did not have any positive effects on functional recovery since the first assessment of function was at 1 month postoperatively. Less pain is often accompanied by a greater range of motion. Additional block could provide comfort to the affected region and a greater range of motion during the immediate postoperative course.The study we conducted was similar to Bushnell et al.  in 2010,Considering that gender is one of the confounders of pain , the basThe best choice of anesthetic for local infiltration has not yet been determined, with bupivacaine and ropivacaine being commonly used. Bupivacaine has a half-life of 3.5 h, whereas ropivacaine is a long-acting local anesthetic with a similar structure to bupivacaine and a half-life of 4.2 h. Ropivacaine has the advantage of being less toxic, and its blockade of sensation is stronger than its block against movement , which iIt was expected that the range of motion would be highly associated with pain intensity. Based on our observations of postoperative patients, patients with less pain did have a greater knee range of motion and were more comfortable moving their knees. Therefore, range of motion was not specifically described in this study.Less early postoperative pain could be observed without the use of a tourniquet during routine knee arthroscopy , suggestSeveral papers previously reported an abnormal sensation in the lower extremities after surgery. This complication often occurs because of injury to the lateral sural cutaneous or saphenous nerve due to the incision or intraoperative retraction . In our There are some limitations of this study. There was no intentional blinding of patients, doctors, or nurses in the postanesthesia care unit. Moreover, patient satisfaction during the whole course, speed of recovery, and the immediate postoperative condition of the body and knee could not be presented merely according to our study data.The simplicity of the donor-site block technique warrants its extensive application. It could effectively improve the early postoperative pain of patients after ACLR and reduce the use of opioids, without affecting follow-up functional outcomes. Future related studies with larger samples may help confirm its beneficial effect.


The aim of this study was to investigate whether pre‐operative comorbidity status measured by the Charlson comorbidity index (CCI) or cardiopulmonary exercise testing (CPET) is associated with postoperative complications and length of stay (LOS) in patients undergoing robot‐assisted radical cystectomy and intracorporeal urinary diversion (RARC‐ICUD).We conducted a retrospective study of a prospectively maintained database of 428 consecutive patients who underwent RARC‐ICUD at a tertiary referral centre between 2011 and 2019. CCI was correlated with peri‐operative outcomes including postoperative LOS, Clavien–Dindo (CD) complications and survival. A planned subgroup analysis was performed to evaluate the relationship between pre‐operative CPET, and the same outcomes utilising the threshold of anaerobic threshold (AT) ≥ 11/ <11 ml/kg/min were analysed.p = 0.02) and at 90‐day IRR 2.495, (p = 0.04) postsurgery. LOS was not associated with CCI; the strongest association with LOS was a CD complication of any grading. CCI did not predict readmission or mortality rates after surgery. Subanalyses of patients who underwent pre‐operative CPET found that CPET <11 ml/kg/min did not predict for LOS, CD complications or death within 1 year of surgery.Of the total cohort, 350 patients undergoing RARC‐ICUD with complete data were included in the final analysis. A CCI score ≥5 was associated with a higher rate of CD III–V complications at 30‐day incidence rate ratio (IRR) = 3.033, (CCI score is a simple, reliable and cost‐effective way of identifying patients at increased risk of complication after RARC‐ICUD. Surgeons performing radical cystectomy should consider utilising CCI to augment pre‐operative patient counselling prior to RARC‐ICUD. RARC‐ICUD and the increasing adoption of robotic surgery have led to older, more comorbid patients with bladder cancer being considered for surgery.There is a need for better tools to facilitate patient counselling about individualised risks of surgery and to enable healthcare professionals to more accurately predict outcomes after RARC‐ICUD, especially in more comorbid populations. Although risk prediction tools have shown utility in patients undergoing open radical cystectomy,The Charlson comorbidity index (CCI) is an established validated method of predicting long‐term survival in an unselected population. The CCI assigns a weighted score to 19 comorbidities; the total score corresponds to a percentage 10‐year mortality prediction. CCI has been assessed as a predictive tool for postoperative outcomes in gastrointestinal (GI), gynaecological and orthopaedic surgeriesThe purpose of this study was to evaluate whether pre‐operative comorbidity status measured by the CCI was associated with LOS, complications and survival at up to 1 year after surgery in a large series of patients undergoing RARC‐ICUD at a tertiary referral centre with an established enhanced recovery programme (ERP). In addition, we aimed to compare the performance of CCI with CPET in our cohort.2A consecutive series of 428 patients undergoing RARC‐ICUD for bladder cancer from our institution's prospectively maintained electronic cystectomy database was analysed. These patients underwent RARC‐ICUD between April 2011 and October 2019. All RARC‐ICUD surgeries were performed by four surgeons DG, AK, EWR and JA  with high volume experience in robotic surgery  prior to the first RARC‐ICUD procedure recorded. No procedure was converted to open; each surgeon performed more than 15 RARC‐ICUD per year over the duration of the study and submitted their outcome data to the BAUS Oncology database. Our database did not include CCI scoring at its inception, so this was retrospectively calculated from patients' pre‐operative medical records using the weighted index of comorbidities.During the study period, all patients undergoing RARC‐ICUD at our institution underwent pre‐operative assessment by a consultant anaesthetist. CPET was requested routinely for patients listed for RARC‐ICUD; however, CPET was only mandated as part of the pre‐operative assessment process if the anaesthetist or surgeon felt this was necessary. Patients undergoing RARC‐ICUD in this study did not undergo a prehabilitation programme, and CCI score did not contribute to the decision to perform CPET testing. The CPET result did not directly influence the peri‐operative management plan of patients undergoing RARC‐ICUD. All patients undergoing RARC‐ICUD were managed according to a standardised peri‐operative enhanced recovery protocol with no additional pathway incorporated based upon the results of the CPET test.Demographic variables including age, sex, height and weight were recorded; in addition, pre‐operative characteristics such as age, American Society of Anaesthesiologists (ASA) score, diabetes, smoking history, pre‐operative haemoglobin (Hb) and eGFR, previous abdominal surgery, previous radiotherapy, CPET and the use of neo‐adjuvant chemotherapy were reviewed.2.1Previous studies have demonstrated that 10‐year survival decreases rapidly once a patient's CCI score increases and patients with a CCI score ≥5 are considered high risk.t‐tests and negative binomial regression analysis (NBRA), which has been used to study the link between CCI and LOS previously.p = 0.05. A planned subgroup analysis was performed to evaluate the relationship between pre‐operative CPET and postoperative outcomes. Patients were divided into two cohorts for the CPET risk stratification evaluation. Those with an anaerobic threshold (AT) of <11 ml/kg/min and those with an AT ≥ 11 ml/kg/min.We investigated the significance of pre‐operative CCI score on LOS, CD complication rates at 30 and 90 days and mortality rates at 30 days, 90 days and 1 year after surgery. Additionally, we correlated demographic and pre‐operative factors including age, ASA, gender, BMI, neo‐adjuvant chemotherapy and pre‐operative anaemia to LOS using Spearman's correlation. Further analysis was then performed using independent 33.1In total, 350 patients, mean age 67.5 years range 18–89), with complete CCI data underwent RARC‐ICUD during the study period. Of these, 259 (74%) were male, and the majority, 260 (62%), were ASA 2 although 126 (36%) were ASA 3 or 4. Table 8–89, wit3.2The mean LOS for the cohort was 9.15 days (range 3–77), and 31 (9%) of patients were re‐admitted to the hospital within 90 days of discharge. In total, 162/350 (46%) patients suffered CD I–V complications and 35/350 (10%) CD III–V complications within 30 days of surgery. When CD complication rates within 90 days of surgery were evaluated, 169 (48%) and 40 (11%) sustained CD I–II complications and CD III–V complications, respectively. About 4/350 (1%) patients died within 30 days of surgery and 10/350 (3%) within 90 days of surgery. At 1 year, 95/350 (27%) had died after their surgery.3.3p = 0.047, one‐tailed t‐test).Table t‐tests demonstrated a significant difference for CD I–V and CD III–V complication rates at both 30 days  and 90 days  between these two groups.When examining the rate of CD complications, patients with CCI scores ≥5 had a higher number of CD I–V and CD III–V complications at 30 and 90 days than those with a CCI score of <5 Table . Indepenp = 0.01) at 30 days and 2.51 (p = 0.026) at 90 days, demonstrating an increased risk of major complications in the order of ×3 at 30 days and ×2.5 at 90 days, (Tables p = 0.001).Using NBRA for complication data, we found that CCI ≥ 5 was associated with an increase in CD I–V complications at 30 days and an increase in CD III–V complications at both 30 and 90 days. This was statistically significant in all cases. For CD III–V complications, the IRR for patients with a CCI score ≥5 was 3.053,  for CD 1–2 complications and IRR 2.181 (p = <0.001) for CD 3–5 complications; prior pelvic radiotherapy and pre‐operative anaemia also marginally increased the risk of an increased LOS, IRR 1.35 (p = 0.03) and IRR 1.121 (p = 0.012), respectively. Age, duration of surgery and intraoperative blood loss were all significant but had insignificant effect sizes, while ASA score, neo‐adjuvant chemotherapy, T‐stage and BMI bore no association.NBRA demonstrated that several factors can increase the risk of a prolonged hospital stay Table . Unsurpr3.4Of the cohort in whom CCI was calculated, 188 had a CPET performed. In the planned subgroup analysis of CPET association with outcomes, an additional 32 patients in whom we could not calculate the CCI were included. These 220 patients were categorised into groups using the AT value <11 or ≥11. Table No significant difference in LOS, CD complication rates at 30 and 90 days from surgery or 1 year survival was identified when cohorts were stratified by AT >/<11. We explored whether using lower AT values to stratify patients undergoing RARC‐ICUD would alter these findings but did not identify any signal that lower values would be associated with poorer outcomes. No correlation between CPET AT measurements and the CCI scores in this cohort was identified. NBRA did not show any correlation between CPET AT and LOS or CD complications at 30 and 90 days.4Minimally invasive techniques have offered the potential to reduce the physiological impact of radical cystectomy for patients with bladder cancer. However, such approaches are still associated with morbidity, and patients with bladder cancer are often a comorbid group. Current methods of risk prediction for minimally invasive surgery are recognised to be in need of improvement.Accurate risk prediction is essential to guide patient counselling and facilitate shared decision‐making. Recent analysis of UK data suggests that a significant proportion of patients with localised MIBC may not be receiving radical treatment,Contrary to our previous work and the work of others in smaller predominantly open radical cystectomy populations,Pragmatically, risk prediction modelling also facilitates patient preparation before surgery and ensures appropriate postoperative support resources are available. Moving forwards our institution will incorporate CCI to identify patients at higher risk of complications and as a consequence a potentially longer postoperative stay. This will have the benefit of allowing us to plan more effectively with regard to critical care utilisation, bed occupancy and the cost of delivering care. CCI has been explored by other surgical specialties and has been found to be useful in predicting LOS and adverse events. CCI has been investigated for morbidity and mortality in GI cancer, ovarian cancer and oesophageal cancer,Our present study has several limitations: We acknowledge that this is a single centre retrospective series and our findings need to be validated in other centres. A weakness is that CCI scores were calculated retrospectively from pre‐operative patient medical records and therefore could be subject to misclassification bias; however, we excluded all patients who underwent RARC‐ICUD in whom the CCI could not be explicitly calculated from the final analysis to minimise this risk. Due to our large cohort, we would not expect the distribution of CCI scores in the patients excluded from the final analysis to be different. Additionally, this study includes a large cohort including cases performed during and after the learning curve, and therefore, we believe that the findings are representative of real‐life practice. In our cohort consistent with UK practice, the majority of patients underwent an ileal conduit urinary diversion.5The Charlson comorbidity score is a simple, reliable and cost‐effective approach to identifying patients at increased risk of postoperative complications following RARC‐ICUD. CPET should not be used as a ‘rule out’ investigation in patients otherwise considered eligible for RARC‐ICUD. Surgeons performing robot‐assisted radical cystectomy should consider utilising CCI as a tool to tailor pre‐operative patient counselling, improve shared decision‐making and service planning.Ethics approval was not applied for or required for this study. The study was performed in accordance with the Declaration of Helsinki.The authors report no relevant financial conflict of interests.Study concept and design: J Aning and A McPhee. Acquisition of data: A Ridgway, A McPhee, and T Bird. Statistical Analysis: A McPhee. Analysis and interpretation of the data: A McPhee, J Aning, and A Koupparis. Drafting of the manuscript and critical revision: McPhee, Ridgway, Bird, Pal, Rowe, Koupparis, and Aning.