Duloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof‐of‐mechanism, randomized, placebo‐controlled, crossover, double‐blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect.Twenty‐five patients completed this cross‐over study with either 18‐week duloxetine (maximum 60 mg/daily) followed by placebo or vice‐versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine.Depending on the clinical pain outcome, 40%–68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect  using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo.A combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo.Duloxetine is proposed as a treatment for chronic pain. Pre‐clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment. Forty patients were randomized to one of two equally sized sequences: (1) duloxetine followed by placebo or (2) placebo followed by duloxetine. Patients were screened for inclusion (visit 0) and assessed before (visit 1 and visit 3) and after the treatments (visit 2 and 4); see Figure ClinicalTrial.gov , and in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT number: 2019–003437‐42). The study protocol is published , The North Denmark Region Committee on Health Research Ethics (case number: N‐20190050), registered at 2.1Patients were recruited through Synexus/C4Pain, Aalborg, Denmark (a contracting research organization). Women and men, 40–75 years of age, with OA of the knee, who agreed to participate and filled in an informed consent, were included. Patients fulfilling the inclusion criteria were invited to a screening visit (visit 0) during which a physical and psychological  examination was conducted by a medical doctor. The screening included x‐ray of the knee, screening of medical records and screening of the eligibility criteria. Patients were asked to discontinue all analgesic pain medication  during the entire trial, and the patients were instructed to note the use of rescue medication (paracetamol) in a trial‐specific diary.According to the inclusion and exclusion criteria, patients who were eligible were invited to visit 1 during which they were included in the study and randomized.2.2Patients diagnosed with unilateral or bilateral OA of the knee according to the American College of Rheumatology criteria based on clinical and radiographic evidence : 20 mg/daily, week 2 (7 days): 40 mg/daily), a 14‐week full treatment period (week 3–16 [70 days]: 60 mg/daily) followed by a 2‐week discontinuation period (week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/daily). The treatment periods were separated by at least 2 weeks (washout period). See Figure The patients were instructed to take one capsule of study drug orally with approximately 200 ml of water at room temperature after breakfast in the morning of each dosing day.This study was initiated before the COVID‐19 pandemic, and all subjects were randomized prior to the lockdown in Denmark. The original protocol aimed for 10 weeks of full treatment of duloxetine and placebo, but this was increased to 14 weeks to allow for study visits during the lockdown period, to minimize suspension of subjects, and to increase the willingness of continued participation.2.4The study drug was encapsulated in a gelatin capsule  with identical size, colour and weight to ensure blinding. The study drug was produced and labelled by the Hospital Pharmacy at Aarhus University Hospital, Aarhus, Denmark. The blinding and randomization procedures were conducted by the Hospital Pharmacy at Aarhus University Hospital. Patients are block‐randomized (four patients at a time) to either sequence 1  or sequence 2 . Patients, study personnel and study management were blinded until the end of the trial. Procedures for unblinding were initiated if the patient safety was at risk.3Mechanistic pain profiles, cognitive factors and clinical pain were assessed at visits 1, 2, 3 and 4.3.1Deep tissue pain sensitivity was evaluated by cuff pressure stimuli using a computer‐controlled cuff algometer , including a 13‐cm wide tourniquet cuff (VBM) and an electronic VAS  for the recording of the pain intensity. The cuff was placed at the head of the gastrocnemius muscle of the lower leg at the index knee. The electronic continuous VAS (sliding resistor) was 10 cm long and sampled at 10 Hz; 0 cm: no pain and 10 cm: worst pain imaginable. Cuff algometry is a reliable assessment for PPTs, TSP and CPM  was defined as the pressure at which the VAS score exceeded 1 cm as in previous studies  at the level of the cPTT were given at the lower leg with a 1 s break between stimuli. The participants were instructed to continuously rate the pain intensity of the sequential stimuli using the electronic VAS and not return to zero during the breaks. For each cuff stimulus, a VAS score was extracted. TSP was calculated as the absolute difference between the last three stimuli and the first three stimuli as in previous studies  (36), which applies a subscale for anxiety and a subscale for depression. The HADS ranges from 0 to 21; 0 to 7 indicate no symptoms of anxiety/depression, 8 to 10 indicate probable symptoms of anxiety/depression and 11 to 21 indicate potential symptoms of anxiety/depression  consists of 13 items focusing on thoughts and feelings in connection with pain . The worst pain and average pain within the last 24 h were evaluated using a 10 cm VAS anchored at 0 cm: no pain, and 10 cm: worst pain imaginable.Additionally, clinical pain was assessed using the Western Ontario and McMaster Osteoarthritis Scale (WOMAC)  with factors time (before and after treatments) and drug (placebo or duloxetine) were conducted for all mechanistic pain profiling methods, cognitive factors and clinical pain parameters to investigate significant differences. Additionally, paired sample Several linear regression models were used to predict the analgesic effect  of duloxetine and placebo using the mechanistic pain profiles, cognitive factors and clinical pain prior to treatment. Backward elimination was applied to the linear regressions to identify independent predictors using cut‐offs for statistical independence and inclusion of 0.05 and exclusion of 0.157, respectively, according to Akaike's information criterion for prognostic models  unless otherwise specified.Statistical tests were conducted using the IBM SPSS Statistics software version 26 (IBM). A value of 3.6The data used and analysed are available by contacting the corresponding author on reasonable request.44.1The first patient was assessed at the first visit on 18 December 2019, and the last patient was assessed at the last visit on 1 July 2021. Administration of the study drug was postponed for two patients in sequence 1, and two patients in sequence 2 due to the COVID‐19 lockdown of Denmark. Later, these four patients withdrew their consent and hence were never administrated any study drug.In sequence 1, three patients discontinued the study in treatment period 1 (duloxetine treatment) due to side effects: one patient experienced psychological issues, one patient experienced constipation, and one patient experienced impaired ejaculation.In sequence 2, two patients discontinued the study in treatment period 1 (placebo treatment) due to side effects: one patient experienced signs of liver cirrose (with dark urine), and one patient experienced dizziness. Additionally, one patient experienced a loss of libido in treatment period 2 (duloxetine treatment).Twenty‐five patients completed all the visits and had full data for the analysis, see Table 4.2t‐test: p = 0.96), age (independent t‐test: p = 0.83), body mass index (independent t‐test: p = 0.60), Kellgren and Lawrence grading (independent t‐test: p = 0.77) or gender distribution (Chi‐square: p = 0.15).No significant differences were found comparing patients who completed the trial and patients who did not complete the trial regarding baseline pain severity (independent 4.3p = 0.03). The most common adverse events during the duloxetine treatment were gastroenterological (58% of patients), neurological (44% of patients), dry mouth and nausea (40% of patients) and fatigue (28% of patients). The most common adverse events during the placebo treatment were neurological (36% of patients), gastroenterological (24% of patients), dry mouth and nausea (24% of patients) and fatigue (16% of patients).Significantly more adverse events occurred during the duloxetine treatment  compared with placebo treatment  and CPM , but no drug effect was seen for cPDT  and CPM . No time or drug effect was seen for cPDT at the contralateral side, cPTT at the ipsilateral and contralateral side, and TSP . See Figure Significant changes over time were observed for cPDT assessed at the ipsilateral side  and PCS . A trend towards a significant time effect was found for PCS (p = 0.06), but the comparing treatments were not different (p = 0.39), see Figure No significant different time or treatment effects were found for HADS , the BPI subscale for average pain , WOMAC pain  and WOMAC total ; neither for absolute nor percentage differences. See Table No drug effects were seen for the BPI subscale for worst pain  to 70.3% (BPI average pain) for Model 1 and 45.7%  to 75.4% (BPI worst pain) for Model 2 for the duloxetine treatment, see Table Additionally, depending on the outcome measure, the predictive values ranged from 4.8%  to 20.5% (WOMAC pain) for Model 1 and 22.0% (BPI worst pain) to 41.8% (WOMAC pain) for Model 2 for the placebo treatment, see supplementary Table 5Depending on the clinical pain outcome parameter, 40%–68% of patients received at least 30% clinical pain reduction and 24%–48% of patients received at least 50% clinical pain reduction during the duloxetine treatment. Depending on the clinical pain outcome parameter, pretreatment mechanistic pain profiles, cognitive factors and clinical pain predicted the analgesic response of duloxetine by 45% to 75%, indicating that patients with high pain sensitivity, higher scores on pain catastrophizing, anxiety and/or depression and higher clinical pain may potentially benefit more from duloxetine treatment. The trial demonstrated no significant changes in stand‐alone mechanistic pain biomarkers, cognitive factors or clinical pain comparing 18 weeks of duloxetine with placebo in patients with painful knee osteoarthritis.5.1Accumulating evidence suggests that QST parameters can predict OA treatment responses to, for example, total joint replacement surgeries , but the treatment periods were conducted during the COVID‐19 pandemic and lock‐down. Studies have demonstrated that COVID‐19 negatively impacted anxiety, depression, and psychological stress in the general population and in different patient groups  is supported by the Danish National Research Foundation (DNRF121). The Aalborg University Talent Management Programme (j.no. 771126), The Danish Rheumatism Association (grant number: A6579), The Shionogi Science Program, and the TaNeDS Daiichi Sankyo Science Center Europe grant funded the study.The authors declare no conflict of interest.Table S1Click here for additional data file.


As the cancer survivors increase, patients using long-term and high-dose opioids are also increasing. Therefore, the promotion of appropriate use is important. This study investigated the actual status of opioid prescriptions in Japan and identified factors associated with long-term, high-dose prescription.We conducted a case-control study using a hospital-based administrative claims database. Patients with a diagnosis of cancer and prescriptions of opioids were included. Patients who received continuous opioid for less than 183 days were defined as the “control,” and patients who received continuous opioid at higher dose levels  for 183 days or more were defined as the “case.” The case was subdivided into two groups: those with the duration of less than 730 days (case I) and 730 days or more (case II). After describing factors possibly associated with long-term, high-dose opioid prescription, ordinal logistic regression analysis was conducted.We included 19,176 patients; of these, 13,517 were in the control, 111 were in the case I, and 682 were in the case II. The analysis showed that distant metastasis, back pain, dose of opioids, non-opioid analgesics, prescription, and chemotherapy during the opioid prescriptions were significantly associated with long-term, high-dose opioid prescription.Four percent of the study population were prescribed long-term, high-dose opioids, and several comorbidities and concomitant medications were identified as associated factors. Opioids might be also prescribed for non-cancer chronic pain. It is necessary to properly distinguish the type of pain and to use opioids safely and appropriately.The online version contains supplementary material available at 10.1007/s00520-022-07121-3. In Japan, the population of cancer patients is growing rapidly with the aging of the population, and the survival time of patients is becoming longer due to progress in early diagnosis and treatment , 2.Cancer pain is associated with decreased quality of life and poor adherence to cancer treatment; therefore, appropriate pain control with opioids is important. When cancer patients survive for a long time, their cancer pain are often complicated by non-cancer pain, and long-term opioid use requires pain-specific treatment while also considering treatment of breakthrough pain .On the other hand, long-term or high-dose prescriptions are more likely to cause the adverse effects such as opioid-induced hyperalgesia, gonadal dysfunction, intestinal dysfunction, cognitive dysfunction, sleep disorders, immune disorders, and addiction. Appropriate use of opioids is also important to prevent the occurrence of an opioid crisis .The study by Jones et al. reviewed the literatures investigating the factors associated with long-term opioid therapy for cancer survivors, and describes a relationship between long-term opioid use and important biopsychosocial factors such as cancer sites, socioeconomic factors, and comorbidities . WhereasIn the present study, we investigated the situation of cancer patients in Japan prescribed opioids and the factors associated with long-term, high-dose prescriptions. We also investigated exploratory associations between rescue medications, which are often used for breakthrough pain, and long-term, high-dose prescriptions of opioids.This study was designed as a case-control study using a hospital-based administrative claims database in Japan constructed by Medical Data Vision Co., Ltd (MDV) . The MDVFrom the MDV claims database, we identified the eligible patients by the following three criteria: (i) having diagnosis of cancer between April 2008 and July 2020  and 730 days or more (case II).The prescription period was defined as the duration from the index date to the date of death or end of the prescription. The end of prescription was defined as an interval of 30 days or more between prescriptions of the relevant opioid after the index date, and the last day covered by the last prescription was defined as the day of end of opioid prescription. Even when the opioid was changed to other opioid(s) or combined with additional opioid(s), the prescription was considered to be continued Fig. .Fig. 1DeThe mean opioid dose during the prescription period was calculated by dividing the active ingredient’s quantity equivalent in potency to the oral-dose morphine hydrochloride hydrate 30 mg (an opioid) prescribed during the prescription period  by the pThe following factors possibly associated with long-term, high dose prescription of opioids were described separately for the case groups and the control group: gender, age, site of cancer, metastasis, comorbidities, dose of opioids, duration from diagnosis of cancer to the start of opioid prescription, prescription of pain-related drugs other than opioids, and types of cancer treatment. Prescription of pain-related medication other than opioids and types of cancer treatment were evaluated both before and after the start of opioid prescription. Each case group was compared with the control group in a multiple comparison using the Dunnett test for continuous variables and the Steel test for categorical variables.p<0.05) as well as categorical variables whose incidence in the case or control group was 5% or higher. Step 2: variables selected from step 1 were re-evaluated for co-linearity and clinical validity.On the basis of the descriptive statistics, ordinal logistic regression analysis was conducted to investigate the factors associated with long-term, high-dose prescription of opioids. The control group, case I group, and case II group were considered as dependent variables. Through this analysis, the odds ratio of long-term, high-dose prescription of opioids for each explanatory variable and its 95% confidence interval were calculated. The explanatory variables were selected by the following steps. Step 1: selection of variables of descriptive statistics showing significant differences both between the control group and case I group and between the control group and case II group  powder, oral immediate release tablet, hydromorphone (Narurapid®) tablets, fentanyl  sublingual tablets, fentanyl (E-fen®) buccal tablets, morphine (Anpec®) suppositories, morphine (Opso®) oral solution, or morphine hydrochloride immediate release tablet. The percentage of patients who received rescue medication during the prescription period of opioid was calculated. In addition, among patients who received rescue medication, the mean daily number of rescue medication use, which is the total number of rescue medication use during the opioid prescription period divided by the prescription period, and the mean rescue medication dose, which is the total doses of rescue medication during the opioid prescription period divided by the opioid prescription period, were described. Each case group was compared with the control group in a multiple comparison using the Steel test for percentage of patients receiving rescue medication and the Dunnett test for the mean daily number of rescue medication use and the mean rescue medication dose.For all calculations of oral morphine equivalent dose, fentanyl sublingual tablets and fentanyl buccal tablets were excluded from the calculation because they are not defined in the guidelines , 7 and cP values of <0.05 were considered significant.All data analyses were carried out with SAS v.9.4, and The patient flow chart is shown in Fig. Table Table Table The present study attempted to identify factors associated with long-term prescription of opioids at high-dose levels for cancer patients for the first time in Japan. As a result, there were 13,517 patients in the control group who were prescribed opioids for less than 183 days, while 111 and 682 patients in the case I and case II groups who were prescribed opioids for more than 183 days and averaged more than 120 mg/day, respectively. The majority of the study population fell into the control group, of which 70.1% averaged less than 30 mg/day, while about 4% of the study population was identified as being on long-term, high-dose prescriptions. In addition, distant metastasis, prescription of non-opioid analgesics, SSRI, SNRI, gabapentinoids, and anticonvulsants during the opioid prescription period, chemotherapy, and back pain were shown to be associated with long-term, high-dose opioid prescribing.In the present study, although esophageal cancer, breast cancer, and colorectal cancer were considered as candidate factors associated with long-term, high-dose prescription of opioids based on descriptive statistics results, no significant association was found in the ordinal logistic regression analysis. Although cancer prognosis varies by race and environmental factors and is not generally comparable, several studies described the relationship between cancer type and long-term opioid prescription. A study by Jones et al. reviewing studies of long-term prescription of opioid in cancer survivors noted a high rate of long-term opioid therapy in head and neck cancer . The heaPatients with distant metastasis are more likely to have severe cancer, which is consistent with the report on opioid use in colorectal cancer patients by Chen et al.  that theRegarding the prescription of non-opioid analgesics, Murphy et al. reported an association between polypharmacy and long-term prescription of opioids , and it We were the first to examine back pain as a factor in long-term, high-dose opioid prescriptions and showed a significant association. The reasons that back pain was identified as a factor are considered to be as follows. Firstly, since patients with bone metastasis were also included in this study, it is possible that pain associated with bone metastasis was diagnosed as back pain. The percentage of patients with bone metastasis among those diagnosed with back pain was higher in case I (44.0%) and case II (42.6%) groups than in the control group (20.8%). Secondly, opioids might have been prescribed for non-cancer pain. When we confirmed the details of the diagnostic names related to back pain, the 90% patients in both the case and control groups were diagnosed with lower back pain . NakamurWe further exploratory evaluated the status of rescue medications. The percentage of patients receiving both periodical medication and rescue medication was higher in the case groups than in the control group, and the rescue drug dosing frequency and level per day were also higher in the case groups. Patients with long-term, high-dose prescription of opioid were shown to have a higher frequency of use and prescription of rescue medications; however, confounding factors could not be ruled out because patients background were not matched; thus, the result needs careful interpretation.The present study using a large-scale, hospital-based administrative claims database involves limitations arising from database characteristics. First, the database employed for this study covered only the data at hospitals having introduced an acute inpatient care system. Because this database does not track data when patients visit to other hospitals, if opioids were prescribed at other hospitals, the dose and frequency of opioid administration may have been underestimated. Second, the opioid dose might be underestimated because fentanyl sublingual tablets and fentanyl buccal tablets are not reflected in the prescription dose. However, since most drugs can be converted to morphine, we believe that this issue will have a small impact on the results. Third, because the data from this database are based on payment-related information, it is not possible to capture whether the patient actually took the drug. Fourth, since we were unable to assess the severity and type of pain, we cannot discuss the clinical appropriateness of the opioid prescription.We investigated the situation of cancer patients prescribed opioids and the factors leading to long-term, high-dose prescription. Within the scope of the study using the claims data, it was found that about 4% of cancer patients prescribed opioids in Japan were prescribed long term and high doses. Some of the factors identified were similar to those previously reported; however, the study also found new risks, such as back pain. This suggests the potential existence of a situation in Japan where opioids are used in cancer patients with insufficient distinction between cancer pain and non-cancer chronic pain. In order to avoid the careless use of opioids, it is essential to be careful about comorbidities in cancer patients, to evaluate the pain in individual patients for distinction between these types of pain and to select analgesics including opioids tailored to individual patients.ESM 1(PDF 189 KB)


Fibrous dysplasia (FD) is a rare bone disorder that can involve any part of the skeleton, leading to bone pain, deformities, and fractures. Treatment with intravenous bisphosphonates has been used with variable results. Therefore, we aimed to evaluate the effects of zoledronic acid (ZA) therapy in patients with monostotic or polyostotic FD.The medical records of thirteen patients with FD evaluated between 2015 and 2020 were retrospectively analyzed. In the subgroup of patients treated with ZA (n = 7), data on pain relief, changes in bone turnover markers (BTMs), and adverse events following ZA infusions were retrieved. Moreover, radiological changes in response to treatment were recorded in patients who underwent radiological follow-up.Of the patients, 5 (38%) presented with monostotic whereas 8 (62%) had polyostotic FD. Bone pain was a common finding (69%), and most patients (62%) exhibited elevated baseline BTMs. Partial or complete pain relief was reported in 6 of 7 patients treated with ZA. BTMs, especially C-telopeptide of type I collagen (CTX), significantly decreased after therapy , and median CTX levels were significantly lower than at baseline . No radiological improvement was observed in cases with radiological follow-up (n = 3). No serious adverse effects of ZA were reported.ZA treatment was well tolerated and provided beneficial effects in relieving bone pain and reducing BTMs, especially CTX. Our data reinforce the role of ZA in the treatment of FD-related bone pain. GNAS , which encodes the Gαs subunit of G-coupled protein receptors. In bone, constitutive Gαs activation impairs the differentiation of skeletal stem cells, leading to the replacement of normal bone and marrow with immature woven bone and fibrotic stroma ( Fibrous dysplasia (FD) is a rare mosaic bone disorder caused by somatic activating mutations in  stroma   – 3 . Ad stroma   .Any part of the skeleton can be affected, and the clinical spectrum ranges from an asymptomatic monostotic lesion discovered incidentally to severely disabling polyostotic disease. FD may occur alone or in association with extraskeletal features, such as café-au-lait skin macules and hyperfunctioning endocrinopathies, which is termed McCune-Albright syndrome (MAS)   , 3 . CoAntiresorptive agents, such as bisphosphonates, have emerged as potential treatment options for FD due to high osteoclastic activity in dysplastic bones. Intravenous bisphosphonates, such as pamidronate and zoledronic acid (ZA), have been used to treat patients with FD and can provide pain relief and a reduction in bone turnover markers (BTMs), but their potential effects on disease progression are unclear   . In an The objectives of this study were: 1) to characterize a cohort of patients with FD/MAS from a single tertiary center in Brazil and 2) to retrospectively evaluate the effects of ZA treatment in this population.Electronic medical records of patients with FD/MAS evaluated at the Bone Unit of the SARAH Network of Rehabilitation Hospitals in Brasília, Brazil from 2015 to 2020 were retrospectively reviewed. The diagnosis of FD/MAS was established based on clinical and radiological findings, with additional histological evaluation as needed.Data on age at presentation, sex, symptoms before and after ZA infusion, and extraskeletal complications were collected. Radiographic findings were evaluated to assess the extent and severity of skeletal disease. In addition, we gathered data about medical treatment with ZA, which was administered at 5 mg per infusion, with the timing of subsequent cycles determined by symptoms, severity of disease, and BTMs levels.Laboratory parameters, including serum levels of creatinine, calcium, phosphate, albumin, 25-hydroxyvitamin D (25 [OH] vitamin D), parathyroid hormone (PTH), total ALP, and serum C-telopeptide of type I collagen (CTX), were also retrieved. Plasma concentrations of calcium, phosphate, albumin, and creatinine were measured using standard laboratory methods; 25 (OH) vitamin D level was analyzed using a chemiluminescent immunoassay; ALP levels were measured by spectrophotometry; and PTH and CTX levels were measured by electrochemiluminescence in a fasting state in the morning. Normal ranges: creatinine 0.6-1.1 mg/dL, calcium 8.5-10.1 mg/dL, phosphate 2.5-4.8 mg/dL in patients age > 18 years, albumin 3.5-5.5 g/dL, 25(OH) vitamin D > 30 ng/mL, PTH 10-69 pg/mL, ALP 42-98UI/L, CTX in premenopausal women < 0.573 ng/mL; < 1.008 ng/mL in postmenopausal women, and < 0.583 ng/mL in men. Normalization rates of ALP and CTX were calculated considering the upper limit of the normal range (ULN) for each one.The response to ZA treatment was evaluated biochemically based on percentage changes in the maximum levels of BTMs before treatment to the minimum level achieved approximately 6-12 months after treatment, and clinically by relief of symptoms. Bone pain was not quantitatively evaluated using the visual analog scale or other validated questionnaires, and pain response following treatment was categorized as increased, unchanged, improved, or disappeared. Data on the potential adverse effects following ZA infusions were also collected.Changes in radiological findings in response to ZA therapy were retrieved for patients for whom radiological follow-up was performed. In such cases, radiological examinations after ZA therapy were compared to the previous radiological examinations by an experienced musculoskeletal radiologist. Bone lesion status was categorized as unchanged, improved, or progressive disease if there was increased lytic changes, increase in diameter of the lesions or worsening of bone deformity. Radiological improvement was defined if cortical thickening, progressive filling of destroyed bone and decreased in diameter of the lesion was observed. In addition, data about bone mineral density (BMD) were retrieved for patients who had a dual-energy X-ray absorptiometry (DXA) performed during the follow-up period.P < 0.05.Descriptive statistics were expressed as numbers with percentages, medians, and interquartile ranges (IQR), as appropriate. The non-parametric Mann-Whitney U test was used to compare levels of serum BTMs before and after treatment, as the data did not follow a normal distribution. Spearman correlation was computed to assess the relationship between clinical characteristics  and baseline values of BTMs, and biochemical response to treatment. Statistical significance was set at This study was approved by the Ethics Committee of the SARAH Network of Rehabilitation Hospitals  and performed in accordance with the tenets of the 1964 Declaration of Helsinki. Informed consent was obtained from all subjects.Thirteen patients (two men) with FD were identified, and their general characteristics are summarized in GNAS mutation, R201H, was identified. The diagnosis was made solely based on typical radiological findings in five patients, whereas a biopsy was performed for eight subjects. In one patient, molecular analysis of the affected tissue was performed, and the Bone pain of variable intensity was reported by most patients  who used a variety of analgesics, including non-steroidal anti-inflammatory drugs and opioids. Three subjects had prior fractures, and three required mobility assistance with canes or crutches.P = 0.009, and r = 0.732, P = 0.004, respectively), and time since diagnosis . All patients exhibited serum phosphate levels within the normal range during the follow-up period.At baseline, 8 (62%) patients exhibited serum BTM levels (ALP and/or CTX) above the ULN, four patients had concurrent elevations in levels of ALP and CTX, three patients exhibited an elevated CTX level with ALP in the normal range, and one patient exhibited an elevated ALP level with CTX in the ULN. The median baseline ALP levels were 129 UI/L (IQR 92.2-209.5 UI/L), and the median baseline CTX levels were 0.682 ng/dL (IQR 0.248-1.07 ng/dL). There was a positive correlation between baseline ALP and CTX levels and the number of affected skeletal sites , and DXA scan of a postmenopausal woman with polyostotic FD P9 –   showed Eight (62%) patients were treated with ZA and a 61-year-old woman with polyostotic FD on long-term ZA therapy for a concurrent diagnosis of osteoporosis was excluded from the analysis. The median age of the seven treated patients was 36 years (IQR 24.5-39.5 years), and all of them reported pain in the affected bones. Patients who were not treated (n = 5) either refused ZA due to the potential side effects associated with bisphosphonate therapy (n = 2) or were not considered eligible according to a clinical judgment (n = 3). All but two patients presented with polyostotic disease. The patients received 2.5 courses of ZA on average (range 1-5), and a second cycle was performed a median of 14.2 months (range 5.7-39.2) after the first one.vs. 135.5 , respectively, P = 0.073). Conversely, median CTX levels were significantly lower after treatment than at baseline , with a change rate of −61.8%     . Five pRadiological follow-up was available for three patients treated with ZA. Follow-up imaging was performed using computed tomography (CT) scans in all patients, and one patient also underwent magnetic resonance imaging. One patient had unchanged bone lesion status compared to previous radiological examinations; one patient P4,   exhibitTransient fever and/or myalgia within 1-3 days of ZA infusion was reported in 6 out of 7 treated patients, of whom one adolescent also exhibited nausea, vomiting, and transient worsening of headache requiring hospitalization for venous hydration and analgesia.None of the subjects developed hypocalcemia or renal toxicity. Furthermore, there were no reports of osteonecrosis of the jaw or atypical femur fractures in any patient during the follow-up period.This study represents the largest single-center review of Brazilian patients with FD and documents the clinical features of 13 patients, including 3 subjects with MAS. Moreover, we retrospectively analyzed the outcomes and complications of ZA therapy in a subgroup of patients who received such treatment. Our data demonstrated that ZA was well tolerated and effective in reducing bone pain and BTMs, notably CTX.GNAS mutation and reflects the stage of embryogenesis in which the mutation occurs, with earlier mutations resulting in more widespread disease, and those occurring later in development leading to limited disease , which is in agreement with other reports that suggest polyostotic FD is more prevalent than the monostotic form   , 10 . HGNAS mutation, R201H, which is the most common GNAS pathogenic variant described in the literature, was identified  in dysplastic lesions may occur in nearly 50% of patients with FD/MAS and can lead to the development of hypophosphatemia and osteomalacia   . AlthouData about BMD measurement in patients with FD are scarce. In our study, baseline DXA scan was performed in 4 patients, but in only one the evaluation included an affected skeletal bone. In this patient with hip involvement, total hip BMD was increased. A similar finding was described by Chapurlat and cols., suggesting that the typical features of FD and the sclerotic rim within a bone lesion, may interfere with BMD measurements, resulting in an overestimation of BMD   .The natural history of FD is not fully understood. Bone lesions become apparent over the first years of life and tend to expand throughout childhood and adolescence, and the final skeletal burden is usually established by the age of 15   , 17 . SBone pain is a common symptom and can affect the functional status and quality of life. The pathophysiology of bone pain is not completely understood, and its frequency and severity increase with age. Notably, bone pain does not correlate with disease activity or skeletal burden   , 19 . OThe management of patients with FD/MAS is challenging, and a multidisciplinary team of specialists, including endocrinologists, orthopedic surgeons, craniofacial surgeons, and ophthalmologists is usually required   , 11 . PBisphosphonates have been used in the treatment of FD because of the increased levels of bone resorption commonly seen in dysplastic bones. Several regimens of bisphosphonates have been tested, but most of the available evidence is derived from observational and uncontrolled studies owing to the rarity of this condition   , 8 . ThStudies with intravenous bisphosphonates, such as pamidronate and ZA, have shown beneficial effects in relieving bone pain and decreasing BTMs, but the response to treatment may be variable and the best treatment regimen and dosing intervals have not yet been established   . In theBased on these data, ZA was offered to our patients who presented with FD-related bone pain and/or elevation of BTMs. We observed that ZA effectively reduced bone pain, although it was not quantitatively measured using the visual analog pain scale or other validated pain questionnaires. In addition, we demonstrated a beneficial effect of ZA therapy on the reduction in BTMs levels, which are commonly used as markers of metabolic disease activity. At baseline, most patients (62%) exhibited BTMs (ALP and/or CTX) above the ULN, of whom three patients had elevated CTX with ALP levels within the normal range. Baseline ALP and CTX levels also positively correlated with the number of affected bones, which was consistent with previous studies   , 22 . IThe possible effect of intravenous bisphosphonates in improving bone quality or preventing bone expansion is controversial. Radiographic response, described as filling of osteolytic lesions, and cortical thickening, has been described in some reports with pamidronate or ZA, although it was not a consistent finding   , 24 . IConsidering the natural history of the disease, in which FD lesions increase in childhood and their metabolic activity decreases over time after the final skeletal burden is achieved, it is plausible that strategies of treatment to prevent the development or expansion of FD lesions would need to be targeted during childhood and initiated soon after the development of FD becomes apparent   . FlorenThe acute phase response , which usually occurs within 24-48 hours following infusion, is a well-known adverse event of ZA therapy. In patients with osteoporosis, it occurs in approximately 18% of cases after the first infusion; however, the incidence rate decreases in subsequent infusions   . In ourOur study had certain limitations. First, it was based on a retrospective analysis, and missing data were unavoidable. In addition, it included a heterogeneous group of patients, and the timing and doses of ZA were variable. Moreover, as previously mentioned, pain and functional status were not formally evaluated using quantitative validated tools, and a placebo effect could not be excluded. However, given the rarity of the disease and paucity of available data on its treatment with ZA, our findings provide a substantial contribution to the current literature, and reinforce the role of ZA as an option in the medical management of FD-related bone pain.In summary, the clinical manifestations of FD were heterogeneous, and some patients presented a debilitating course. ZA therapy was generally well tolerated and provided beneficial effects on the relief of bone pain and a reduction of bone turnover, although without radiological benefits. Prospective controlled studies are still required to assess the efficacy and long-term safety of ZA therapy in patients with FD.


Multidisciplinary biopsychosocial rehabilitation (MBR) in patients with chronic low back pain (CLBP) is superior to less intensive treatments for at least one year, but the long-term course of the disease is largely unknown. The primary aim of this study was to describe the long-term course of an MBR in relation to pain, disability, and quality of life from the beginning of an MBR to between 4 to 15 years after participation. The secondary aim was to explore the long-term course of an MBR in relation to physiological outcomes of functioning.This was a observational study conducted at a university hospital. The cohort consisted of participants of a 3-week, CLBP-specific MBR program between August 2001 and January 2013. The North American Spine Society questionnaire (NASS) pain and disability scale was the primary patient -reported outcome measure (PROM). The NASS neurogenic symptoms scale and the Short-Form 36 (SF-36) health survey were secondary PROMs. Patients were assessed before entry to the MBR (T0), at entry (T1), at discharge (T2) and 4 to 15 years after discharge (T3). Effects were quantified by effect size (ES). Score differences were tested for significance using parametric or non-parametric tests and linear mixed models.p < 0.001). The NASS neurogenic symptoms scale was stable. The SF-36 scales showed an improvement in the bodily pain domain , but no significant changes for physical functioning, physical role, general health, vitality, social functioning, emotional role, or mental health. The physical health component summary was improved , and the mental health summary was unchanged. The linear mixed model analysis confirmed improvements in pain and disability between T1 and T3 (p = 0.010).Of 299 consecutive patients from the MBR program, 229 could be contacted. Of these, 84 declined participation, five did not meet the inclusion criteria, and 26 had incomplete data. Thus, 114 patients were included. The mean follow-up time was 9.2 years. At T3, patients exhibited beneficial effects for NASS pain and disability with a moderate ES (ES = 0.63; The results of this study suggest that there is a long-term benefit of MBR participation in patients with CLBP. Low back pain (LBP) is a common health condition with more than 500 million people globally affected at any one time . It rankMultidisciplinary biopsychosocial rehabilitation (MBR) addresses the multiple factors that contribute to CLBP . They coHowever, there is little evidence for the long-term effects of MBR (more than one year following treatment) –13. SomeKnowledge concerning the long-term course after an MBR would help clinicians counsel candidates for an MBR about the course patients could expect when they become older. If the long-term course in pain and disability is favorable, this could assure patients who are worried that CLPB necessarily gets worse with age and help motivate them to participate in an MBR. For health insurances, knowledge concerning long-term course outcomes could support them in deciding whether to provide coverage for MBR programs.Previous long-term studies have measured outcomes in functioning via patient self-reporting, but have not added physiological measures –13. If pTherefore, we designed a long-term follow-up study of patients with CLBP who had participated in an MBR. A previous evaluation of this particular MBR demonstrated that patients improved for at least 12 months after treatment . In thisThe primary aim of this study was to describe the long-term course of an MBR in relation to pain, disability, and quality of life from the beginning of an MBR to between 4 to 15 years after participation. The secondary aim was to explore the long-term course of an MBR in relation to physiological outcomes of functioning.In this observational study, the data were prospectively collected from a cohort of patients that participated in an MBR. The schedule and measures for the assessments before the 3-week MBR (T0), at the beginning of the MBR (T1) and at the end of the MBR (T2) were defined before data collection started. The mean waiting time between T0 and T1 was 139 (± 159) days. The long-term follow-up occurring between 4 to 15 years after the MBR (T3) was defined only after the data at T0, T1, and T2 had already been collected. The study was approved by the institutional review board at the medical faculty of the Ludwig Maximilian University Munich (project number 632–16). The study was conducted in accordance with the Declaration of Helsinki. All patients signed informed consent forms. The study was not preregistered.University Hospital, Ludwig Maximilian University Munich, day clinic of the Department of Orthopedics, Physical Medicine and Rehabilitation.Patients who had participated at least 4 years previously were selected from a database of all MBR patients. A member of the study team attempted to call all selected patients. He explained the content of the study and evaluated patients for inclusion in the study. Patients with severe illness at T3 that could have caused disability that would have masked the long-term course of pain and disability were excluded. Further exclusion criteria were insufficient German language skills to fill in questionnaires and participation in another MBR in the 12 months before T3. Furthermore, patients were excluded if the primary outcome measure was missing at T1, T2 or T3. If a patient was interested in participating, information and informed consent were sent to the patient by mail.The included patients were retired or older working adults as this program complemented a pre-existing MBR program at the University Hospital Munich for young, working adults .A subgroup of 37 patients was invited for reassessment using the same physiological measures that had been conducted at T1 and T2. To form a representative subgroup, the whole cohort was divided into eight groups according to gender , age (above/below the median), and participation in a one-week MBR refresher approximately one year after the MBR (yes/no). Each group had between 6 and 27 patients. One third of the patients from each subgroup was randomly selected.The clinic has been offering this LBP-specific MBR program since 2001. The recommendation for participation in the MBR was based on an interdisciplinary assessment. The criteria for participation in the MBR have been presented elsewhere .The intervention was a 3-week MBR with three treatment days every week and a total of 44 treatment hours .The rehabilitation team included a specialist in Physical and Rehabilitation Medicine, a psychologist, a physiotherapist, and an occupational therapist. Figure Patients completed questionnaires at T0, T1, and T2 on-site in the clinic on the same day as the examination for the physiological measures. At T3, the questionnaires were sent by postal mail. The study team provided pre-addressed and stamped envelopes and asked the patients to return the questionnaires by postal mail. If patients did not return the questionnaire after two weeks, the research assistant called the patient by phone and asked for the questionnaires to be returned.Data were manually transferred from the questionnaires into a database by a member of the study team. Unclear responses, e.g., those with 2 or more crosses, were considered missing values. For data cleaning, two members of the study team independently controlled all data visually for duplicate data, duplicate rows, missing values, or obvious typing errors. Then, statistical tests were calculated to ensure that all data were within the specified range. In the next step, the lower and upper extreme scores of all scales and physiological measures were identified. The data from these patients were validated against the original data in the questionnaires and the forms for the physiological measures.Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) , 18 at TThe number of comorbidities was counted via the validated Self-administered Comorbidity Questionnaire  at T1 anPatient education was assessed at T1 by a single written question.The primary outcome was pain and disability as measured by the North American spine society lumbar spine outcome assessment Instrument (NASS) pain and disability scale , 21 at TPhysiological measures were applied according to standardized written protocols. A highly experienced physiotherapist  trained the examiners. At T1 and T2, physiotherapists or occupational therapists conducted the tests. At T3, the examiner was a doctoral medical student.Isometric muscle strength during flexion and extension of the knee joints was measured with a hand-held pull gauge  connected to a belt . The patThe timed-up-and-go-test assesses mobility, as well as static and dynamic balance, and is associated with the risk of falls. The patient sits on a chair, stands up, walks three meters, turns around, walks back to the chair and sits down again. The unit of measure is seconds. It has high reliability and is frequently applied in older persons . It is tThe 6-min-walk-test assesses a patient's physical aerobic endurance and walking ability. Before and during the test the patient received standardized instructions. The unit of measure was the walking distance in meters . The 6-mThe course of pain and function was described by the scores from the PROMs and physiological measures. Changes from T1 to the follow-ups at T2 and T3 were quantified by effect size (ES) . The ES p < 0.05. The significance tests were confirmatory for changes in the primary outcome NASS pain + disability between T1 and T3. All other significance tests were exploratory.Significant changes in scores were tested by means of paired t-tests if data were normally distributed. Otherwise, the Wilcoxon signed-rank test was applied. The significance level was set at No data was imputed. Only cases with valid scores for the variable under consideration at T1, T2, and T3 were included. In the analysis of the SF-36 scales, only cases with valid scores in all scales were included.Results of the primary outcome measure NASS pain + disability and the SF-36 physical and mental health component summaries were corroborated using linear mixed models that allowed for adjustment of the possible confounders of gender and age. These models used a random intercept per patient and the fixed effects of time , age, gender, and baseline NASS or SF-36 scores. The formula used was:y_i(t) = β_0i + β_1 × (t = T0) + β_2 × (t = T2) + β_3 × (t = T3) + β_4 × y_i (t = T1) + β_5 × age + β_5 × male.Where:y_i (t): individual value of the outcome variable of patient i at time t.β_0i: random intercept for patient i.β_1,β_2,…,β_5: regression coefficients for the fixed effects .A longer follow-up could result in a selection bias for healthier patients as the longer the observation period, the more likely it is that no current contact information would be available because the patient would have moved to a retirement home or died. This risk of selection bias was addressed via a subgroup analysis of patients with differing lengths of follow-up time. Patients were divided into groups with more or less than 9 years of follow-up time, as 9 years was the nearest year to the median.Statistical analyses were performed with the software package SPSS 25.0  for Windows. ES values were calculated using Microsoft EXCEL 2016. These analyses were performed using SAS 9.4 for Windows .We compared the age and gender of patients who were included in the long-term follow-up analyses to patients who were not included in the follow-up.In an earlier study, the MBR had an average ES of 0.36 in the primary outcome pain + disability after one year . We assuIn December 2016, of the 299 patients that had been participating in the MBR at least four years before, there was no current contact information available for 56 patients, and we received information about the patient's death for 14 patients. The remaining 229 patients were contacted by phone between December 2016 and July 2017. Of these, 84 declined participation. Two were excluded due to severe illness, two due to participation in another MBR less than 12 months previously, and one due to insufficient German language skills. Of the remaining 140 patients, 26 were excluded due to incomplete data in the primary outcome measure. Thus, 114 patients (38.1%) were included in the primary analysis.A subgroup of 37 patients was also invited for reassessment of physiological measures. A study inclusion flow diagram is presented in Fig. The participant characteristics of the 114 patients included in the study are presented in Table The mean patient age was 62.8 (± 8.3) at T1 and 72.0 (± 7.7) years at T3. Females accounted for 68.4% of participants. Patients were followed for a mean time of 9.2 (± 3.5) years.Table p < 0.001). Further significant improvements were found for the SF-36 bodily pain scale and the SF-36 physical health component summary. The other scales showed no significant differences from T1.At T3, NASS pain + disability showed a moderately beneficial effect  remained. Other physiological measures showed no significant differences between T1 and T3.At T3, a beneficial effect for left knee extension  and right knee flexion . The significance of the improvement persisted until T3 (p = 0.010). There was no change during the waiting time between T0 and T1. These results suggest that the improvements were due to the MBR and not to natural variations over the course of LBP.The pain + disability scale improved between T1 and T2 .Changes between T1 and T 3 were not significant  and gender distribution .This prospective study of patients with CLBP after MBR had a substantially longer follow-up period and larger sample size in comparison to previous long-term studies. The results confirmed our hypothesis that patients with CLBP have less pain and disability, as well as a stable quality of life, at a long-term follow-up that was 4 to 15 years following discharge (mean: 9.2 years) compared to before their MBR. The ES for the primary outcome NASS pain + disability remained moderate and was clearly above a minimal clinically important difference , and theThe long-term improvement in pain and disability seen in our study is in line with the majority of the results in four previous studies investigating patients with CLBP , 12, 13.The study of Bendix et al.  showed iThe second study by Cassisi et al.  showed iIn the study by Zhuk et al. , the MBRIn line with our study, Patrick et al.  have alsOverall, the comparison of these four previous studies and ours is limited as all of the studies applied different outcome measures. Furthermore, they differed in terms of patient characteristics, program content, methods of data collection, comparison groups, and the duration of follow-up. Despite these differences with our study, all four studies showed an improvement in disability in line with our study , 12, 13.The long-term effects in this study were larger than those in a meta-analysis of randomized controlled trials  that repThe long-term, stable SF-36 scores of the physical function component suggest that an MBR may also improve the long-term course of general health because, in the average population from the age decade 60–69 to the 70–79 decade, these scores decline . These gThe differences in the course from T1 to T3 between the NASS pain and disability scale and the SF-36 scales for physical function and physical role are surprising. One reason for these differences is the combination of pain and disability in the NASS scale, as improvements in pain were greater than in disability. This is confirmed by the large improvement in the SF-36 pain scale in this study, as well as by results from a previous study in which the NASS items for pain and disability were analyzed separately . AnotherThis is the first long-term study after an MBR that measured physiological outcomes. Muscle strength for knee extension and flexion remained stable during the long observational period. Strength training of these muscles is important in patients with LBP because the strength of knee extension, and probably also knee flexion, is reduced in patients with LBP compared to healthy controls . FurtherIn addition, mobility as measured by the timed-up-and-go-test and walking ability measured by the 6-min-walk-test were stable. These results suggest that continued physical activity may have counteracted age-related decline in physical performance. Accordingly, continued physical activity could have contributed to the positive, long-term outcome for pain and disability as higher levels of physical activity are associated with less pain .However, it must be considered that the physiological measurements were exploratory, and the subgroup was small. Accordingly, the favorable course of these results could also be due to selection bias or chance. Therefore, these results need confirmation in future studies before firm conclusions can be drawn.To corroborate the results for the primary outcome of pain and disability, we tested the significance of change with a second statistical method, mixed linear models. This method allows for the modeling of the effects of time, disease severity, age, and sex on the response variables for potentially heterogeneous individuals. The significance of the changes at the long-term follow-up confirmed the favorable long-term course for pain and disability.It is interesting to note that despite the expected increase in comorbidities during follow-up, pain and disability improved. One possible reason for the maintained improvement is that some comorbidities that become more prevalent with age, such as hypertension or diabetes mellitus, have little impact on condition-specific outcomes. Furthermore, increased physical activity due to the MBR may also reduce potential disability associated with new comorbidities.An important limitation of this study is the lack of a control group. Accordingly, it is not possible to determine which factors other than the MBR contributed to our long-term results. For example, another MBR during the follow-up could have led to an overestimation of the effects. In contrast, a new onset of osteoporosis and associated pain and disability could have led to an underestimation of the effects. We intended to include as many patients as possible to capture the long-term course in real life. Accordingly, this study showed that after participation in an MBR, there is not necessarily a new deterioration in pain and disability, and improvements can last for many years despite increasing age.A second limitation is the loss to follow-up of 62% of the participants of the MBR. However, the response rate was in the medium range compared to previous studies with follow-ups lasting many years after an MBR –13. The A third limitation is the exclusion of two patients with severe illness at T3. This criterion, and the exclusion of 14 patients who had died, could have led to an overestimation of the benefits as these patients likely had a worse course compared to the included patients. The reason for the exclusion criterion of severe illness was that severe illness at the time of follow-up and the associated disability would have masked the long-term course of pain and disability.A fourth limitation is the very broad time frame of follow-up between 4 and 15 years. For the primary outcome of pain and disability, the subgroup analysis of patients with less and more than nine years follow-up suggests that this outcome improves significantly independently of the length of follow-up.The older age of participants in this study compared to other CLBP studies limits the generalizability of the results to younger patients. However, the investigation of CLBP outcomes in older adults is important given that there is still little evidence of effective therapy for CLBP in this population, even though back pain is quite common in this group .Unfortunately, it is an ethical problem to conduct randomized controlled trials to evaluate the long-term course after MBR in CLBP patients because it is unethical withholding patients from a treatment that is recommended in guidelines. This may be an important reason for the lack of recent controlled studies on this topic.The results of this study suggest that patients with CLBP benefit from participation in MBR in terms of improved pain and disability for a number of years and perhaps for the remainder of their lives. This is an encouraging finding for patients who consider participating in an MBR (or for those who had participated in an MBR) and are concerned that, following participation, their CLBP may worsen with increasing age. The long-term improvements should be considered by health insurances when making decisions concerning whether to provide coverage for MBR programs.Future studies with periodic follow-ups could further evaluate those factors that contribute the most to the long-term benefits following MBR, e.g., exercise adherence, sport activities, strategies for stress reduction, ergonomics in daily activity, social factors, co-morbidity, or the social environment.


The growing number of patients undergoing total hip arthroplasty (THA) and postoperative outcomes receive increasing attention from doctors and patients. This study aimed to elucidate the effects of comorbidities on postoperative function, pain, complications, readmission rate, and mortality.We included consecutive patients who underwent primary unilateral THA between 2017 and 2019. The Charlson comorbidity index (CCI) and the WOMAC and SF-36  scales were assessed preoperatively and at 3, 6, 12, and 24 months postoperatively. The complications, 30-day readmission, and mortality rates assessed the impact of comorbidities and their changes over time on the WOMAC and SF-36 scores during follow-up. We used mixed model linear regression to examine the association of worsening comorbidity post-THA with change in WOMAC and SF-36 scores in the subsequent follow-up periods, controlling for age, length of follow-up, and repeated observations.This study included 468 patients, divided into four groups based on comorbidity burden . The physiological function recovery and pain scores in the CCI ≥ 3 group were inferior to the other groups and took longer than the other groups (6 vs. 3 months) to reach their best level. The four groups preoperative waiting times were 2.41 ± 0.74, 2.97 ± 0.65, 3.80 ± 0.53, and 5.01 ± 0.71 days, respectively. The complications, 30-day readmission, and 1-year mortality rates for the overall and the CCI ≥ 3 group were 1.92% and 4.69%, 0.85% and 2.01%, and 0.43% and 1.34%, respectively, with no mortality in the other groups.Patients with higher CCI were more susceptible to physical function and pain outcome deterioration, experienced longer waiting time before surgery, took longer to recover, and had higher rates of complications, 30-day readmission, and mortality after THA. Older age in the group led to a greater impact. Total hip arthroplasty (THA) is a safe, successful, and economical treatment for advanced hip osteoarthritis. It relieves pain and improves patient function and quality of life –5. TheseApproximately 1.2 million THAs are performed worldwide each year . The rapTotal joint replacement usually improves health-related quality of life; however, when the improvement is insignificant, the role of comorbidities is often emphasized , 16. TheIn some studies –27, highWe selected the target population from our hospital according to the following selection criteria. The inclusion criteria were as follows: (1) consecutive patients who had to undergo primary unilateral THA between 2017 and 2019 and were willing to cooperate in completing outpatient follow-up after the THA procedure, and (2) the first language was Chinese to better understand the questionnaire. All enrolled patients provided informed consent. All surgical procedures were performed by the chief physician at our hospital.Exclusion criteria: (1) patients with coagulation disorders or lower extremity venous thrombosis; (2) patients with local foci of infection or other diseases affecting postoperative hip function assessment; (3) patients with psychiatric disorders; (4) patients with bilateral THA.All patients underwent a posterolateral approach with DePuy or Stryker implants (cementless or cemented). Cemented implants were used when intraoperative cortical thinness was determined, and the stability of the cementless prosthesis was considered insufficient. Otherwise, all patients received the same treatment regimen that included intraoperative antibiotic prophylaxis, prevention of thromboembolism complications, abduction pads, and postoperative full weight bearing. Perioperative multimodal pain management comprised of preoperative preemptive analgesia, intraoperative local infiltration anesthesia, and postoperative opioid-sparing analgesia. Patients could stand as of the first day after surgery, as the general circumstances permitted. A physical therapist guided their resumption of walking while teaching them how to avoid positions that could contribute to dislocation.The enrolled patients were divided into five age groups: ≤40, 40–50, 50–60, 60–70, and ≥70 years. The 36-item Short Form health survey (SF-36) body pain (BP) and physical function (PF) scales and Western Ontario and McMaster Universities Osteoarthritis Index  assessed the primary outcome before surgery and 3, 6, 12, and 24 months after surgery.Comorbidity information was collected through patient self-reported history. The medical records were collected with the patients consent, and any relevant information was retrieved to guarantee the self-reported psychiatric history and diagnostic status accuracy; changes in comorbidities were collected at different follow-up time points. The SF-36 and WOMAC scales were completed at each follow-up visit. The preoperative diagnosis, preoperative comorbidities, waiting time before surgery, complications, 30-day readmission rate, and other factors were retrospectively studied by reviewing the hospital records.Comorbidities were evaluated using the Charlson comorbidity index (CCI), which was originally used to predict mortality. However, CCI is commonly used to evaluate comorbidity in orthopedic patients because of its good prognostic value in terms of revision surgery, mortality, and various medical complications , 34–36. The patients were divided into four groups based on their comorbidity burden scores: CCI-0, no comorbid conditions; CCI-1 and CCI-2, comorbid conditions equal to a score of 1 and 2, respectively; CCI ≥ 3, comorbid conditions equal to a score of 3 or higher .The WOMAC is a widely used self-administered pain and functional ability scale for patients . It asseThe SF-36 is a generic health status measure, scored between 0 and100, with 100 being the best score. The SF-36 is composed of eight subscales: BP, PF, role physical (RP), role emotional (RE), social functioning (SF), mental health (MH), vitality (VT), and general health (GH). The postoperative SF-36 BP and PF scores were collected. SF-36 and WOMAC were shown to be effective and reliable .The surgical complications were defined as dislocation, periprosthetic fracture, or surgical site infection (SSI) requiring surgical revision. Medical complications included those that were not life threatening, such as deep venous thrombosis, and those that were life threatening, such as myocardial infection, acute mesenteric ischemia, stroke, pulmonary embolism (PE), or any other ailment requiring a stay in the intensive care unit .p-values for these associations. The composition of preoperative diagnosis in different CCI groups was analyzed by chi-square test, and the influence of different preoperative diagnosis on postoperative function in different CCI groups was analyzed by one-way variance analysis.We examined SF-36 PF, SF-36 BP, WOMAC PF and WOMAC pain subscale scores as continuous outcome variables. Model diagnostics including Q-Q plots for residuals and Q-Q plots for random effects were tested. Based on the inherent skewness evident on these plots, we used gamma distribution for response with log link for these continuous variables. We used random intercept gamma generalized linear mixed model with log link to examine the association of increasing comorbidity score (Charlson and three indices from our novel comorbidity measure) with worsening QOL, as measured by the WOMAC and SF-36 PF and pain subscale scores, in the subsequent intervals (see above), that controlled for repeated observations. These reported effects were adjusted for age, baseline respective QOL score and the length of time from index THA. We present beta coefficients (ß) and We recruited 468 consecutive patients who underwent unilateral THA at our department between 2017 and 2019. All patients were followed up for 24 months, except two who died after one year. Information on the five age groups is shown in The preoperative CCI in the five age groups  was found to increase with age . Postoperative CCI increased in two age groups (60–70 and ≥70 years). In the 60–70 years group: 2.16 ± 0.79, 2.24 ± 0.25, 2.46 ± 0.85, 2.71 ± 1.02, and 2.76 ± 1.06, and the ≥70 age group: 3.85 ± 1.22, 4.16 ± 1.27, 4.65 ± 1.33, 5.19 ± 1.30, and 5.42 ± 1.52. There were no further CCI changes in the other three age groups during the two years of postoperative follow-up. Among them, the older the patients, the greater the postoperative CCI increase and the faster the physical state deteriorated . And prep > 0.01). The WOMAC score in the CCI = 2 group had even rebounded during the 2-year follow-up.The baseline average WOMAC levels before surgery in the four CCI groups  were 13.18 ± 1.94, 19.00 ± 2.44, 24.28 ± 3.16, and 32.71 ± 4.62, respectively, for BP, and 42.43 ± 2.10, 46.44 ± 1.49, 50.09 ± 2.93, and 66.32 ± 9.38, respectively, for PF. The respective average baseline SF-36 levels of PF and BP were 51.93 ± 3.70, 42.35 ± 5.78, 34.39 ± 4.14, and 25.25 ± 5.69, and 50.74 ± 4.00, 43.31 ± 6.45, 38.86 ± 5.16, and 31.57 ± 7.88, respectively. The changes in values of CCI, WOMAC and SF-36 scores at the 3, 6, 12, and 24-month follow-up evaluations are shown in p < 0.01; BP, β = 0.277; p < 0.001; the lower the score, the better), and SF-36 .As shown in We found that the preoperative waiting time in the four CCI groups  were 2.41 ± 0.74, 2.97 ± 0.65, 3.80 ± 0.53, and 5.01 ± 0.71 days, respectively. We found no complications during follow-up in the CCI = 0 and 1 groups, 1 joint dislocation and 1 periprosthetic fracture in the CCI = 2 group, respectively, and 3 joint dislocations, 2 postoperative infections, 1 periprosthetic fracture, and 1 venous thrombosis in the CCI ≥ 3 group. The total complications rate during the follow-up period was 1.92%, and it was 4.69% in the CCI ≥ 3 group. The overall 30-day readmission rate was 0.85%, and it was 2.01% in the CCI ≥ 3 group. The overall mortality rate within one year was 0.43%. It was 1.34% in the CCI ≥ 3 group, the only group in which mortality was recorded.Joint replacement was shown to reduce pain, enhance function, and improve the quality of life , 42. In Advanced age is associated with more comorbidities and disabilities before surgery. Previous studies have found that age is an important predictor of moderate-to-severe activity limitation after TKA . The preSeveral studies have shown that pain and satisfaction after THA are affected by preoperative comorbidities –47. HoweWe also found that WOMAC and SF-36 pain and function scores improved significantly from the preoperative to the postoperative assessment. Most of the patients showed the most significant improvement at 3, or 6 months after surgery, probably because the patients overcame the psychological impact of the surgery and were able to be more active in their own rehabilitation and participation in life work as the pain level decreased or disappeared. However, this improvement was not sustained during the 2-year follow-up after surgery. Patients with different preoperative CCI scores had different degrees and rates of functions and pain recovery after surgery. Comorbidities were related to a gradual deterioration of function and pain outcomes after THA.In a study in Australia, the baseline comorbidities of patients undergoing THA or TKA predicted the change in the SF-36 score 12 months after the surgery . A studyOur study found that the patients postoperative complications change over time, and the older the patient, the greater the CCI increase. This explains why older patients after THA do not continue to improve. This knowledge could also guide clinicians monitoring and early interventions aimed to improve the THA patients long-term quality of life by reducing the postoperative impact of comorbidities on pain and functional results.Comorbidities in cancer patients are associated with mortality, length of hospital stay, postoperative complications, progression-free survival rate, and disability , 52. ThiResearchers found that for every one-point increase in CCI, the risk of delayed THA surgery increased by 52% . The surThe exponential increase in surgeries has increased the probability of postoperative complications for overall patients, including surgical site infection, sepsis, joint dislocation, and revision arthroplasty. These complications increased the length of hospital stay and readmission rate . PreviouReducing the incidence of THA delays without reducing the quality of treatment might be an important strategy for optimizing surgical efficiency and reducing costs. Our study identified the risk factors that affect delayed THA surgery, striving to better understand and manage these risk factors in THA patients.Hospital readmission is used as an indicator of the quality of care . The wasThe risk of all-cause mortality after THA and TKA decreased from 1% in 1997 to 0.6% in 2011 . This coAlthough the mortality rate after joint replacement is very low, studies have found that it increases by comorbidities , 66. KreWe acknowledge that our study has several limitations: First, only patients with primary unilateral THA were included; patients with revision and bilateral THA were excluded. Second, the number of patients was small. Third, the duration of follow-up was short. We will continue to follow these patients to obtain long-term results and further evaluate the impact of complications. Fourth, the use of CCI as a measure of comorbidity might have limitations. It was developed to quantify the impact of comorbidities on mortality, and it was validated in breast cancer patients but not in THA patients. Although this indicator has been widely used in orthopedic research, its suitability might still affect its effectiveness. Fifth, another limitation of using CCI is that the only mental illness it considers is dementia . Sixth, We found that comorbidities were associated with worse physical function and pain outcomes after THA. A higher CCI score in THA patients was associated with longer preoperative waiting time and postoperative function and pain recovery time, a lower degree of recovery, and higher rates of complications, 30-day readmission, and mortality. These impacts were greater in the older age group. Understanding this information allows us to place greater emphasis on the management of perioperative comorbidities, guide postoperative recovery, and provide more realistic expectations for our patients.


The optimal CPOT cut-off score was >2, with a sensitivity of 71% and a specificity of 80%, and self-reported pain was the gold standard criterion. Significant correlations (<0.40) were found between CPOT scores, the heart rate and the respiratory rate during the nociceptive procedure. Conclusions. The CPOT appears to be a valid alternative for both ventilated and non-ventilated patients who are unable to communicate.Aim. The study aim was to validate the Portuguese version of the Critical-Care Pain Observation Tool (CPOT) in the critically ill adult population of Portugal. Methods. A prospective, observational cohort study was conducted to evaluate the CPOT in mechanically ventilated patients who were admitted to an intensive care unit. A consecutive sample of 110 patients was observed at rest pre-procedure, during a nociceptive procedure (NP) which includes turning/positioning and endotracheal or tracheal suctioning and 20 min post-procedure. Two raters participated in the data collection. The discriminative validity, criterion validity, convergent validity and inter-rater reliability of the CPOT were examined. Results. The inter-rater reliability was excellent (0.93 ≤ α ≤ 1.00) at rest and fair to moderate (0.39 ≤ α ≤ 0.60) during the NP. The CPOT could discriminate between conditions with higher scores during the NP when compared to CPOT scores at rest ( Pain is a multidimensional and personal experience, and its assessment is key to optimal pain management . It can The patient’s self-report should be obtained whenever possible, as it is the gold standard measure of pain. However, critically ill patients may be incapable of self-report due to mechanical ventilation and sedation ,8. ThereConsidering their continuous presence at the bedside and their close proximity to the patient and his/her family, nurses play a key role in the assessment and management of pain . Nurses Studies have shown that the Behavioural Pain Scale (BPS)  and the However, in some studies, BPS scores increased during both painful and a nonpainful procedures, whereas CPOT scores only increased during a painful procedure ,12. TherSo far, the BPS has been the only validated pain scale in the Portuguese population and was selected by the Portuguese Society of Intensive Care . NeverthThis study aimed to translate the CPOT into Portuguese and validate the translated version. Our specific objectives were to determine the CPOT discriminative validity, criterion validity and convergent validity as well as the inter-examiner reliability of the Portuguese version.A prospective observational cohort study was conducted, reported according to the STROBE statement for observational studies .We used a consecutive sample of 110 medical and surgical patients who were admitted to a 11-bed intensive care unit (ICU), at a University Hospital located in Lisbon . For this study, we defined the inclusion criteria described below: (a) were admitted to the ICU; (b) had a minimum length of stay in the ICU of 24 h; (c) were 18 years old or older; (d) were mechanically ventilated; and (e) were able to understand Portuguese before intubation. Patients with neurological deficits  were excluded. In the initial stage of the study, following a written authorisation by the author of the CPOT (CG) and after obtaining permission to use the English version of the CPOT, the tool was translated into Portuguese. International guidelines relevant to the cross-cultural adaptation process were followed to ensure linguistic equivalence, conceptual equivalence and psychometric equivalence ,19.The process included the following steps: preparation, forward-translation, reconciliation, back-translation, back-translation review, expert panel and pilot testing.The translation from English to Portuguese was carried out by two professional translators. After the translations were analysed and the consensus version was obtained, two professional English translators performed the back-translation. Following the results for the back-translation, all versions were harmonised to detect and address any discrepancies that might arise between different language versions, ensuring conceptual equivalence. Content and face validity were submitted to a Delphi panel consisting of eight nurses (with a master’s degree and experience working in the ICU) and two PhD experts in scale validation. Each of the Delphi panel members gave their opinion on the adequacy of the translation and the relevance of the item. The level of agreement for each item was 100%. The Portuguese translation was pilot tested by three ICU nurses on 15 patients to check the interpretation and ease of comprehension. No changes were necessary. Following the completion of the transcultural adaptation process, we appraised the CPOT’s psychometric characteristics. The patients were assessed with the CPOT and the BPS  at rest pre-procedure, during a nociceptive procedure (NP) and 20 min after the procedure (t2), for a total of three assessments of each patient. The NP included one of the following standard care procedures commonly used in previous validation studies: turning/positioning and endotracheal or tracheal suctioning ,22,23,24The raters (ICU nurses) received a 90-min standardised training session  from the primary investigator, during which they were taught how to use the CPOT and practiced its administration, inspired by the one developed by the authors of the CPOT ,24. FollThe CPOT and the BPS were used for all participants. In several studies, authors reported a correlation coefficient between the scores of two scales  and described this strategy as convergent or criterion validation . Whenever the BPS score exceeded 5, pain was considered to be present. The inter-rater reliability of nurses’ CPOT scores was described at each time point. Comparison of CPOT scores at rest pre- and post-procedure with the NP allowed the examination of discriminative validity. Criterion validity was established using the BPS threshold for the absence (BPS ≤ 5) versus the presence (BPS > 5) of pain to examine their association with CPOT scores. The association between the two scales (BPS and CPOT) was commonly performed as a validation strategy in previous studies . FinallyCritical-Care Pain Observation Tool: The CPOT was initially developed in French Canadian by Gélinas and colleagues in 2006 based on a thorough content validation process and was translated into English using a forward–backward method . The CPOThe raters completed a 90-min standardised training session, inspired by the one developed by the author of the CPOT, during which they were taught how to use the CPOT and practiced scoring using the tool in the presence of the primary investigator ,24. FollBehavioural Pain Scale: The BPS was initially developed in French from France by Payen and colleagues in 2001 and includes four behavioural indicators: facial expression, upper limb movements and compliance with mechanical ventilation. Each item is scored from 1 to 4, and the possible total score ranges from 3 to 12 . Its iniSocio-demographic and clinical information: Sociodemographic (sex and age) and clinical data , presence of continuous and/or intermittent sedation and analgesia), as well as vital signs  available through continuous monitoring in the ICU, were also collected.The GCS is used to assess the patient’s level of consciousness, which includes three sections: eye opening (scored from 1 to 4), verbal response (scored from 1 to 5) and motor response (scored from 1 to 6). The probable score ranges from 3  to 15 . Patients were classified as unconscious with GCS ≤ 8 and conscious with GCS > 9.Data were analysed using SPSS version 21 for Windows . Descriptive data analysis was performed using frequencies, percentages, mean  ±  standard deviation (SD) and ranges. Data normality was analysed through the Shapiro–Wilk test. Several non-parametric tests were used to assess validity, and the alpha was set at 0.05. The Wilcoxon Signed-Rank test (Z) was performed to evaluate the differences in CPOT scores at all time points . The Mann–Whitney test was performed to compare CPOT scores using the BPS threshold for the absence versus the presence of pain as the reference standard, and receiver operating characteristic (ROC) curve analyses were also performed . ROC analyses is a common strategy to establish the performance of a tool to detect a condition  as well as the sensitivity and specificity associated with the best threshold . SpearmaThe study was conducted in accordance with the Declaration of Helsinki , and theSample Description: The sample included 110 participants. A total of 38.2% of them were women, and their ages ranged from 20 to 95 (67.24 ± 14.61) years. Almost half of the participants were admitted to the ICU for a surgical diagnosis , 53 did not receive analgesia (48%) and 93 did not receive any sedation (85%). Patients were classified as ‘unconscious’  or ‘conscious’ . p < 0.001) . Within-group analysis revealed higher CPOT scores during NP compared with those obtained at rest (< 0.001) .The ROC of Rater 1 CPOT scores during the nociceptive procedure for the total sample is presented in p < 0.001) with a sensitivity of 71% and a specificity of 80%. A similar performance of the CPOT was found based on ROC analysis of Rater 2’s scores. In this sample, the optimal CPOT threshold was ≥3.The ROC of Rater 1′s scores during NP showed good performance of the CPOT to classify patients with pain based on BPS > 5 , heart rate (HR) and respiratory rate (RR), at each time point. At rest pre-procedure: MAP = 84.50 (16.47), RR = 21.50 (6.14) and HR = 85.10 (19.45); during a nociceptive procedure: MAP = 94.14 (16.40), RR = 23.97 (6.48) and HR = 91.10 (20.53); 20 min after the procedure: MAP = 83.28 (17.34), RR = 20.68 (6.02) and HR = 85.97 (19.16).Positive mild associations were found between CPOT scores, HR (both raters) and RR (Rater 2) . Very loRegarding criterion validity, CPOT scores during NP were significantly associated with the presence of pain (BPS > 5) for Rater 1 and Rater 2 . In factInter-rater reliability: Weighted kappa coefficients between ICU nurses’ CPOT scores ranged from 0.39 to 1.00, indicating moderate to excellent inter-rater reliability.This study aimed to translate and validate the Portuguese version of the CPOT in 110 medical and surgical mechanically ventilated ICU patients, either conscious or unconscious. The level of consciousness and sedation may influence pain behaviours, which are less frequent or blurred in patients who are unconscious or heavily sedated . In this validation process, we examined the discriminative validity, criterion validity, convergent validity and inter-rater reliability of the CPOT. Through these validation strategies, we were able to determine the tool’s psychometric characteristics in this Portuguese sample.Similar to previous studies ,21,28,29Inter-rater reliability was satisfactory. Most kappa coefficients were moderate to excellent . These rIn this study, we found that the correlation between vital signs and the score obtained with the CPOT assessment were low, because when individually assessed vital signs were not relevant, they could have been influenced by other factors such as anxiety, sedation or breathing difficulties.The Danish study  confirmsOur study, as well as the Swedish  and the As in previous studies on this study, 53 patients did not receive analgesia and 93 patients did not receive sedation, which allowed for the observation of higher CPOT scores during painful procedures in comparison to non-painful procedures. However, it was not possible to verify a correlation between pain and PFM increase, which justifies the aforementioned statements.In our study, we used another BPS behavioural assessment scale as a comparison in our pain assessment, which showed a good correlation between the two. In the Danish study , the CAMDespite this, we can say that the results obtained in the different studies were convergent, with regard to the increase in the CPOT score during painful procedures.Some limitations must be mentioned. Due to difficulties in reconciling the presence of three raters in all instants of assessment, we chose to use only two. This strategy had already been employed in other validation studies ,30. HoweThe Portuguese version of the CPOT was shown to be valid in this sample of Portuguese mechanically ventilated ICU patients, who were conscious or unconscious. Portuguese ICU nurses should not rely on vital signs for pain assessment and are encouraged to use a valid behavioural scale such as the CPOT when they suspect that their patient may be in pain.The Portuguese version of the CPOT seems to be a valid and reliable tool for pain assessment in mechanically ventilated ICU patients, whether they are conscious or unconscious. Thus, the CPOT is an alternative option to the BPS which, until now, has been the sole validated scale for pain assessment in Portuguese ICU patients. The CPOT can be applied to ICU patients who are incapable of communicating verbally or using signs, whether they are mechanically ventilated or not.The inter-rater reliability of the CPOT was excellent at rest and fair to moderate during the nociceptive procedure. The CPOT could discriminate between conditions with higher scores during the nociceptive procedure when compared to CPOT scores at rest. The optimal CPOT cut-off score was >2 with a sensitivity of 71% and a specificity of 80% using self-reported pain as the gold standard criterion. Significant but low correlations were found between CPOT scores, the heart rate and the respiratory rate during the nociceptive procedure.Nurses have a fundamental role to play in monitoring and managing pain. For this purpose, they must use appropriate pain assessment tools adapted to the patient’s ability to communicate their pain, such as self-report or behavioural scales. In Portugal and in addition to the BPS, the CPOT appears to be another valid alternative scale to use because it is applicable to patients unable to self-report, whether they are mechanically ventilated or not.