Access to multidisciplinary pain treatment facilities (MPTF) is limited by extensive waiting time in many countries. However, there is a lack of knowledge about the impact of waiting time on clinical outcomes, particularly for patients with rheumatic conditions. This study examined the association between waiting time for MPTF and clinical outcomes in patients with rheumatic conditions.Data were extracted from the Quebec Pain Registry, a large database of patients who received services in MPTF. The associations between waiting time  and change in pain interference, pain intensity and health-related quality of life, from the initial visit at the MPTF to the 6-month follow-up, were tested using generalized estimating equations.p ≤ 0.001). Only patients waiting less than 2 months reached a clinically important improvement in pain interference (1.12/10), pain intensity (1.3/10) and physical and mental quality of life (3.9 and 3.7/100).A total of 3230 patients with rheumatic conditions  were included in the analysis. Small significant differences in improvement between waiting time groups were revealed, with patients waiting less than 2 months having a larger improvement in all clinical outcomes compared to patients who waited 2–6 months or over 6 months before their initial visit (adjusted time X group effect Longer delays experienced by patients before receiving services in MPTF were associated with statistically significant smaller improvements in pain interference, pain intensity and health-related quality of life; these differences were, however, not clinically significant. Based on these results, we advise that strategies are developed not only to reduce waiting times and mitigate their impacts on patients with rheumatic conditions, but also to improve treatment effectiveness in MPTF. Rheumatic conditions, which include autoimmune , inflammatory , degenerative conditions  and widespread body pain  , affect For many patients with rheumatic conditions, the biopsychosocial and chronic nature of their pain condition may require a multidisciplinary pain management approach combining pharmacological  and non-pharmacological interventions  . EvidencMultidisciplinary pain management programs can be delivered in multidisciplinary pain treatment facilities (MPTF), where integrated and patient-centered care is provided by different health professionals in order to improve patients’ pain, disability, quality of life and empowerment . HoweverData used in this retrospective study were extracted from the Quebec Pain Registry, a large database of patients with chronic non-cancer pain who received services within five MPTF in the province of Québec, Canada. Consecutive patients aged 18 years and over who consented to participate were enrolled in the registry. Patients unable to understand written and spoken French or English or patients unable to participate due to severe physical or cognitive impairments were excluded. The registry includes data collected between 2008 and 2014 using self-administered questionnaires, structured interviews with a research nurse who had received a training specific to the registry, and a physician assessment. The self-administered questionnaires and the nurse interview were completed just prior to the initial visit at the MPTF and a follow-up was conducted 6 months after the initial visit. Patients enrolled in the registry usually received a combination of medical , psychological , physical  or self-management interventions that were personalized to their needs , 16. DetPatients from the Quebec Pain Registry were included in this study if they 1) had received a diagnosis of a rheumatic condition by the referring or the MPTF’s physician , 2) self-reported having a rheumatic condition as a comorbidity or 3) reported a rheumatic condition was the cause of their pain . This combination of physician-diagnosed and self-reported rheumatic conditions allowed to select a relatively exhaustive, although less specific, sample of patients with rheumatic conditions. In this study, ‘rheumatic conditions’ were defined using the National Arthritis Data Workgroup (NADW) case definition recommended for health services research  that proWaiting time (independent variable) was defined as the period between receipt of the referral and the first patient’s visit at the MPTF, which were all recorded by a research nurse in the baseline questionnaire. Considering the usual non-normal distribution of waiting time data (positively skewed with multiple outliers), the sample of patients with rheumatic conditions was divided into the following waiting time categories: less than 2 months, 2 to 6 months and more than 6 months. The 2 months cutoff was based on the International Association for the Study of Pain’s benchmark for chronic pain treatment , while tThe outcomes (dependent variables) were changes in pain interference, pain intensity and health-related quality of life between the initial MPTF visit and the 6-month follow-up. Measures used in this study follow the recommendations of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials . The tenThe average pain intensity in the past week was obtained from the numeric pain rating scale (NPRS), a reliable and valid assessment tool for populations with rheumatic conditions . The NPRHealth-related quality of life was measured by the self-administered 12-item Short-Form Health Survey version 2 (SF-12v2), a short version of the SF-36 covering eight subscales . SF-12v2 scores range from 0 to 100, where higher scores represent a better quality of life. A mental component scale (MCS) and a physical component scale (PCS) are derived from the subscales by applying a normative scoring algorithm, where a score of 50 represents the norm of the general population, thus facilitating the interpretation of the results and the comparison across studies . The SF-Participant characteristics, waiting times and clinical outcomes were summarized using descriptive statistics . Data were examined to identify missing values, outliers and coding errors. Patients’ baseline sociodemographic and clinical characteristics were compared between the three groups of waiting time  using ANOVA for continuous variables and Chi-square tests for categorical variables. Similar analyses were conducted to compare patients with and without follow-up data at 6 months.Associations between waiting time and change in clinical outcomes between the initial visit and the 6-month follow-up were tested using generalized estimating equations (GEE) . GEE is Patients’ sociodemographic and clinical characteristics known to be associated with the independent (waiting time) and dependent  variables based on the literature and previous research by our team  were ideJoint pain, effusion and other unspecified joint disorders only and Other rheumatic conditions or combinations of conditions) were not retained for these secondary analyses because they included a variety of heterogenous diagnostic codes.Given that treatment options, potential for improvement, and waiting times may differ between rheumatic conditions, we conducted analyses to assess whether associations between waiting time and clinical outcomes differed for different rheumatic conditions. Separate GEE models were computed for patients who had one of two main diagnostic categories: osteoarthritis and fibromyalgia. Thus, analyses were successively computed for patients who only had osteoarthritis and then for patients who only had fibromyalgia in order to remove the effect of having other concomitant rheumatic conditions, as many patients had more than one. Analysis of patients with rheumatoid arthritis was not possible due to the small number of participants with this specific condition. Other categories (Institut de réadaptation en déficience physique de Québec (IRDPQ) Ethics Committee (#EMP-2015-449).All statistical analyses were computed with IBM SPSS Statistics v.25.0 . The study was approved by the Of the 8402 patients included in the Quebec Pain Registry, 3665 were identified as having a rheumatic condition. Of those 3665 patients, 3230 had valid waiting time data and were included in the analysis see Fig. . Twenty-Mean age of the patients was 55.8 ± 14.0 years (mean ± standard deviation) and the majority were women (66.2%) and Caucasian (92.6%). Thirty-six percent were on permanent or temporary disability and 45.6% had an annual household income of less than $35,000 CDN. Patients’ mean duration of pain was 6.8 ± 8.9 years . Self-reported depression (45.7%) and anxiety (41.7%) were highly prevalent. Twenty-one percent had osteoarthritis as their only rheumatic condition, 21.0% had only fibromyalgia and 1.3% had only rheumatoid arthritis  responded to the 6-month follow-up patient questionnaire. The 1282 patients with missing follow-up data were slightly younger (54.6 vs. 56.5) and did not significantly differ from the rest of the sample at baseline in terms of sex, pain duration, BPI, SF-12v2 PCS and pain intensity scores.p < 0.001). Only the < 2 months group reached a mean improvement above the MCID (1/10). Results from the GEE analyses (Table p < 0.001). In post-hoc analyses, the < 2 months group experienced a larger decrease in pain interference based on adjusted change in estimated marginal means (EMM) from baseline to 6 months than patients in the 2–6 months or the > 6 months groups (Table p < 0.001).An overall change of − 0.75 ± 2.05 (out of 10) in patients’ BPI scores was observed from baseline to 6 months (time effect p < 0.001) and there was a significant time X group effect (adjusted p < 0.001) (Table p < 0.001).There was an overall change of − 0.8 ± 2.1 (out of 10) in pain intensity from baseline to 6 months (time effect 1) Table . Only th1) Table . Again, p < 0.001), but the mean improvement was clinically significant (MCID = 3.3 pts) only in the < 2 months group. GEE analyses showed a significant time X group effect (adjusted p ≤ 0.001) for both scales (Tables p = 0.010). For the MCS, no significant differences were observed, as 45.4% of patients in the < 2 months group reached the MCID, compared to 39.4% in the 2–6 months group and 40.2% in the > 6 months group (p = 0.078). Sensitivity analyses  yielded similar results for all four outcomes (data not shown).An overall improvement over time was observed for the SF-12v2 PCS (2.3 ± 7.8) and MCS 2.2 ± 9.5) (time effects s Tables  and 5. P (time efs Tables  and 5. Tp < 0.05) between waiting time groups, with the < 2 months group having a larger improvement in pain interference compared to groups with longer waiting time. Again, the differences in improvement between groups were smaller than the MCID and there was no significant difference in change in BPI between patients who waited 2–6 months and those who waited > 6 months. There were no significant time X group effects in changes in pain intensity and SF-12v2 mental component scale for the targeted rheumatic condition. Analyses for the SF-12v2 physical component scale yielded opposite results, with significant unadjusted time X group effect and non-significant adjusted time X group effect.The association between waiting time and the outcome measures in patients with only osteoarthritis and patients with only fibromyalgia are presented in Tables p < 0.05). The < 2 months group experienced a greater improvement in these outcomes from baseline to 6 months compared to the groups with longer waiting time, while no difference was found between the last two groups. For pain intensity, unadjusted and adjusted models showed non-significant and significant effects, respectively.Analyses with fibromyalgia patients found statistically significant between-group differences below the MCID in mean changes (EMM) in BPI, SF-12v2 physical component scale and SF-12v2 mental component scale . Upstream interventions could be developed and implemented. For example, education and self-management resources could be offered by primary care providers to improve management of the disease in its early stage. The use of online support groups, pain management videos, blogs  or eConsOur secondary objective was to determine if the association between waiting time and clinical outcomes was different for specific rheumatic conditions. Approximately 21% of the sample had osteoarthritis as their only rheumatic condition, and the same proportion had fibromyalgia only. In patients with osteoarthritis, the results showed a statistically significant but not clinically important group difference in terms of improvement in pain interference, with patients waiting less than 2 months having a greater improvement compared to patients with longer waiting time. There were no between-group differences in terms of pain intensity and health-related quality of life for patients with osteoarthritis. Analyses conducted with patients having fibromyalgia revealed statistically significant but not clinically important group differences in changes in pain interference and health-related quality of life from baseline to 6 months, again favoring patients who waited less than 2 months. There were no differences between waiting time groups regarding pain intensity. These findings may have implications for patients with fibromyalgia, who often face longer waiting times before receiving services in MPTF compared to patients with other rheumatic conditions .A first limitation of this study was the high proportion of patients lost to follow-up. Despite the fact that patients with missing follow-up data did not differ from the rest of the sample in most sociodemographic and clinical characteristics, there was a risk of selection bias. Consequently, the choice of using GEE analyses provided a suitable approach with respect to missing follow-up data . In addiduring the waiting time . However, considering patients’ high pain intensity and interference and their low quality of life at baseline, it is less likely that a significant decrease of symptoms occurred before the initial visit. Also, mean baseline outcome measures were similar between waiting time groups, which may be an indication that symptom intensity was stable regardless of the time since referral.Another possible limitation was the categorization of the waiting time variable in three groups instead of using a continuous variable. This may have affected the strength of the associations found with the clinical outcomes. However, GEE analyses conducted with a different categorization (five categories of waiting time) and regression analyses with a continuous waiting time variable yielded similar results and did not change the conclusions. In addition, our study did not take into account the waiting time prior to the MPTF referral . Patients may face multiple delays along their care trajectories that may affect the progression of their condition. Also, patients with rheumatic conditions may experience fluctuations in their symptoms during the wait. Such fluctuations could have influenced the results, since they were likely to be referred to the pain clinic at a point when they reported worst symptoms. The data available did not allow us from drawing conclusions regarding the evolution of symptoms Lastly, prioritization processes used in MPTF, which were not documented in the Quebec Pain Registry, may have influenced the results. For example, some MPTF may have considered the potential for improvement as a prioritization criterion. Hence, patients identified with a limited potential for improvement may have received a lower priority level, leading to a longer waiting time. We believe this limitation was nonetheless attenuated by controlling for pain duration, age and comorbidities, three characteristics that likely influence the potential for improvement.In conclusion, patients face long delays before receiving services in MPTF. Longer delays were significantly associated with less improvement in pain interference, pain intensity and health-related quality of life. However, differences were below the minimal clinically important difference. In addition, there was a significantly higher proportion of patients achieving clinically significant improvements in the group of patients waiting less than 2 months compared to patients waiting longer. The effect of waiting time on patients’ condition deserves the attention of clinicians, MPTF administrators and policy-makers. Our study suggests possible variations between types of rheumatic conditions, with more consistent effects seen in patients with fibromyalgia than in patients with osteoarthritis. Future studies are needed to investigate the impact of waiting time on patients’ condition prior to the admission to the pain clinic, that is from the point of referral to the initial visit. Finally, the findings suggest the need to investigate and implement strategies to reduce waiting times and improve outcomes, for example self-management interventions, prioritization of referrals and increased resource allocation.Additional file 1. Method to identify confounding variables.


Pectoral type I and II (Pecs I and II) blocks are regional anesthesia methods that have shown to decrease postoperative analgesia after breast surgery. Typically, these blocks consist only of a local anesthetic. We performed preoperative Pecs I and II blocks in a female patient undergoing surgical excision and biopsy of a breast mass. The anesthetic consisted of ropivacaine, dexmedetomidine, and dexamethasone (Dex-Dex). The patient experienced an extended postoperative pain relief period. She did not require any opiates postoperatively. Adding dexmedetomidine and dexamethasone to a local anesthetic for peripheral nerve blocks seems to have a synergistic effect and can extend the duration of pain relief. This combination has the potential to decrease postoperative opiate requirements for analgesia. Further studies need to be conducted to further determine the safety and efficacy of the Dex-Dex block. Pectoral type I and II (Pecs I and II) blocks are safe and effective methods of providing postoperative analgesia for patients undergoing mastectomy . These bWe performed a preoperative ultrasound-guided Pecs I and II blocks for surgical excision and biopsy of a cystic mass of the left breast located on the medial aspect of the breast 2 cm from the sternal border. Our patient was a 68-year-old African American female with a past history remarkable for dyslipidemia, mitral valve prolapse, partial hysterectomy, and appendectomy. She was requiring oxycodone-acetaminophen as needed for pain. Patient consent to publish this case was obtained. After induction of anesthesia, we performed Pecs I and II blocks for postoperative pain control. The patient was supine on an operating table, with her left arm placed at her side. A low-frequency ultrasound transducer was placed over the lateral aspect of the anterior chest wall and sterile coupling gel was applied. The thoracoacromial artery, pectoralis major, pectoralis minor, serratus anterior, and intercostal muscles were identified Figure . An echoHer sensory nerve block lasted for seven days, and the patient reported no postoperative pain 14 days later. Postoperatively, she required no opioid medications and her pain was adequately managed with acetaminophen 1,000 mg by mouth three times daily. In this patient, the Dex-Dex combination demonstrated extended postoperative pain relief. The patient experienced no adverse effects. Although both dexamethasone and dexmedetomidine have been extensively studied separately, there is little data on the use of these two agents together.Hassan et al. compared the effects of the Dex-Dex combination to using each agent by itself in combination with bupivacaine in caudal blocks for pediatric hypospadias repair. Primary outcomes of the study were pain scores and time to analgesia request. Patients who received the Dex-Dex combination had significantly decreased pain scores up to six hours after surgery compared to those who received only dexamethasone or only dexmedetomidine. Time to first use of analgesia was four hours longer than the dexmedetomidine group and six hours longer than the dexamethasone group, respectively . AnotherDexamethasone is commonly used in clinical practice as an adjuvant for regional anesthesia. There has been conflicting evidence as to whether or not it prolongs postoperative analgesia. The mechanism of action is not fully understood, but the belief is that dexamethasone has an anti-inflammatory effect when administered perineurally . In animThis case exhibits a possible additive and/or synergistic mechanism of dexamethasone and dexmedetomidine when used together in a peripheral nerve block. More studies need to be conducted to evaluate the safety and efficacy of this combination. The Pecs I and II blocks have been shown to decrease postoperative pain and opiate consumption. Adding Dex-Dex could potentially extend the postoperative analgesia period of the Pecs I and II blocks. This treatment modality could be an advancement in regional anesthesia and provide patients with superior pain control and reduced postoperative opiate use.


Pain catastrophizing may contribute to the altered trunk muscle activity in patients with nonspecific chronic low back pain (NSCLBP). It is unclear if pain catastrophizing influences static postural control in patients with NSCLBP. This study aimed to investigate the relationship between pain catastrophizing and static postural control in NSCLBP patients.  Sixty-eight participants with NSCLBP and 40 healthy participants were recruited. Postural control was assessed by the sway area and the sway length of the center of pressure (COP) during balance tests. Pain catastrophizing in participants with NSCLBP was assessed by the Pain Catastrophizing Scale (PCS). Bilateral transversus abdominis (TrA) activation was evaluated by ultrasound imaging-measured percent change in muscle thickness. Associations between COP parameter and PCS/subscales of PCS were examined by multiple linear regression (MLR). p < 0.001) and a lower level of voluntary activation of the bilateral TrA (p < 0.001), compared with the healthy control group. The MLR analyses revealed that the COP area sway under eyes-closed condition was significantly associated with the PCS score/helplessness score of PCS, voluntary activation of the left TrA, and age in participants with NSCLBP .  Our results observed a larger COP sway area in NSCLBP group under eyes-closed condition ( Static postural control was associated with pain catastrophizing, voluntary activation of TrA, and age in participants with NSCLBP. This indicated that pain catastrophizing may affect postural control and should be considered when interpreting balance test results and managing NSCLBP. Chronic low back pain (LBP) is considered as the leading cause of disability. It has a high lifetime prevalence worldwide, affects people of all ages, and causes tremendous economic and societal burden , 2. Up tPostural control is responsible for spine stability, posture, and movement. It is fundamental for bearing loads and avoiding injury and pain . Body swIn the catastrophizing-based fear-avoidance model, because of the overestimation of the threat value or seriousness of painful stimuli, people with greater pain catastrophizing are more likely to tighten the spine to avoid excessive spinal movement and reduce the risk of injuries , 14, 15.This aims of this study were to (a) estimate whether static postural control was impaired in patients with NSCLBP by comparing the COP parameters between NSCLBP patients and healthy controls and (b) investigate the relationships between pain catastrophizing and static postural control in people with NSCLBP.The inclusion criteria for the NSCLBP group were as follows: 1) has been clinically diagnosed with NSCLBP with intermittent or persistent pain from T12 to the buttocks that has lasted for at least 3 months  has been, (2) is Two licensed medical doctors confirmed the diagnosis of NSCLBP in accordance with the diagnostic guidelines published by the American College of Physicians and the American Pain Society . The paiThe Chinese version of the Hamilton Depression Scale, which has good reliability with Cronbach's alpha value of 0.714 , was adoAverage pain intensity in the past week was measured using the VAS . The Chinese version of the Short-Form McGill Pain Questionnaire (SFMPQ) was used to measure each patient's pain experience. The main component of the SFMPQ consists of 15 items and is divided into 2 main categories: sensory scores (11 items) and affective scores (4 items) . Each itLBP-related disability was assessed using the 100-point Chinese version of the ODI, which consists of 10 items that are each answered with a numeric value between 0 and 5 , 34. TheThe level of pain catastrophizing was measured by the Chinese version of the PCS. The PCS consists of 13 items, and each item was answered with a numeric value between 0 and 4; 0 corresponded to “not at all,” and 4 corresponded to “all the time” . An aggrhttp://imagej.nih.gov/ij/) by a single examiner who was blinded to the allocation results of the participants.Ultrasound images of bilateral TrA muscles were obtained with Sonosite M-Turbo with a linear transducer probe . To standardize the technique and to facilitate access to the abdomen, a supine crook-lying position  was adopted by all of the participants . The intThe perpendicular distance between the thickest parts of the superior and inferior hyperechoic muscle fasciae was measured and defined as the thickness of TrA at rest (RTrA) and during contraction (CTrA) . All theThe COP sway area and path length were recorded by PROKIN Systems . A recent systematic review  indicateTwenty participants from the healthy control group underwent the reliability measures for the aforementioned balance tests over 2 sessions with a 2-week interval between sessions. As all of the balance tests in this study were conducted by the same investigator; therefore, only the intrarater reliability was measured.t-tests were conducted for continuous variables that were normally distributed, Mann–Whitney U tests were conducted for continuous variables that were not normally distributed even after log transformation, and chi-square tests were performed for categorical variables. The balance tests were analysed by repeated-measures ANOVA with 2 conditions (eyes-open and eyes-closed conditions). Independent-samples t-tests were conducted for those tests in which significant group interaction effects were noted. Multiple linear regression (MLR) analysis was performed to assess the multivariate relationships between static postural control parameters, clinical measures, and TrA activation in participants with NSCLBP. Only the COP variables that had significant between-group differences were established as criterion variables. MLR analysis does not allow the inclusion of variables that are associated with each other. However, each subscale of the PCS was associated with each other and the total scores of PCS. The sensory and affective scores of SFMPQ were also associated with the total scores of SFMPQ. Therefore, in the first model, we included the total scores of PCS and SFMPQ as covariates of interest in the MLR analysis. In the second model, each subscale of PCS was entered separately, while the sensory and affective scores of SFMPQ were also included as covariates of interest in the MLR analysis. The demographic variables  were also included as candidate predictor variables within the MLR analyses [Statistical analysis was performed with SPSS, version 26.0 . The continuous variables are presented as the means ± standard deviations (SDs), and the categorical data are presented as absolute numbers. The continuous variables in healthy control group and NSCLBP group were assessed for normality by the Shapiro–Wilk test and Kolmogorov–Smirnov test, respectively. The homogeneity of the dataset was assessed by the Levene test. Log transformation was conducted to normalize the distributions of variables in the balance tests. For between-group analyses, independent-samples analyses . The mosanalyses . The staDuring the recruitment process, 160 patients were screened for eligibility. A total of 92 patients were excluded due to the following reasons: 11 patients were not diagnosed with NSCLBP; 33 patients did not meet the criteria for duration of symptoms or severity of pain; 5 patients were excluded for history of surgery; 6 patients were excluded for cardio-cerebrovascular disease; 2 patients were excluded for history of cancer; 2 patients were excluded for cognitive deficits and difficulties in communication; 1 patient was excluded for BMI above 30; 22 patients were unable to participate because of location and time conflicts; and 10 patients declined to participate. The study included 68 participants with NSCLBP and 40 age- and sex-matched healthy controls.The two groups did not differ significantly regarding age, gender, body mass index, weight, height, and education length .For COP sway length, the ICCs , 1 were F = 9.022, p=0.003). The COP sway area was larger in the NSCLBP group than in the healthy control group under the eyes-closed condition (p < 0.001) but not under the eyes-open condition (p=0.270)  .F = 4.340, p=0.040), but no significant differences between groups were observed in any of the tests of COP sway length (p > 0.05)  .p < 0.001)  .β = 0.222, 0.341, and 0.328; p=0.045, 0.002, and 0.004, resp.) significantly contributed to changes in COP sway area in participants with NSCLBP (p < 0.001) significantly contributed to changes in COP sway area in participants with NSCLBP (p < 0.001) . In the h NSCLBP . This mo< 0.001) . The staTo our knowledge, this study is among the first to evaluate the relationships between negative cognitive-emotional responses to pain, TrA activation, and static postural control in patients with NSCLBP. The findings of this study showed that (a) the COP sway area under the eyes-closed condition was larger in participants with NSCLBP than in healthy controls and (b) the COP area sway under the eyes-closed condition was positively correlated with PCS scores, specifically the helplessness subscale of PCS, and the activation of the left TrA in patients with NSCLBP.This study showed a larger COP sway area in the double-leg stance test under the eyes-closed condition in the NSCLBP group than in the control group. These findings are consistent with those in previous systematic reviews that reported static postural control impairment in individuals with NSCLBP under visual obstruction condition , 40. OneContrary to a previous study  that fouCompared with subacute LBP patients, chronic LBP patients demonstrated higher pain intensity . The incDeep core muscles, such as the transversus abdominis (TrA), are part of the active zone and play an essential role in postural stability . UltrasoOur study suggested that, compared with the healthy individuals, the participants with NSCLBP in this study showed reduced TrA voluntary activation during the ADIM, which is consistent with the results in a previously published study . HoweverThe results of this study showed that pain catastrophizing may affect static balance in patients with NSCLBP, implying that pain catastrophizing may influence postural control in patients with NSCLBP. It may be appropriate to combine motor control exercises with interventions that target pain catastrophizing and other psychological factors to optimize treatment outcomes for patients with NSCLBP.The findings of the present study should be interpreted with caution due to some limitations. First, this study investigated TrA activation during the ADIM but not during a static balance task. Thus, the results of the relationships between pain catastrophizing and TrA activation in the balance tests are limited. However, measuring TrA activation by ultrasonography during the balance trials was not technically feasible and likely affected the results. Second, the sample size of the present study was not power-calculated. Thus, it is likely to contain type II error. Further study of sufficient power should be conducted to confirm the findings of the present study. Third, this study investigated the activation of the TrA but not the multifidus muscles, which also play an essential role in postural control. Additional studies that include measurements of multifidus may allow us to gain a deeper understanding about how the activation of multifidus influences static postural control in people with NSCLBP. Last but not least, because of the cross-sectional design of this study, more cohort studies are needed to further investigate the relationships between postural control and pain catastrophizing and core muscle activation in the future.The results of this study showed that impaired static postural control was evident under the visual deprivation condition and the static postural control in NSCLBP patients was correlated with pain catastrophizing and voluntary TrA activation. These relationships suggest that pain catastrophizing may also affect static postural control in patients with NSCLBP and should be taken into consideration in the interpretation of balance test results and the management of NSCLBP. Additional studies should be conducted to investigate the underlying biological and psychosocial interactions to explore the multidimensional nature of NSCLBP.


Background:  Cancer is the second leading cause of death globally. Up to 86% of advanced cancer patients experience significant pain, while 10-20% live in chronic pain. Besides, increasing prescription of opioids resulted in 33,000 deaths in the US in 2015. Both reduce patients’ functional status and quality of life. While cancer survival rates are increasing, therapeutic options for chronic opioid refractory pain are still limited. Esketamine is the s-enantiomer of ketamine, with superior analgesic effect and less psychotomimetic side effects. Intranasal esketamine was approved by the FDA for treatment-resistant depression. However, its use in chronic cancer pain has never been tested. Therefore, we propose a phase II, randomized, placebo-controlled trial to evaluate the efficacy and safety of intranasal esketamine in chronic opioid refractory cancer pain.Methods and analysis: We will recruit 120 subjects with chronic opioid refractory pain, defined as pain lasting more than 3 months despite optimal therapy with high dose opioids  and optimal adjuvant therapy. Subjects will be randomized into two groups: intranasal esketamine (56mg) and placebo. Treatment will be administered twice a week for four consecutive weeks. The primary outcome is defined as reduction in the Numeric Pain Rating Scale (NPRS) after first application. Secondary outcomes include NPRS reduction after four weeks, the number of daily morphine rescue doses, functional status and satisfaction, and depression.Conclusion: This study may extend therapeutic options in patients with chronic pain, thus improving their quality of life and reducing opioid use.Trial registration: Clinical Trials.gov,NCT04666623. Registered on 14 December 2020 The etiology is complex, with a mix of nociceptive, neuropathic and inflammatory mechanisms5, resulting in a situation that can be difficult to control. Tolleet al., described in 2000 that around 46% of family members of terminal patients referred that there is lack of adequate pain treatment when death is imminent6. When opioids are not enough to relieve pain, it is necessary to associate an adjuvant, such as ketamine, as recommended by current National Comprehensive Cancer Network guidelines in pain not responding to other analgesics8.Refractory pain is a challenging condition in Oncology. More than half of the patients with advanced stage cancer experienced pain5. It is commonly used as a general anesthetic agent, administered by intravenous or intramuscular route, but other usage and routes for this drug are being studied. Ketamine can cause not only dissociative anesthesia but also an analgesic and antidepressant effect5. Low doses of ketamine, have minimal effect on cardiovascular and respiratory function, produce analgesia, modulate central sensitization, hyperalgesia and opioid tolerance9.Ketamine was discovered in 1980, described as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor causing the inhibition of excitatory glutamate receptors in the central nervous system3. The advantage of this enantiomer is that it induces less dissociative effects and more powerful analgesia and anesthesia10. As an antidepressant, esketamine was approved by the FDA10, and as an analgesic it is not labeled yet due to the lack of studies assessing its efficacy and safety in relieving pain11.One of the ketamine enantiomers largely studied nowadays for other potential use is esketamine, the most effective optical isomer of ketamine12. There are a couple of recently completed or ongoing trials testing intranasal esketamine for pain14. A pilot study recently published found similar results in analgesia between esketamine plus midazolam via intranasal, and intravenous morphine by patient controlled analgesia in spinal surgery patients13.Intranasal esketamine use is approved by the FDA for refractory major depression16. However, a large randomized controlled trial is needed to prove that this drug is effective to relieve pain, is safe, and causes a reduction in opioid consumption. Esketamine has shown promising results superior to those observed for ketamine due to its more potent analgesic effect, associated with less psychomimetic side effects referred above17.Finding a better approach to manage severe and refractory cancer pain through rapid and efficient analgesia would redound to the benefits of the health care of these patients. Having an alternative to escalating doses of opioid would allow a reduction in opioid consumption in this population. This would decrease the risk of overdose and the frequent and unwanted side effects associated with high doses of these drugs. Opioid consumption is an epidemic health care concern in the United States and many other countries and efforts are strongly directed to combat itThis research aims to assess the efficacy and safety of a four-week treatment with intranasal esketamine (56 mg) twice a week, combined with opioid analgesic and adjuvant standard therapy in the management of adult patients with severe and opioid refractory chronic cancer pain.18.The primary aim is to investigate the analgesic efficacy of intranasal esketamine as an add-on therapy to potentially improve opioid resistant pain in cancer patients. We will evaluate whether intranasal esketamine alleviates chronic pain in this population by assessing the reduction with the Numeric Pain Rating Scale (NPRS) after the first dose of esketamine compared to baselineOur secondary aims are:1.19 of this novel treatment. This will be measured by a self-reported and questionnaire-guided adverse events report.Assessment of safety2.Evaluation if esketamine treatment reduces the number of morphine rescues required daily by the patient.3.To compare the patients’ functional status between both treatment groups.4.To evaluate the response of depression score to esketamine therapy5.To analyze if there is a difference in the efficacy of esketamine depending on the type of cancer and depression disorder of the patient.6.To analyze the sustainability of the effect after each dose throughout the time of treatment.18 .We propose a single-center, randomized, placebo-controlled, phase II, double-blinded with two parallel groups, superiority trial. The primary endpoint will be the change in pain intensity measured by the NPRSnd of December 2020.This is version 2 of the protocol from the 22The study will be conducted at a reference tertiary cancer hospital that will be selected based on willingness to participate and availability of qualified participants willing to take part in the study.20.We plan to conduct a single hospital trial and randomization will be done by the OxMaR software. Allocation sequence will be concealed for everyone involved in the trial, except for the pharmacist and the nurse responsible for patient’s allocation. This allocation will remain hidden for health care professionals and participants until the final result of the study are obtainedhttp://www.swordfishsecurity.com/).First approach will be performed by patient's physician and subsequent recruitment steps will be conducted by trained clinical staff. Written informed consent will be explained and signed. The recruiting physician will have access to a computer with OxMar software, the initial forms will be fulfilled and imputed personal data should be confirmed. The software will generate the allocation, which is automatically sent to the pharmacist that will provide the medication or placebo to the participant. The access to this allocation will be protected by Swordfish  the trial medicines . He or she will label and deliver them with corresponding randomized number received from OxMar records.22.All investigators, patients, care providers, outcome assessors, and study statisticians will remain blinded with respect to the treatment allocation throughout the trial. The masking will be assured by delivering identical unlabeled nasal injectors with the same volume (200 μL) and color of active drug and placebo. Each device will deliver 28mg of esketamine or placebo in a 200 μL solution, so in order to achieve the 56mg dose two devices will be requiredEsketamine nasal spray has a certain taste often described as bitter, that can cause dysgeusia. Therefore, blinding of subjects will be further guaranteed by adding denatonium benzoate to the water-based placebo agent mimicking the taste of esketamine intranasal solution.On each dosing day during the trial, participants will self-administer at 2 time points 1 spray of the study drug (esketamine or placebo) into each nostril. Each administration will be separated by 5 minutes. The administration will take place at the facility to ensure adherence and surveillance in regard to side effects.Emergency unblinding. In case of problems and safety concerns that cannot be solved with on-going blinded treatment, the participant’s allocated intervention will be revealed. Unblinding procedure will be performed at the request of the Data Monitoring Committee .During the period of treatment, the patient's status will be evaluated weekly by an experienced blinded anesthesiologist. Vital signs and oxygen saturation levels will be examined and recorded. Also a physical examination will take place to follow up the patients’ functional status.Sealed envelopes will be stored safely and access will be available 24/7 if needed. Treating physicians and the responsible pharmaceutical staff will be instructed and encouraged to maintain blinding status if possible. Certainly, they are advised to maintain blinding towards other subjects and ensure disclosure towards corporate sponsors, office staff, data analysts and study personnel.The Investigator must report all code breaks (with reason) as they occur on the corresponding electronic case report form page. Unblinding should not necessarily be a reason for study drug discontinuation.Inclusion criteria:Age ≥ 18 years; Male or female patients.Patients with refractory cancer pain, defined as: multiple evidence-based biomedical therapies used in a clinically appropriate and acceptable fashion have failed to reach treatment goals that mainly include adequate pain reduction and/or improvement in daily living functioning activities; AND/OR patients’ functional activities do not allow a quality of life, which is acceptable and/or pharmaceutical therapies have resulted in intolerable adverse effects.24; in practice, when the patient with cancer pain responds positively to any of these two questions:Psychiatric disorders and psychosocial factors that could influence pain outcomes have been assessed and appropriately addressed1.Is your pain under the current drug medication intolerable for your quality of life?2.Do you have intolerable adverse effects with your current treatment?25, and currently refractory despite optimized analgesic therapy including an opioid. Cancer pain classified as chronic (persistent or recurrent pain lasting longer than 3 months)No increase in baseline long acting opioid dose or addition of a new adjuvant analgesic drug within 2 weeks prior to study entryAbility to communicate the intensity of pain using the NPRS pain scale ranging from (0 as no pain to 10 with severe pain).Ability to give fully informed written consent.Expect survival more than 3 months.Exclusion criteria, taking into consideration the safety profile of the drug22 were defined as:History of allergy or intolerance to esketamine or ketamine.History of allergy to disinfecting products containing quaternary ammonium, who might be susceptible to be allergic to denatonium benzoate.Concomitant use of xanthine derivatives , ergometrine, or monoamine oxidase inhibitors.Active nasal/sinus dysfunction  or presence of any lesion of the nasal mucosa.Pregnancy, breastfeeding and women of childbearing potential not using a highly effective contraception method.Uncontrolled hypertension, arrhythmia, heart failure, or untreated coronary artery disease. History of transient ischemic attacks, stroke, neurovascular disease, hemorrhage, severe head injury, hydrocephalus or elevated intracranial pressure within the last 3 months.History of primary or metastatic malignant brain lesions (uncontrolled or without previous treatment).Known aneurysmal vascular disease  or arteriovenous malformationUncontrolled psychiatric illness with psychosis/hallucination .Alcohol abuse, drug abuse/dependence within the past 6 months as self-reported.Cirrhosis or severe hepatic impairment defined as 5-fold elevation of transaminases.Uncontrolled hyperthyroidism.Globe injuries or increased intraocular pressure (e.g. glaucoma).History of ulcerative or interstitial cystitis.Subjects scheduled to receive radiotherapy (RT) to a site of pain during the study period, or who have received RT to a site of pain within 2 weeks before study entry.Subjects scheduled to undergo surgical treatment during the study period likely to affect pain.Subjects on or starting chemotherapy if there is a significant expectation of that therapy affecting pain.Subjects who have not provided signed informed consent form.Concomitant use of drugs moderately or severely affecting cytochrome P450 activity.Participants will be recruited at the oncology and pain clinics of a tertiary academic hospital by the attending physicians during routine appointments. Participants may also be identified via review of medical records from the oncology and pain clinics and contacted by telephone prior to the next scheduled appointment with information about the study, in order to allow more time for consideration. Screening will continue until the target sample size is achieved . Expected recruitment time will be two years.To achieve adherence in the present clinical trial, the characteristics and main objective of the study will be exposed to the patients and their relatives who are in charge of their care during recruitment interviews and informed consent. An instructional video will be provided, which contains information about the correct drug administration, as well as the benefits of having a quick and easy application therapy. Adjuvant drugs currently used will be provided at each visit.In the initial interview with the subject the following information will be given:-Objectives of the study-Mode of administration of interventions-Importance of continuing with regular treatment 1 .The patients will be using around the clock baseline analgesia with long-acting opioid, and morphine rescue dose for the management of breakthrough pain. In the case of neuropathic pain, patients should start the use of an antidepressant or anticonvulsant in an optimized dose. If the participant is already using any of these drugs, they should continue the medicationTM” and a similar placebo device should be provided by the manufacturer Janssen Pharmaceutical Company of Johnson & Johnson. The participants should initially self-administer the nasal spray device containing either active drug or placebo under the supervision of a health care provider in the researcher center. Health care providers (physicians or nurses) will be informed and trained prior to the beginning of recruitment. Training will be provided by the investigators. One spray must be administered into each nostril in a 45-degree reclination to deliver 28mg. After a 5 minute interval the second device is used to deliver the second 28mg dose or placebo22.The study drug will be provided in two disposable nasal spray devices containing either 28 mg of esketamine or placebo in a 200 uL of solution - equivalent to two sprays doses. The 28 mg esketamine nasal spray device labeled “SpravatoThe nasal spray device contains an indicator with two green dots referring to the two spray doses. After one spray is delivered, one green dot will disappear. When the device empties after the two doses, all green dots will have disappeared. The participants will receive the intervention twice weekly for 4 consecutive weeks.27. NPRS will be taken for both during physical activity and at rest. The difference in NRPS after first dose of esketamine and baseline will be measured to analyze efficacy.The primary outcome of this trial is a reduction in the 11-point Numeric Pain Rating Scale (NPRS). It will be used to assess pain intensity at enrollment and at each visit. Patients will be asked to rate their weekly pain on a scale from 0 to 10 where 0 equals “no pain” and 10 equals "the worst pain they can imagine”30.The use of a unidimensional measure is justified as the goal of this study is to evaluate the efficacy of the investigational drug as an analgesic complement for patients already consuming morphine. There are several tools to approach pain intensity and this choice (NRPS) was based on literature review on similar situationsOncological patients suffering from chronic pain frequently present associated degrees of depression, which is why we chose a scale evaluating exclusively pain over other multidimensional questionnaires. This strategy enables to differentiate the analgesic action of esketamine from its role as antidepressant, as this itself might improve the patients’ overall well-being and disposition.Secondary outcomes. Sustainability of effect. NRPS will be used to identify the pattern of effect after each dose over the 4 weeks.Rescue morphine use. The use of morphine rescue . If pain decreases or stabilizes during the trial. This will be monitored using either the Aircure artificial intelligence through a mobile application or personal diaries.Patients’ functional status and satisfaction. These will be measured by the change in Brief Pain Inventory (BPI). A multidimensional standardized tool as the BPI will allow the researchers to assess pain intensity in relation to its interference in functional activities31.Depression symptoms. Depression is frequently described in association with chronic pain and affects its threshold. On the other hand, esketamine has a proven antidepressive effect. We propose to examine a depression score using the Patient Health Questionnaire (PHQ9) at enrollment and at each visit32. We would also evaluate the effect of depression on the analgesic effect of esketamine.Side effects. Reported side effects in other studies include decline in mood, conscious perceptions and intellectual performance. It is well established that esketamine presents fewer side effects than the racemic ketamine33. In this protocol the dissociative effects of the drug will be monitored applying the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) at enrollment and at each visit34. It assesses fatigue, dizziness, headache, nausea, changes in vision and mood changes. The cognitive performance will be addressed using Speed Reading Test (where the time for reading 20 independent characters is noted)33.Vital signs. Blood pressure, heart rate, respiratory rate and temperature, pulse oximetry and 12-lead-ECGs will be measured at enrollment and at each visit . In the occurrence of any abnormality, patients will be advised to stay at the institution for complementary evaluation. Furthermore, lower urinary tract symptoms will be asked and in case of positive answers, further examination will be performed35.36 . All members of the DMC will have to declare competing interests. Besides, the DMC will also monitor recruitment, inclusion rate, baseline characteristics, participant adherence, adverse events and safety monitoring every 15 days confidentially37.A DMC will be established, which is independent of the trial sponsor and study investigators. The DMC will be composed by experts of the field related to the studySolicited and spontaneously reported adverse events will be collected by the outcome assessors at each planned visit for a clinical assessment. Details about efficacy and safety of the trial medication have been reported previously (see above).38 we obtained a standard deviation of 5.5 . However, we would like to emphasize that power alone will not be relevant for the clinical interpretation of the study results, especially in a clinical trial40.Sample size is based on practical and clinical considerations for this phase II trial. Based on a previous study (case series) assessing the analgesic effect of nasal esketamine41, so for reasons of compensation, a total sample size of 120 participants will be recruited43.Considering the population of patients with refractory cancer pain (20%), to achieve a primary outcome reduction of 3 points on the 11 points NPRS with a power of 80% and an alpha error of 5%, a sample size of 108 subjects is needed. Based on previous studies in this patient population a dropout rate of 10% is estimatedFor the purpose of descriptive statistics all numerical continuous data will be presented as means or medians with standard deviation (SD) and interquartile ranges (IQR) respectively, as measures of dispersion. Categorical data will be presented in the form of proportions, frequencies or percentages. For all primary and secondary analysis, the intervention arm  will be compared with the control group (placebo plus opioid therapy plus adjuvant standard therapy).The P-values will be reported with two decimal points; all our tests will be 2-sided p-values with a level of significance of <0.05 to consider statistical significance. The statistical software to be employed is an up-to-date version of STATA , managed by professional blinded statisticians. After the analysis of all data, if the effect of esketamine doesn't last until next dose, a clustered analysis might be performed using results from all visits to evaluate acute efficacy of the drug against placebo.Missing data. According to our sample size calculation, we are considering an estimation of missing data of 10% of the participants, which may leave the study for several reasons that can include death secondary to cancer, adverse reactions, lack of improvement, early recovery, and others45.Research ethics committee/institutional review board (REC/IRB) approval will be obtained by the local ethics committee or institutional review board of the site center prior to begin of recruitment.Protocol amendments, if any, should be registered and approved by the local ethics committee. Accordingly, study protocol and if applicable informed consent form will be adjusted and investigators involved in the trial informed immediately.After completion of data acquisition and analysis, the results will be summarized and published. Accordingly, patients will be informed about allocation and trial results via telephone calls and optional visit in person. Manuscript writing will be performed by the investigators and there will be no public access granted to the raw data.Personal information about enrolled patients will be collected by study nurses of the study site. Collected information will be saved in coded folders and investigators, outcome assessors and statisticians will receive a pseudononymized version of the data. The data and information will be stored at a previously defined location after completion of the trial for 5 additional years.Only investigators and statisticians will have access to the final version of the data. To secure restricted access to the data, corresponding files will be coded.Meanwhile and after completion of the trial patients will be treated according to current guidelines and standards of care. Any harm associated with the participation of the trial is not expected as patients continue to receive standard of care.Not yet recruiting.No data is associated with this article.https://doi.org/10.6084/m9.figshare.13435742.v246.Figshare: SPIRIT and TIDieR checklist for ‘IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain’,Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).Data are available under the terms of the MPORTANCE trial. The IMPORTANCE trial   evaluates the efficacy and safety of intranasal administration of S-Ketamine in chronic opioid refractory cancer pain. The primary outcome is the reduction in the Numeric Pain Rating Scale. The article represents the protocol of the I The study is well designed with appropriate questionnaires to determine primary and secondary outcomes.  For me, sample size calculation based on ref. 38 is possible but addresses a different patient set. Maybe the authors comment on that briefly.  Moreover, I would comment on the fact that no midazolam is used in combination with S-Ketamin. However, this would imply 3 study groups (S-Ketamine + Midazolam i.n. versus Midazolam i.n. versus placebo).  The manuscript sounds scientific. I have no additional comments on this issue.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Cardiology, Oncology, ImmunologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This is a well-written description of a prospective clinical trial that will test the efficacy of intranasal esketamine in the reduction of chronic, refractory, cancer pain. A total of 120 patients will be recruited and randomized to receive placebo or intranasal esketamine 56 mg twice a week for 4 weeks. The primary outcome is a reduction in pain score, after the first dose of medication, on Numerical Pain Rating Scale. There is an appropriate data safety monitoring plan.PHQ-9 is a screening tool for depression, but not measuring changes in depression.There is a section for missing data, however, how missing data will be handled is not specified. Also, there's can be several reasons for missing data besides patients leaving the study. Few critiques below:Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:Intranasal ketamine for cancer and chronic neuropathic pain, cancer pain, neuropathic pain, non-opioid and non-pharmacological treatment for cancer painI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Recovery trajectories differ between individual patients and it is hypothesizes that they can be used to predict if an individual patient is likely to recover earlier or later. Primary aim of this study was to determine if it is possible to identify recovery trajectories for physical functioning and pain during the first six weeks in patients after TKA. Secondary aim was to explore the association of these trajectories with one-year outcomes.Prospective cohort study of 218 patients with the following measurement time points: preoperative, and at three days, two weeks, six weeks, and one year post-surgery (no missings). Outcome measures were performance-based physical functioning (Timed Up and Go [TUG]), self-reported physical functioning (Knee injury and Osteoarthritis Outcome Score-Activities of Daily Living [KOOS-ADL]), and pain . Latent Class Analysis was used to distinguish classes based on recovery trajectories over the first six weeks postoperatively. Multivariable regression analyses were used to identify associations between classes and one year outcomes.n = 203), “moderate gain group” (n = 8) and “slow gain group” (n = 7), KOOS showed two classes: “gain group” (n = 86) and “moderate gain group” (n = 132), and VAS-pain three classes: “no/very little pain” (n = 151), “normal decrease of pain” (n = 48) and “sustained pain” (n = 19). The” low gain group” scored 3.31  seconds less on the TUG than the “moderate gain group” and the KOOS “gain group” scored 11.97  points better than the “moderate gain group” after one year.TUG showed three classes: “gain group” (Patients who had an early trajectory of “sustained pain” had less chance to become free of pain at one year than those who reported “no or little pain” (odds ratio 0.11 .The findings of this study indicate that different recovery trajectories can be detected. These recovery trajectories can distinguish outcome after one year. An increasing number of studies focussed on the effectiveness of total knee arthroplasty (TKA) surgery for people with end-stage osteoarthritis. They showed that on the average 80% of the patients is satisfied one year after surgery , 2. HoweLatent Class Mixture Models (LCMM) are widely used statistical models in social, behavioural and medical science. They can be used to identify latent subgroups, classes or clusters of individuals based on their common growth trajectories over time . These mWe hypothesized that there are different subgroups of patients with distinctly different recovery trajectories after TKA as reported by others , 9. RecoThe secondary aim is to explore associations of these early recovery trajectories over six weeks with physical functioning (performance-based and self-reported) and pain after one year.This is a prospective cohort study with clinical data. The flowchart of this cohort study is presented in Fig. Participants were recruited from the MST community hospital in Enschede, the Netherlands between February 2011 and December 2014. Patients who followed a high-intensity physiotherapy program after TKA were included. The decision whether a patient was eligible to participate in the program was made by the orthopaedic surgeon and the physiotherapist together. A requirement was that patients are able to maintain the high-intensity physiotherapy program. Therefore, the following inclusion criteria were mandatory: 1) 18 years or older and diagnosed with primary osteoarthritis; 2) admitted for TKA surgery; 3) preoperatively independent in activities of daily living; 4) no comorbidity that hindered doing exercises  or number of patients (percentage). The subpopulations of patients based on the postoperative performance-based physical functioning and self-reported physical functioning outcome trajectories and pain outcome trajectories during six weeks were identified using latent class mixed model (LCMM). The LCMM finds potential latent profiles in heterogeneous populations. It combines a latent class model to identify homogenous latent classes of subjects and a mixed model to describe the mean trajectory over time in each latent group, while taking into account the individual correlation between repeated measures. Each subpopulation has its own physical functioning  or pain (VAS) growth parameters. We fitted the models using not only linear functions of time but also quadratic functions to allow nonlinear mean trajectories over time. The optimal number of classes was determined using a forward procedure, starting with one class and no subpopulations in the study sample. Then one class was added for each model. To evaluate if the model with one added class improved, three steps were taken: 1) The Bayesian information criterion (BIC) was used , 13, 32.The association of the identified groups with the one year outcomes was analysed using multivariable regression analysis . BecauseR2 for the linear regression models and Nagelkerkes R2 for the logistic regression model.The one year responses were regressed on the identified subgroups and on a set of relevant baseline covariates: Age, gender and BMI. Linear regression models were used for the one year TUG and KOOS scores, and a logistic regression model for the one-year dichotomized VAS outcome. The association was determined with the regression coefficient and the 95% confidence interval (linear regression models) for TUG and KOOS and the odds ratio and the 95% confidence interval (logistic regression model) for the VAS of pain during the last week. The overall fit of the models were assessed using the total variance explained, the Statistical analysis was performed with R software version 3.4.4  and IBM n = 2), infection (n = 1) and not able to do exercises (=1). Therefore, 218 patients were definitively included in the study, as shown in Fig. n = 218).In total 222 patients were selected and agreed to participate in the 10-day high-intensity physiotherapy program. After surgery four patients were excluded for the 10-day high-intensity training program because of wound problems (Appendix n = 7), “gain group”  and “moderate gain group” . In total 211 patients (97%) were recovered (class 2 and 3) and 7 patients (3%) were not recovered (class 1) based on the six weeks recovery trajectories.Figure n = 86) and “moderate gain group” , so all patients recovered .The most optimal LCMM model for KOOS-ADL with the lowest BIC was the linear two-class model (see Table n = 48), “sustained pain” (class 2 n = 19), and “no/very little pain” . In total 199 patients (91%) were recovered on pain (class 1 and class 3) and 19 patients (9%) were not recovered (class 2) based upon the six weeks recovery trajectories.The most optimal model retrieved by LCMM was a quadratic three-class model for VAS with the lowest BIC amongst the other presented models  89% lower odds to become free of pain after one year than the “no/very little pain” group (class 3).The “normal decrease of pain” group (class 1) had a 8% lower odds to become free of pain after one year than the “no/very little pain” group (class 3), but this was not significant. However, the “sustained pain” group (class 2) had a statistically significant (n = 203), a “moderate gain group” (n = 8) and a “low gain group” (n = 7). Self-reported physical functioning showed two recovery trajectories, namely a “gain group” (n = 86) and a “moderate gain group” (n = 132). For pain three classes were identified: “no/very little pain” (n = 151), “normal decrease of pain” (n = 48) and “sustained pain” (n = 19). Patients had further improvements for physical functioning and pain between six weeks and one year.The purpose of this study was to identify recovery trajectories in patients who attended a high-intensity physiotherapy program after TKA surgery. For performance-based physical functioning three classes were identified: a “gain group”  of the patients experienced “sustained pain”, while in the study of Dowsey et al. [Identifying recovery trajectories using LCMM is a relatively new technique, which was as far as known only once researched in patients after TKA between 1 and 5 years after surgery by Dowsey et al.  The recoy et al.  21.5% wey et al.  were clan = 19), had the possibility to get pain free after one year (n = 15). At one year almost all patients were pain free, so the outcome was favorable for this group of patients.Patients in this study showed progress on the measurements between six weeks and one year. The minimal clinical important difference for TUG was 2.27 s,  for KOOSThe differences of the TUG and KOOS-ADL trajectories between the “gain” and “moderate gain” group was considered clinically relevant, while for VAS trajectories differences between “no/very low pain,” and “sustained pain” were statistically significant but small.Our population included patients with a favourable prognosis and our data showed favourable recovery trajectories for most patients. If all patients after TKA surgery will be included in further research, we expect to find more or less similar recovery trajectories as in our population. Literature shows satisfaction rates of 80% after TKA, so in that case more patients will be in the “sustained pain” and “low gain” group.Recovery trajectories for patients after TKA including a high-intensity physiotherapy program were determined in the first weeks after TKA procedure. Studies looking at recovery trajectories in all patients after TKA, including those who followed other rehabilitation protocols and a less favorable prognosis are needed to generalize the results to all patients after TKA. Identifying patients at risk for less favorable outcomes  is important to get realistic expectations of patients regarding the TKA surgery. This improves satisfaction after TKA . Prognos


Introduction: Approximately 80% of non-small cell lung cancer (NSCLC) patients with bone metastases have cancer induced bone pain (CIBP).Methods: The NVALT-9 was an open-label, single arm, phase II, multicenter study. Main inclusion criterion: bone metastasized NSCLC patients with uncontrolled CIBP [brief pain inventory [BPI] ≥ 5 over last 7 days]. Patients were treated with six milligram ibandronate intravenously (day 1–3) once a day. Main exclusion criteria: active secondary malignancy, systemic anti-tumor treatment and radiotherapy ≤4 weeks before study start, previous bisphosphonate treatment. Statistics: Simon's Optimal two-stage design with a 90% power to declare the treatment active if the pain response rate is ≥ 80% and 95% confidence to declare the treatment inactive if the pain response rate is ≤ 60%. If pain response is observed in ≤ 12 of the first 19 patients further enrollment will be stopped. Primary endpoint: bone pain response, defined as 25% decrease in worst pain score (PSc) over a 3-day period (day 5–7) compared to baseline PSc with maximum of 25% increase in mean analgesic consumption during the same period. Secondary endpoints: BPI score, quality of life, toxicity and World Health Organization Performance Score.Results: Of the 19 enrolled patients in the first stage, 18 were evaluable for response. All completed ibandronate treatment according to protocol. In 4 (22.2%), a bone pain response was observed. According to the stopping rule, further enrollment was halted.Discussion: Ibandronate loading doses lead to insufficient pain relief in NSCLC patients with CIBP. Cancer induced bone pain (CIBP) is an important issue in metastasized non-small cell lung cancer (NSCLC). During the course of the disease, 24–60% of NSCLC patients are diagnosed with bone metastases and up to 80% will experience CIBP –3. FurthN = 607 of which only 1 NSCLC patient), which evaluated the effect of ibandronate  on bone pain showed pain relief within 7 days to 12 weeks after start of ibandronate  in NSCLC patients , 8–10. Hndronate . TherefoThe primary aim of this open label single arm phase II study  was to establish the efficacy of intravenous loading doses of ibandronate to achieve acute bone pain relief in NSCLC patients with CIBP. The trial was approved by the appropriate ethics committee (METC 07-2-035.6/ivb).The trial was performed in eight Dutch hospitals , with no more than a 25% increase in mean analgesic consumption over the same 3-day period compared to baseline analgesic consumption. Secondary endpoints were mean worst bone pain scale of the BPI in the first 7 days, interference scales of the BPI, analgesic consumption, WHO-Performance Score (WHO-PS), QoL, and safety. In the context of safety spontaneous adverse events (scored by Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) were collected.Patients were treated with six mg ibandronate once a day intravenously on day one, two, and three. Concomitant analgesic use was assessed using the WHO pain ladder. On day 1–7 patients recorded their worst bone pain score of the BPI and their analgesic consumption in a diary. Patients were evaluated for BPI, WHO-PS, and QoL on day 1 and 7. On day 7, a serum chemistry panel (including serum creatinine) was performed to assess the renal safety of ibandronate. Adverse events were recorded on day 1–3, on day 7, and at the end of follow-up (day 28).The study was designed following a Simon's Optimal two-stage design with a 90% power to declare the treatment active if the pain response rate was ≥ 80 and 95% confidence to declare the treatment inactive if the pain response rate was ≤ 60%. The 60% pain response rate is comparable to expected response rates of radiotherapy and opiates on cancer related pain . In the Between December 2007 and November 2010, 19 NSCLC patients were enrolled in the first stage. Eighteen out of 19 patients were evaluable for response. The patient characteristics are shown in In This study of intravenous loading doses of ibandronate in NSCLC patients with CIBP did not show adequate pain reduction in most patients. However, in four out of 18 patients a sufficient pain response was observed. In contrast to most other trials in which patients used concomitant anti-cancer therapy , patients in this study were only eligible if they did not start an anti-cancer therapy (systemic therapy and/or radiotherapy) in the 4 weeks before study entry. To not unnecessarily expose patients to a treatment that was not beneficial enough, a Simon 2-stage design was used, and the trial was stopped due to futility.CIBP remains important in NSCLC. Despite these older data of ibandronate loading dose for acute pain relief in lung cancer patients with CIBP, no new treatment options with rapid pain relief are currently available. Furthermore, phase II/III trials in metastasized NSCLC evaluating systemic anti-cancer treatment modalities  are not focused on rapid bone pain reduction and only report pain as an adverse event of therapy. We show that loading doses of bisphosphonates do not induce a rapid reduction of CIBP and that other strategies should be pursued.There is evidence of the effects of bisphosphonates on pain reduction for breast cancer, multiple myeloma and prostate cancer –14, 16. -PS; only one of the bone pain responding patients improved while two patients with a reduction in pain had a deteriorating WHO-PS, probably due to progression of cancer. Bone pain response was associated with survival as all four patients in the bone pain responding group were alive at study completion, whereas five of the 14 patients in the no bone pain responding group already had died because of progressive disease. Of all enrolled patients, 27.8% died within 1 month, although only patients with a life expectancy of more than 1 month could be enrolled. This stresses that it is difficult for physicians to accurately estimate the prognosis of a patient. It is already known that physicians tend to overestimate survival of patients in 27–42% of patients . Furthermore, we assessed changes in WHO-PS at 7 days after ibandronate infusion. Additional collection of WHO-PS through day 28 would have likely added value in identifying long-term changes in performance status. A strength of this study is the separation of systemic treatment and treatment for CIBP as there is no potential interaction in efficacy on rapid pain relief.In conclusion, loading doses of ibandronate do not lead to rapid bone pain relief in a sufficient number of NSCLC patients with uncontrolled CIBP to constitute its use. Studies evaluating other treatment options for rapid bone pain relief in this patient population are necessary.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Medisch ethische toetsings commissie (METC) Maastricht. METC 07-2-035.6/ivb. The patients/participants provided their written informed consent to participate in this study.A-MD and BEEMB: conceptualization. VN: formal analysis. AB: writing-original draft preparation. LH, VN, BEEMB, FS, HG, BB, and HS: writing-review & editing. All authors agree to be accountable for the content of the work.A-MD has taken part on an advisory board for Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The transversus abdominis plane (TAP) block is used increasingly in parturients after caesarean delivery. This is a randomized controlled trial to evaluate the effectiveness of bilateral single-shot of TAP blocks in patients who received multimodal oral analgesia for postoperative pain relief.Parturients who were scheduled for elective caesarean delivery under spinal anaesthesia were recruited and randomized to receive bilateral single-shot of TAP blocks or placebo in addition to multimodal oral analgesia which consisted of regular tramadol, celecoxib and paracetamol, with oral oxycodone used as a rescue for breakthrough pain. Only parturients in the TAP group would receive the TAP blocks with an injection of 15 ml (0.25%) ropivacaine on each side under aseptic techniques. All the parturients were evaluated for pain or related complications in the first 24 h after surgery. The primary outcome is the percentage of parturients who required oxycodone as a rescue analgesia.P = 0.122.Eighty and 79 parturients were allocated to the TAP and placebo group respectively. Nine out of 79 (11.4%) parturients in the TAP group and 15 out of 73 (20.5%) parturients in the placebo group required oxycodone for breakthrough pain, Bilateral single-shot of TAP blocks confer little additional benefit when a multimodal oral analgesic regimen is used for pain control after caesarean section under spinal anaesthesia.http://www.chictr.org.cn) identifier: ChiCTR-INR-16010130, retrospectively registered on Dec 12, 2016.Clinical Trial Registry of China (The online version contains supplementary material available at 10.1186/s12871-020-01223-3. With the availability of ultrasound machines, transversus abdominis plane (TAP) block may be easily performed after a caesarean section for postoperative analgesia. It was shown to be effective to relieve pain and reduced intravenous morphine consumption in patients who used patient-controlled intravenous morphine analgesia for post-caesarean pain relief . Previou2, major systemic disease, chronic pain disorders, neurological disorders, abuse of drugs or alcohol, and allergies to any medication included in the study protocol and inability to comprehend or use the visual rating pain scoring system.The study was carried out in a tertiary care public hospital in Shenzhen, China. It was approved by the Hospital Institutional Review Board (szkcw201628) and registered with the Clinical Trial Registry of China (ChCTR-INR-16010130). After patient informed consent was obtained, the parturients scheduled for elective caesarean delivery under spinal anaesthesia were enrolled in the study. Spinal anesthesia was performed in a lateral position at the L2/3 or L3/4 interspace with 0.5% hyperbaric bupivacaine 10 mg (2 ml) combined with fentanyl 15 μg (0.3 ml) in both groups. Inclusion criteria were American Society of Anaesthesiologists physical status I or II parturients, scheduled for elective caesarean delivery under spinal anesthesia. Exclusion criteria included a body mass index of more than 35 kg/mAn independent statistician prepared a randomization list while block of group allocation was kept in concealed opaque envelops. Attending anaesthetists would disclose group assignments at the start of surgery, and prepare for the TAP blocks if necessary. In order to ensure the recruited parturients who had spinal anaesthesia were blind from group allocation and to avoid sham block, the surgical drape which blocks the parturient’s view of her surgical site was kept after surgery. After a wound was covered with dressing, an ultrasound-guided bilateral single-shot of TAP blocks was performed by the attending anaesthetists who are experienced with this technique before conducting the investigation. A linear 13- to 6-MHz ultrasound probe  was placed transversely on the anterolateral abdominal wall between the iliac crest and costal margin. The three layers of muscles - the external oblique, the internal oblique, and the transversus abdominis - were identified. Only parturients who were allocated to have TAP blocks would receive an injection of local anaesthesia under aseptic techniques. A 22-gauge, 90-mm SonoPlex Stim needle , attached with flexible tubing to a syringe filled with 0.9% normal saline, was introduced through the skin anteriorly in the plane of the ultrasound beam, and advanced into the fascial plane between the internal oblique muscle and transversus abdominis muscles. Ropivacaine15 ml (0.25%) was injected on each side of the abdominal wall for the TAP blocks. A local anaesthetic solution was injected in 5 ml increments after aspiration. After each 5 ml bolus, patients were monitored for an increase in heart rate or signs of local anesthetic toxicity such as tinnitus, perioral numbness, metallic taste in mouth, slurring of speech, and mental status changes. Since the parturients who had effective spinal block would not feel the needle injection of TAP blocks, it was possible to blind the participants from group allocation as an ultrasound scan would be performed even if TAP blocks were not administered.All recruited patients had intravenous parecoxib 40 mg before the end of the operation. They were also prescribed multimodal oral analgesics postoperatively, and this included slow release tramadol 100 mg twice a day for the first two days, celecoxib 200 mg twice a day for three days, and paracetamol 1000 mg four times a day for four days. Oxycodone 10 mg for once as PRN was prescribed and used when necessary.Participants were given instructions to fill in a survey for postoperative pain control. The numeric rating scale (NRS) for pain and satisfaction scale was explained. NRS consists of scores of 0 to 10, where 0 equal to no pain and 10 equal to the worst pain. A scale of 5 was used as a satisfaction score, with 1 equal to “very unsatisfactory” and 5 equal to “very satisfactory” with pain relief. The participants were asked to record the NRS at rest, with movement, and with uterine massage and the satisfaction score at 2 h, 4 h, 6 h and 12 h after completion of surgery. In addition, they were asked to record if there was an episode of nausea and vomiting. The parturients would also record if oxycodone or uterotonic was used in the first 24 h. Moreover, they would also record if there was any instance of pain when the NRS score was greater than 6 in the first 24 h. The survey was collected by the pain nurse during follow up on day 1 after the operation.The primary outcome is the percentage of parturients who required oxycodone as rescue analgesia. Secondary outcomes include the NRS at rest, NRS with movement and NRS during uterine massage, patient satisfaction score, the percentage of parturients who experienced pain with NRS > 6 during the first 24 h after surgery, and the incidence of nausea and vomiting. According to our record of routine postoperative visits, approximately 20% of our patients required oxycodone as rescue pain relief. If TAP blocks were to decrease the requirement of oxycodone from 20 to 5%, 73 parturients per group would be required for 80% power with a 5% type 1 error.P value < 0.05 was considered significant. Data were analysed using SPSS .Parametric primary and secondary outcomes are presented as the mean (SD) or number (percentage) and were compared by t-test or Chi-square test. Non-parametric data are presented as the median (IQR [range]) and compared by the Mann-Whitney U test. The area under the curve (AUC) for pain scores and satisfaction scores was derived using the trapezoidal rule. The mean AUC of pain scores and satisfaction scores were presented as the mean (SD) and compared using a t-test. A P = 0.122, Table P = 0.87 and P = 0.95 respectively, Table P = 0.66, Table P = 0.58, Table P = 0.07) during the first 24 h post-operatively (Table One hundred and sixty-three patients were approached, and 159 patients consented to take part in this study between April and September in 2016. Eighty parturients received TAP blocks and 79 were allocated to the placebo group (Fig. ly Table .Fig. 1COur study demonstrated that TAP blocks were not associated with reducing the use of rescue oxycodone, and we revealed in this study that bilateral single-shot of TAP blocks conferred little additional benefit when a multimodal oral analgesic regimen inclusive of tramadol, celecoxib and paracetamol was used.With the advancement of ultrasound technology, TAP blocks have become technically easier and safer to perform . UltrasoThe advantage of multimodal oral analgesia is the ease of drug administration without device request. This would facilitate early mobilization after surgery. Recently the U.S. Food and Drug Administration has issued a warning to mothers that breastfeeding is not recommended when taking tramadol due to the risk of serious adverse reactions in breastfed infants . In a reSince patients and pain nurses who performed the postoperative visits were blind to group assignments, this allowed us to evaluate the effectiveness of TAP blocks without bias. Moreover, all anaesthetists who performed the block were experienced in doing TAP blocks. After all, with the use of ultrasound, TAP blocks were easily performed. Since the postoperative pain score was recorded by the patients themselves before our routine postoperative pain round, this would also further reduce the possibility of bias regarding pain assessment. However, it was also difficult to exclude failed TAP blocks, which served as a cause for analgesia inefficacy due to the fact that residual sensory block from spinal maintained.In conclusion, this double blinded randomized controlled trial revealed that bilateral single-shot TAP blocks confer little additional benefit when a multimodal oral analgesic regimen is used for post caesarean section. It would be interesting to investigate if intrathecal morphine would confer any additional benefit when a multimodal oral analgesic regimen is used for post caesarean section pain relief.Additional file 1. CONSORT Checklist