Pain management in the Emergency Department has often been described as inadequate, despite proven benefits of pain treatment protocols. The aim of this study was to investigate the effectiveness of our current pain protocol on pain score and patient satisfaction whilst taking the patients’ wishes for analgesia into account.We conducted a 10-day prospective observational study in the Emergency Department. Demographics, pain characteristics, Numeric Rating Scale pain scores and the desire for analgesics were noted upon arrival at the Emergency Department. A second Numeric Rating Scale pain score and the level of patient satisfaction were noted 75–90 min after receiving analgesics. Student T-tests, Mann-Whitney U tests and Kruskall-Wallis tests were used to compare outcomes between patients desiring vs. not desiring analgesics or patients receiving vs. not receiving analgesics. Univariate and multivariate logistic regression models were used to investigate associations between potential predictors and outcomes.In this study 334 patients in pain were enrolled, of which 43.7% desired analgesics. Initial pain score was the only significant predictive factor for desiring analgesia, and differed between patients desiring (7.01) and not desiring analgesics (5.14). Patients receiving analgesics (52.1%) had a greater decrease in pain score than patients who did not receive analgesics (2.41 vs. 0.94). Within the group that did not receive analgesics there was no difference in satisfaction score between patients desiring and not desiring analgesics (7.48 vs. 7.54). Patients receiving analgesics expressed a higher satisfaction score than patients not receiving analgesics (8.10 vs. 7.53).This study pointed out that more than half of the patients in pain entering the Emergency Department did not desire analgesics. In patients receiving analgesics, our pain protocol has shown to adequately treat pain, leading to a higher satisfaction for emergency health-care at discharge. This study emphasizes the importance of questioning pain score and desire for analgesics to prevent incorrect conclusions of inadequate pain management, as described in previous studies. As pain is a common complaint of patients visiting the Emergency Department (ED) , its earSince Marks and Sachar published a landmark paper about undertreatment of pain in the ED , this beThe main goal of our study was to prospectively investigate the effectiveness of our current pain protocol on pain score and patient satisfaction in our ED; the desire for analgesia by the patient is hereby taken into account. ‘Effectiveness’ of pain treatment was defined as a decrease in pain score and increased level of satisfaction with care. A pain score reduction of > 2 Numeric Rating Scale (NRS) was considered clinically relevant , 10. SecThis study had a prospective, observational design and was conducted at the ED of the University Medical Center Groningen (UMCG). The ED of this tertiary teaching hospital has an annual volume of approximately 32.000 patients, of which around 22.000 are estimated to be non-trauma patients. At the onset of the study, an analgesic protocol was present in the ED Fig. . Data waAll patients with complaints of recent pain (< 3 months) were questioned. Exclusion criteria were patients < 18 years, no recent pain (< 3 months), patients in a life-threatening situation, patients with impaired mental status or neuropsychiatric diseases leading to inability to fill in the questionnaire , a language barrier or absence of informed consent.We used a manual questionnaire for a continuous period of 10 days, 24 h a day, to collect data for every patient visiting the ED.During their stay, all patients were questioned twice. Immediately after triage of the patient, data was collected on demographics , triage colour code Table , allergyPrimary outcomes were change in pain score and patient satisfaction score. Secondary outcomes were reasons to refuse analgesics and identifying why patients did not receive analgesics, despite desire for pain relief.After completion of the study, all blinded questionnaires were manually entered in SPSS and checked by two investigators.P-values were described to demonstrate differences between groups, with p < 0.05 considered significant.Binominal and categorical data are presented as frequencies of occurrence and percentages. Continuous variables are presented as means and standard deviations (SD). The student T-test or Mann-Whitney U test was used to compare means between patients desiring vs. not desiring analgesics or patients receiving vs. not receiving analgesics. To compare between multiple groups, the Kruskall-Wallis test was used, followed by post hoc Mann-Whitney U tests. P-values of < 0.05 were again considered significant. All analyses were performed using IBM SPSS Statistics version 22.To investigate associations between potential predictors and outcomes, logistic regressions were conducted. Factors that showed to be significant in univariate logistic regressions were included in a multivariate logistic regression model. Associations are presented by odds ratios (OR) and confidence intervals (CI). The total number of patients that visited the ED during the 10 days of inclusion was 797 Fig. . Of thosThe total number of patients included during the 10-day study was 334. The mean age was 49 years and 53% were male. The overall mean initial pain score was 5.96 NRS SD 2.28). Half of the patients had already taken analgesics before entering the ED (50.9%) and 5.1% of the patients indicated to have an allergy for an analgesic. Patient and pain characteristics are outlined in Table .28. HalfOf the 334 enrolled patients, 146 (43.7%) patients desired analgesics upon arrival at the ED. Initial pain scores were higher in patients with a desire for analgesics compared to patients who did not wish analgesics  received analgesics. The most commonly prescribed analgesics were acetaminophen (50.2%), NSAID’s (13.9%) and opioids (21.2%) . Of the 188 patients that initially refused analgesics, 51 patients had required and received analgesics at the time of the second questionnaire. Of the patients initially desiring analgesics, 23 patients did not receive them  for pain management. The majority of patients (67.1%) was satisfied (patient satisfaction score between 6 and 8 NRS), and 25.7% of the patients were even highly satisfied (patient satisfaction score 9–10). Only 7.2% of all patients included were dissatisfied (patient satisfaction score < 6 NRS).After only analyzing patients who received analgesics in compliance with their initial wish, results show that patients receiving analgesics were significantly more satisfied than patients who did not receive analgesics (satisfaction score 8.06 [95% CI 7.80–8.31 vs. 7.54 [95% CI 7.24–7.84]).The most common reason for not wanting analgesics, even though in pain, was bearable pain (57.4%), wanting to know the diagnosis first (10%) and using analgesics before visiting the ED (8%).As stated before, not all patients received analgesia according to their initial wish. Of the 146 patients desiring pain management, 23 patients did not receive analgesics. After performing subgroup analyses on patient satisfaction scores, results show that within the group that did not receive analgesics, patients who initially desired analgesics were not more dissatisfied than patients that did not desire analgesics  did not desire analgesics. Also, there was no difference in satisfaction between those patients and patients that did not receive analgesics despite their wish, suggesting that analgesics were not incorrectly withheld from patients. According to Allione et al., almost 10% of the patients do not receive analgesics despite their expressed desire 6% did no.Nevertheless, it has to be mentioned that despite the statistically significant differences, one might wonder if a difference of 0.52 in patient satisfaction score is clinically relevant. Previous studies have investigated the association between pain scores and patient satisfaction and stated that pain relief on itself is not the only factor affecting patient satisfaction , 14. McNAnother important limitation of many earlier studies on ‘oligoanalgesia’ is their retrospective nature. Since pain perception is a subjective phenomenon, the presence or severity of pain should be determined by asking the patient at the moment of pain itself. Estimating the pain score, without asking the patient or asking the patient in retrospective, will not reliably reveal the real severity of pain . Also, tMeasuring severity of pain among ED patients can be challenging since pain perception is considered a subjective phenomenon. A retrospective way of investigating pain management will not provide a reliable picture . HoweverAn important challenge in investigating patient satisfaction on pain management was the subgroup of patients where no analgesics were given. For that reason, all patients were asked to rate the overall management routine regarding pain treatment in the Emergency Department, and not only the effect of the therapeutics itself. Nevertheless, it is possible that less attention was given to patients who initially did not desire analgesics, possibly causing the differences in satisfaction scores between the two groups. Patient satisfaction score was expressed as one overall grade in our questionnaire. Thus, specific reasons for expression of (dis)satisfaction regarding e.g. waiting time and communication, were not investigated.This study is limited to a single, tertiary university hospital in Groningen, the north of the Netherlands. ED’s of all Dutch hospitals adhere to the same guidelines for pain management . TherefoIn summary, our results show that less than half of the patients in pain entering the ED desire analgesics. Patients receiving analgesics were adequately treated according to the pain protocol, showing a clinically relevant reduction in pain score and higher satisfaction scores at discharge compared to patients who did not receive analgesics. Patients who did not receive analgesics despite their expressed wish were not incorrectly withheld from pain treatment, since satisfaction scores were comparable to patients who did not desire and did not receive analgesics. Additionally, most of the patients who did not receive pain medication despite desiring analgesics, received a non-pharmacological pain treatment. This study demonstrates that in this ED setting with a pain protocol in use, pain is adequately treated, and emphasizes the importance of taking the patients’ wish for analgesia into account when investigating ‘oligoanalgesia’ in the ED.


There has been a surging interest in the putative role of peripheral growth factors in the pathophysiology of fibromyalgia, specifically in the peripheral sensitization that occurs in chronic pain disorders. This cross-sectional study set out to assess and compare brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in plasma samples from fibromyalgia patients and healthy controls. Plasma BDNF and NGF were measured in 89 fibromyalgia patients and 36 pain-free controls, and compared using ANCOVA controlling for potential confounders, as well as Bayesian methods for parameter estimation and model evaluation. BDNF and NGF levels in fibromyalgia patients did not differ from those in pain-free controls. Statistical methods were consistent, with both frequentist and Bayesian approaches leading to the same conclusions. Our study fails to replicate the finding that peripheral BDNF is altered in fibromyalgia, and instead our findings suggest that plasma levels of growth factor appear normative in fibromyalgia. Fibromyalgia is one of the most pervasive primary pain syndromes, affecting 2–5% of the general population3. It has been proposed that both alterations in central and peripheral sensitization partially underlie the development of the disorder4. In order to identify biomarkers that may explain central and peripheral sensitization at the molecular level, research has turned to growth factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Excessive activity of these markers has been posited to drive sensitization, and a maladaptive role for BDNF and NGF has been highlighted in preclinical evidence5. Indeed, there are reports that BDNF6 and NGF7 are increased in the cerebrospinal fluid of fibromyalgia patients. Whilst growth factors have primarily been hypothesized to exert sensitizing effects at central and spinal levels, several studies have reported that that peripheral BDNF is increased in fibromyalgia11, and that it correlates with altered pain pressure threshold12. However, there are also reports of normative BDNF serum levels13, and to the best of our knowledge there are no published data on peripheral NGF levels in fibromyalgia patients. Thus, the utility of neurotrophic biomarkers in fibromyalgia remains unclear.Fibromyalgia is a chronic musculoskeletal pain condition marked by widespread painFor the present study we investigated plasma levels of NGF, as well as BDNF as a replication attempt in a large sample of fibromyalgia patients. We hypothesized increased levels of BDNF and NGF in fibromyalgia patients as compared to pain-free controls, indicative of peripheral sensitization in the chronic pain population.16. All participants provided written informed consent before their inclusion in the study. The Ethics Research Committee of the Medical Faculty, University of Heidelberg approved the study (S-261/2010), which was performed in accordance with the Helsinki Declaration.This study was part of the research consortium “Localized and Generalized Musculoskeletal Pain: Psychobiological Mechanisms and Implications for Treatment” (LOGIN), funded by the German Federal Ministry of Education and Research (01EC1010A-F) and reported on recently15. See our previous studies on this sample17 for a more comprehensive description of inclusion and exclusion criteria. Pain-free controls were recruited through opportunity sampling and subjected to the same inclusion criteria, plus the absence of any chronic pain condition.For the present study, 97 fibromyalgia patients were recruited from a tertiary care pain center at the University Hospital Heidelberg, as well 35 pain-free controls. To be included, fibromyalgia patients had to be at least 18 years of age, not suffer from specific pathologies, and not take antipsychotics, benzodiazepines or prescription opiates. In addition, participants were advised not to take any pain medication 24 hours prior to the investigation. Fibromyalgia status was confirmed using the 1990 American College of Rheumatology criteria, according to which participants had to report chronic widespread pain  with at least 11 of 18 positive tender points. Symptoms had to be present for ≥45 days of the past 3 months to ensure clinically relevant chronicity18. In the present study, the HADS showed reliability of the 7-item depression  and the 7-item anxiety  subscales. All participants underwent venepuncture to assess peripheral growth factors. We used 2.7 ml EDTA vacutainers. Bloods were immediately (<1 min) centrifuged at 4 °C at 2000 g for 10 min, plasma was aliquoted and frozen in liquid nitrogen. An immunoassay for analysis of NGF was developed using a prototype based on electrochemiluminiscense (ECL) technology . All samples were measured in duplicate. The plates (96- well format) were preprocessed by the manufacturer with a specific antibody directed towards human NGF. Recombinant human beta NGF was used as a calibrator . Equal volumes of diluent and sample were added to the wells and incubated for 2 hrs. After a washing step a biotinylated detection antibody provided with MSD Sulfo TAG was dispensed to all wells and incubated for another 1.5 hrs. Plates were subsequently washed and read buffer was added prior to analysis on the SECTOR Imager. Lower limit of quantification was 0, 61 pg/mL. Intra- and interassay coefficient of variation were 10% and 19% respectively. BDNF was measured in assay buffer diluted serum using commercial fluorometric enzyme-linked immunosorbent assay kits  as described previously20.All participants completed a sociodemographic assessment capturing age, gender, marital status, level of education and employment. Additionally, average pain intensity and pain days were reported for the previous 4 weeks. Pain intensity was rated using a numerical rating scale ranging from 0 (“no pain”) to 10 (“worst pain imaginable”). All participants completed the Hospital Anxiety and Depression Scale (HADS) to determine the severity of anxiety and depressive symptomsTo control for variations in dietary behaviours and health, body-mass index (BMI), time since last meal, time of day at venepuncture, diabetes mellitus, hours of sleep the previous night, as well as recent consumption of coffee, chocolate and spicy foods were recorded. We further recorded current medications, including antidepressants, ion channel blockers , opiates and NSAIDs.21 indicated that the present sample was sufficiently powered to find effect sizes above Cohen’s d = 0.56. All biomarkers were log-transformed to ensure normal distribution. For frequentist methods, ANCOVA were carried out. Associations with potential covariates were carried out using simple regressions for continuous variables and logistic regression for categorical variables. To allow for conservative model estimations, all ANCOVAs were run twice, once excluding variables significantly different between groups, and once including those variables. If no statistically significant differences between the resulting models were observed, the “classic” model excluding divergent variables is reported. The potential covariates assessed were age, gender, cigarettes per day, grams of alcohol per day, time since last meal, body-mass index (BMI), diabetes mellitus, hours of sleep the previous night, time of day at sampling, level of anxiety and depression, average pain in the last 4 weeks, medication status and basic demographics.All statistical analyses were carried out in R (3.4.1). To maximise confidence in statistical findings, both frequentist as well as Bayesian statistical models were calculated. For descriptive statistics, t-tests and chi-square statistics were used. Power analysis using G*Power10) as well as Highest Density Intervals (HDIs) with default priors using Monte Carlo Markov Chains were calculated using the BayesFactor, JAGS and BEST packages. Bayes factors of 3 and above were interpreted as sufficient evidence for group differences, and Bayes factors of 1/3 and below as sufficient evidence for no group differences22. Monte Carlo Markov Chain converge was verified using the Potential Scale Reduction Factor11. Effect sizes are expressed in Cohen’s d.Using Bayesian methods to express posterior probabilities of the data, Bayes Factors (BFDescriptive statistics are presented in Table In the case of NGF (reported in pg/mL plasma), ANCOVA controlling for cigarette smoking identified no significant group differences  = 0.14, p = 0.71). Bayesian analyses suggested no significant differences, with a BF10 of 0.22 and similar mean and HDI estimates for the probable parameter values in fibromyalgia patients  and healthy controls . The mean difference was estimated at −0.06 .For BDNF (reported in pg/mL plasma), ANCOVA controlling for channel blockers no significant group differences  = 0.0, p = 0.995). Bayesian analyses suggested no significant differences, with a BF10 of 0.22 and similar mean and HDI estimates for the probable parameter values in fibromyalgia patients  and controls . The mean difference was estimated at −4.93 . Results for BDNF and NGF are presented in Fig. , 131 = 0Contrary to the study hypotheses, fibromyalgia patients were indistinguishable from pain-free controls on both plasma NGF and BDNF levels. Our findings therefore do not suggest that peripheral growth factors levels are not a pathophysiological feature of fibromyalgia, or that they contribute to the development of peripheral pain sensitisation.The likely explanations of these findings are two-fold. First, heterogenous nature of fibromyalgia makes generalisation difficult. Phenotypical phenomena such as central sensitisation may be more easily established than underlying endophenotypical mechanisms of such phenomena. Second, previous studies measuring BDNF had typically less than half the sample size of this study and typically assessed a range of biomarkers, and thus suffered from greater likelihood of chance findings. By concentrating on only growth factors in a large sample of well characterised patients, our study was able to show that they are unlikely to be systematically increased or altered. Given that the extant literature broadly implicates BDNF as a biomarker in fibromyalgia, and further hypothesises NGF to be implicated in the peripheral pathophysiology of fibromyalgia, our null findings will adjust how clear the current study consensus appears.Several strengths of the present study can be noted. To our knowledge, this is the first study to assess peripheral NGF in a large sample of fibromyalgia patients and pain-free controls. We further employed rigorous methods to ensure the sample is well defined and characterized and blood samples deliver accurate measurements.23. Second, heterogeneity between the clinical and control groups may have also skewed reliability of our findings, as there were significant group differences in age, gender and important psychosocial variables such as medications or alcohol consumption. However, these were not identified as potential covariates, suggesting they did not influence growth factor levels.The most marked study limitation is that no cerebrospinal fluid measures of BDNF and NGF were taken, and thus no conclusions can be drawn as to whether central growth factor levels are altered in fibromyalgia. However, it should be noted that BDNF can efficiently cross the blood-brain barrierThe present study findings contradict those from previous studies measures BDNF in blood of fibromyalgia patients, and this finding should be explored further. Future research should further utilise cerebrospinal fluid to seek whether central growth factors levels are similarly unaltered, and how these levels correspond to those in the periphery. Further, the association to peripheral and central sensitisation and growth factors should be investigated.This is the first study to show that peripheral NGF is unperturbed in fibromyalgia patients, and further sheds doubt upon previous findings that plasma BDNF is increased in fibromyalgia.


Patients with very good partial response (VGPR) or better reported reduced scores for pain severity and worst pain; those with progressive disease reported increased scores for these domains and pain interference. These findings show that previously reported improvements in progression-free survival and response rate with elotuzumab are achieved without detriment to HRQoL, which is maintained over time.Treatment of relapsed/refractory multiple myeloma (RRMM) aims to prolong survival while maintaining health-related quality of life (HRQoL) by managing disease-related symptoms and complications—one of the most frequent and debilitating being bone pain. In the ELOQUENT-2 study (NCT01239797), which evaluated the addition of elotuzumab to lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone, pain and HRQoL were assessed in patients with relapsed/refractory disease using the Brief Pain Inventory–Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-C30) and myeloma-specific module (QLQ-MY20). Mean baseline pain scores were low and remained so throughout treatment with both regimens; mean HRQoL scores did not change substantially from baseline. A significantly higher proportion of patients with objective response than without had clinically meaningful improvements in worst pain over two consecutive treatment cycles  contains supplementary material, which is available to authorized users. Multiple myeloma (MM), considered incurable, accounts for 10% of hematologic malignancies , 3, and Demonstrating improvements in HRQoL is challenging in patients with advanced or chronic diseases as patients’ perceptions of their health status and responses to HRQoL-related questions can be affected by adaptations to the disease , 16. In An informed treatment decision requires an adequate understanding of the potential benefits and risks by both physician and patient. When treatments offer a clear survival benefit but have increased toxicity, it is important to consider the patient’s experience of treatment and HRQoL. In order to inform benefit-risk assessments, it is essential to use validated, disease-relevant, patient-reported outcome (PRO) measures in clinical studies to assess symptoms, functioning (activity limitations), health status/HRQoL, patient satisfaction, treatment preferences, and adherence.p < 0.001) [Elotuzumab, an immunostimulatory antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is indicated in combination with lenalidomide and dexamethasone (Ld) for the treatment of MM in patients who have received one to three prior therapies in the US  or at le< 0.001) . PFS was< 0.001)  and 50% < 0.001) . Overall< 0.001) , 21. Pat< 0.001) , 23 achi< 0.001) , consist< 0.001) –24. ELd In ELOQUENT-2, PRO measures  were included as pre-specified secondary or exploratory endpoints. In this paper, we investigated HRQoL measures and whether there is a relationship between treatment response and patient-reported pain. These analyses, performed using data from the extended 3-year follow-up, aim to provide patients and physicians with a more comprehensive benefit-risk assessment of elotuzumab in RRMM.The ELOQUENT-2 study design has been previously described see . InstituThe PRO population comprised all randomized patients with a baseline assessment and at least one follow-up PRO assessment. Pain and HRQoL were assessed using the BPI-SF, EORTC QLQ-C30, and QLQ-MY20 at screening, on day 1 of each 28-day cycle, and at the end of treatment. Change from baseline in mean BPI-SF scores for pain severity and pain interference was pre-specified secondary endpoints of ELOQUENT-2  , 32. In t test) and between groups (unpaired t test). Hypothesis testing was at the 5% (two-sided) significance level.Statistical analyses were pre-specified. Descriptive statistics were generated to describe outcomes at each time point for the absolute value and calculated change from baseline. Absolute values were compared with baseline within each treatment group  and time to sustained response (log-rank test) were compared between treatments see .The study population baseline characteristics have been described previously . In totaMean baseline scores for the pain severity domain of the BPI-SF were low for both ELd and Ld arms (2.6 versus 2.9) and were equivalent to a “ mild pain” rating . BaselinThese observations were supported by the pre-specified mixed-model repeated-measures (MMRM) analyses, which showed very small average increases in pain scores (mean increases of 0.717–1.121 for ELd and 0.673–0.998 for Ld) across the three domains; the difference between treatments was not statistically significant for any domain  performance status (for a performance status of 0 or 1 versus 2), and age (for age ≥ 65 versus < 65 years) and prior stem cell transplantation (with versus without prior transplantation) in the pain severity and worst pain models.Subgroup analyses showed that age (≥ 65 versus <65 years) and severity of pain at baseline (pain severity score of ≥ 5 versus < 5) influenced patient-reported pain. Mean pain severity scores in the older age group were lower with ELd versus Ld; the differences between treatments were statistically significant at cycles 1, 16, 20, 25, 26, and 28. In the younger age group, mean scores were also slightly lower with ELd than with Ld; differences between treatments were statistically significant at cycles 1, 16, 19, 20, and 22–30  to treatment ; however, differences between treatments also emerged in later cycles, in subgroups based on age. In several patients with vertebral compression fractures, it took several months for the pain to improve. Although these results are surprising and possibly due to the heterogeneity in the data, the pattern was consistent across several pain endpoints (BPI-SF domains and pain domain of the EORTC QLQ-C30).Addition of a new therapeutic agent to an existing single or double regimen may improve clinical outcomes without compromising HRQoL, as observed with the ELd combination in RRMM, and with other double and triple combinations in metastatic melanoma and metastatic pancreatic ductal adenocarcinoma , 36. TreThe quality of PRO data collected during clinical studies is improving, as are the analyses and reporting of these data; however, there are still elements, such as dosing convenience, that may affect HRQoL but are not adequately measured by current PRO instruments .PRO data are important to demonstrate the effects of cancer and its treatment on patients’ lives; identify patients who may benefit the most from a specific therapy; and inform clinicians about the relative benefits and risks of its efficacy, toxicity, and value from the patient perspective . SeveralOur robust, scientifically valid methodology addressed many issues common to analyses of PRO data, particularly regarding missing data. Following a pre-defined statistical analysis plan, data were analyzed from all PRO and HRQoL domains included in the study. Validated and disease-specific PRO instruments were used to measure outcomes important to patients with RRMM. We focused on the experience of pain during treatment, as patients with MM have reported that this significantly impairs HRQoL , and conData from the ASPIRE study  showed cThis study has some limitations. The open-label trial design may have influenced investigators’ and patients’ treatment expectations during self-reported assessments. However, it is worth noting that, according to the study protocol, response was evaluated every 4 weeks from date of first dose of study drug until disease progression, death, or withdrawal of consent. Therefore, the differences seen between treatment groups in terms of patient-reported pain response at cycle 2 of treatment


N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient’s assessment on a 0–100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain , and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments. The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib ( Rapid, sustained pain control is a foremost goal for many patients with rheumatoid arthritis (RA); notably, in a survey approximately two-thirds of patients responded that pain was their treatment priority . Many paIn RA-BEAM, a Phase 3 clinical trial of baricitinib, an oral, selective inhibitor of Janus kinase (JAK)1 and JAK2, baricitinib plus methotrexate (MTX) was associated with significant clinical improvements compared to patients treated with adalimumab plus MTX or placebo plus MTX. Baricitinib- and adalimumab-treated patients demonstrated similar improvement in swollen joint count (SJC), with both groups demonstrating significantly greater improvement relative to the placebo group beginning at Week 1 that was maintained through the placebo-controlled period (Week 24). For patient-reported pain, however, baricitinib-treated patients reported significantly greater improvements as early as Week 1 compared to placebo-treated patients, and as early as Week 2 when compared with adalimumab-treated patients. These statistical differences in pain relief between the active treatment arms were maintained through the duration of RA-BEAM (Week 52) . This obPublications of clinical trials in RA traditionally evaluate pain improvement only as central tendencies . To our knowledge, no prior reports have more fully characterized treatment effects or explored the relationship between the control of pain and inflammation with treatment. The objectives of this analysis were two-fold: first, to use the RA-BEAM data to assess the proportion of patients who achieve pain relief thresholds and the time needed to achieve these thresholds, and second, to investigate the relationship between inflammation and patient-reported pain.The design and procedure of RA-BEAM have been described previously ,8. BriefPatients were ≥18 years old with active RA  ≥6 mg/L). Patients had an inadequate response to MTX and either ≥3 joint erosions (based on radiographs), or ≥1 joint erosion with seropositivity for rheumatoid factor or anti-citrullinated peptide antibodies .Pain was measured with the patient’s assessment of pain visual analog scale (VAS), consisting of one question, “How much pain are you currently having because of your rheumatoid arthritis?” Responses range from 0 mm (no pain) to 100 mm (worst possible pain). The pain VAS was administered at every study visit.Our initial observation of differential pain response between baricitinib and adalimumab was based on mean change from baseline. We wanted to understand if these differences persisted when pain relief was evaluated against various thresholds of success, as is typical for other patient-reported outcomes in RA. Because there are no established, standard pain thresholds in RA, we reviewed the literature and selected two approaches. First, we applied percent change from baseline threshold recommendations from the general chronic pain literature, specifically those from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), a multidisciplinary organization with the mission to develop consensus reviews and recommendations and to improve clinical trials of treatments for pain ,10. A 30The proportion of patients achieving ≥30%, ≥50%, or ≥70% improvement from baseline by Week 24 was assessed, as was the median time when 50% of patients achieved these thresholds of pain relief. The proportion of patients achieving remaining pain VAS values of ≤10 mm, ≤20 mm, or ≤40 mm was assessed at Week 24. To evaluate if the differences in pain response were associated with inflammation, we assessed the relationship between levels of inflammation and pain relief at Week 24.All analyses were conducted with an intention-to-treat approach in which data from patients who received ≥1 dose of study drug were assessed, regardless of whether they completed the trial. Missing values were imputed with modified last observation carried forward for all analyses where applicable. Analyses were not adjusted for multiplicity.Comparisons were made on the percent change in pain VAS from baseline to Week 24 using analysis of covariance (ANCOVA) and on the proportion of patients achieving pain relief at Week 24 between treatment arms using logistic models, adjusted for randomization factors ) and baseline pain VAS score. The median time needed for patients to achieve these pain relief thresholds were assessed through Week 24 using the cumulative incidence estimate with ‘competing risks’ which included rescue or discontinuation due to lack of efficacy before reaching the pain relief threshold. The Cox proportional hazards model with ‘competing risks’  ,15 was uRemaining pain was analyzed across treatment groups with logistic regression models. Pain relief at Week 24 by CRP was evaluated using ANCOVA.A mediation analysis with multiple mediators was conducted to evaluate the relationship between levels of inflammation and pain relief. The effects of change in inflammatory factors , SJC) as multiple mediators on change in pain outcome for each treatment over placebo during the 24-week period were evaluated in this analysis . The totp value < 0.05 was considered statistically significant.Statistical analyses were performed in SAS . A two-sided As noted by Taylor et al. , patientp < 0.0001). At Week 24, the mean percentage reduction in pain from baseline for baricitinib, adalimumab, and placebo, respectively, were 51%, 39%, 17% .As early as Week 1, significantly greater improvement in pain relief was observed between baricitinib and placebo  of baricitinib-treated patients achieved ≥30% and ≥50% pain relief as early as Week 4 and ≥70% pain relief at Week 8. Differences between baricitinib and adalimumab for ≥50% and ≥70% pain relief were maintained through Week 24 . Compared with adalimumab, baricitinib-treated patients were more likely to achieve ≥50% or ≥70% pain relief; the HR values for the ≥30%, ≥50%, or ≥70% pain relief thresholds, respectively, were 1.1 (p = 0.145), 1.2 (p = 0.032), and 1.3 (p = 0.003).The median time to achieve the ≥30% pain relief threshold was 2 weeks for baricitinib- and adalimumab-treated patients and 5 weeks for those on placebo . For ≥50p ≤ 0.001) at Week 4, and a difference was observed between the active treatment groups at the ≤20 mm threshold by Week 12 . For patients achieving ≥30% pain relief, baricitinib and adalimumab had similar median time to onset (approximately 2 weeks). Remaining pain is commonly reported by patients with RA despite achieving satisfactory disease control by adopting the treat-to-target approach in disease management. A threshold of ≤20 mm remaining pain is considered to represent a point where health satisfaction is not adversely affected ,12. In oTo explore the relative contribution of anti-inflammatory and other mechanisms of pain relief obtained with either baricitinib or adalimumab, we explored relationships between changes in patient-reported pain and an objective marker of inflammation, namely CRP. This analysis suggests that the difference in pain relief between baricitinib and adalimumab cannot be solely accounted for by differential effects on inflammation.While it is clear from multiple clinical studies that baricitinib has a profound anti-inflammatory effect, as would be expected of a multi-cytokine inhibitor, these observations imply that JAK1 and JAK2 inhibition also has anti-nociceptive effects that are independent of at least certain aspects of the inflammatory process . A rodenIn rodent arthritis models, autoantibodies to citrullinated proteins (ACPA) are reported to induce joint pain independent of inflammation via a chemokine-dependent mechanism . HoweverThis analysis has limitations. Specifically, the present findings represent post hoc analyses in which patients were not randomized according to their baseline pain. Pain studies may be complicated by the subjective experience of pain and the inherent limitations of a VAS as an instrument to measure pain experience. Additionally, the pain relief thresholds and remaining pain values are not yet firmly established for RA ,13. FurtPain relief with treatment may have clinical and holistic implications. Patients who experience pain relief are likely to report clinically significant improvements in other patient-reported outcomes, such as the Patient’s Global Assessment of Disease Activity and functional disability ,23. MoreThe observations from this analysis may be of importance in managing the unmet needs of adequate pain relief in RA, whether in patients attaining the treatment targets of remission or low disease activity or in those who are unable to achieve these targets with biologic anti-TNF treatment.


Very little is known about the burden of chronic low back pain in Africa. This study aimed at assessing disability and associated factors in chronic low back patients in Cameroon.We carried a hospital-based cross-sectional study including patients suffering from low back pain (LBP) of at least 12 weeks’ duration. Disability was assessed using the Roland Morris Disability Questionnaire (RMDQ). RMDQ > 4 described persons with dysfunctional levels of disability.Multivariable linear regression was used to investigate factors associated with higher RMDQ scores hence greater disability. Variables investigated included; gender, age, marital status, employment status and type, smoking history, alcohol consumption, income, pain intensity, LBP duration, psychological wellbeing, sleep satisfaction, leg pain, numbness/paresthesia, bowel/bladder dysfunction symptoms (BBDS), body mass index (BMI), and days of work absence.p = 0.002), longer days of work absence  and BBDS  were associated with greater disability. Factors such as consumption of alcohol  and higher psychological wellbeing scores  significantly contributed to less disability (lower RMDQ scores). Dysfunctional levels of disability were present in 88.1% of patients.A sample of 136 adults  with a mean age of 50.6 ± 12.2 years participated in the study. Median duration of LBP was 33 (25th – 75th percentile: 12–81) months. Mean RMDQ score was 12.8 ± 6. In multivariable linear regression, pain intensity (β = 0.07, CLBP is associated with significant disability and this relationship is driven by several factors. Multidisciplinary management strategies especially those targeted to improve pain control, manage BBDS and improve psychological wellbeing could reduce disability and improve quality of life. LBP is described as “pain, muscle tension, or stiffness localized below the costal margin and above the inferior gluteal folds, with or without leg pain (sciatica), and is defined as chronic when it persists for 12 weeks or more” .In Africa, LBP is increasingly recognised as a major health problem. A systematic review of epidemiological studies across Africa reported a pooled adult prevalence of 32% with an average lifetime prevalence 62% . This isInterestingly, though a frequent cause of clinic visits, the specific aetiology of the pain in LBP is not often identified; in which case it is referred to as “non-specific LBP”. Therefore, the first aim of the clinical evaluation is usually to situate the patient in one of three categories; non-specific low back pain, back pain with radiculopathy or stenosis, and back pain associated with another specific spinal cause . It is eAccording to the Global Burden of Disease (GBD) 2015 study, LBP is the leading cause of disability worldwide, accounting for 815 Years Lived with Disability (YLD) per 100,000 populations. This value represents a 17.2% increase since 2005 [In Sub-Saharan Africa (SSA), a Ugandan hospital based cross-sectional described significant disability in LBP patients with 87% of participants reporting up to 14 days of work loss due to LBP . In nineA number of methods assessing disability in LBP have been described in the literature, broadly classified as self-report or performance-based measures. Performance-based tests like the Isernhagen Work Systems Functional Capacity Evaluation (IWS-FCE) are thought to provide an objective representation of a patient’s functional capacity , 13, andStudies in Brazil  and in Egypt  among paCore muscle dysfunction is believed to be a major trigger for low back pain , 24. TheLike core muscle dysfunction, impaired psychological wellbeing and impaired sleep quality are recognized risk factors of LBP , while equally prolonging disability in these patients –28. FearIn Cameroon, there are no published studies exploring disability among CLBP patients. This represents an immense knowledge gap that this study sought to fill. The purpose of this study was thus to assess the level of and factors associated with disability among patients with CLBP. Our goal was to provide a better understanding of the factors that contribute to disability in CLBP patients in Cameroon in order to inform management strategies.This was a cross-sectional study conducted during January to March 2017 at the Rheumatology unit of the Douala General Hospital (DGH) in Cameroon. Three rheumatologists  are responsible for this unit. The unit runs outpatient consultations from Monday to Friday. Each rheumatologist has two consultation days, with an average of 1 or 2 rheumatologists consulting daily. Each rheumatologist consults approximately 15–30 patients a day, 20–40% of which are low back pain patients presenting either de novo or for follow-up visits. DGH is a tertiary referral and teaching hospital receiving patients from all ten regions in Cameroon and surrounding African countries. Douala, the economic capital is the most populated city of Cameroon with an estimated population of 2,768,400 in 2015 .We consecutively included adult patients aged 18–70 years with LBP of at least 12 weeks’ duration who presented de novo or for follow up visits during the study period. LBP was defined as: sensations of pain, muscle tension, or stiffness, localized below the costal margin and above the inferior gluteal folds. The area involved identified on a human diagram. Patients with pregnancy, and suspicion of cauda equina syndrome, recent trauma or LBP surgical emergencies, and patients unable to comprehend questions were excluded.Eligible and consenting participants were invited to complete an interviewer-administered semi-structured questionnaire. This was available in English and French  to serve participants expressing themselves in either language. Data on general characteristics obtained included; gender, age, marital status , employment status , employment type , smoking history , alcohol consumption (consumer or non-consumer), quantity of alcohol consumed (expressed in units per week). An “alcohol consumer” was considered to be a study participant who admitted to consuming at least one alcoholic drink in the month preceding the interview. Other data included level of education  and average monthly income .Disability was assessed using the Roland Morris Disability Questionnaire (RMDQ), a 24-item LBP-specific tool that assesses impairment in activities of daily living. The RMDQ was chosen for its low administrative burden, easy comprehensibility, proven high responsiveness and sensitivity in LBP, and the availability of validated versions in English and French . It is sPain intensity was measured with a 100 mm visual analogue scale (VAS). Participants were required to report the total duration of their CLBP by answering the question; “For how long have you had an ongoing low back pain problem?”, adapted from the recommendations of the CLBP Research Task Force of the American National Institute of Health Pain Consortium [duration of the current pain symptoms/episode by answering the question “How long has it been since you went for a whole month without low back pain?”, based on the definition of a LBP episode by Vet et al. [leg pain, numbness/paresthesia in lower limbs ; BBDS or bladder/bowel dysfunction symptoms .nsortium . They eqt et al. . This waPsychological wellbeing of participants was assessed using the psychological domain score of the World Health Organization Quality of Life brief tool (WHOQOL-BREF). This is a generic tool that assesses quality of life with six measures. The psychological domain score is computed by summing scores of seven specific items covering bodily image and appearance, negative feelings like anxiety and depression, positive feelings, self-esteem, spirituality/religion/personal beliefs, and thinking, learning, memory and concentrations. The summed score is transformed to a scale of 0–100 using the steps described in the WHOQOL manual [L manual , with hileep satisfaction was assessed by asking patients to rate their satisfaction with their sleep in the past month on a scale of 1 to 5 (1 representing ‘very dissatisfied’ and 5 representing ‘very satisfied’). This was expressed as a percentage score.Sweight and height were also measured. This was done with participants wearing light clothing and without shoes; their weight was measured using Seca® scales while height was measured with the adult Leicester® stadiometer. The stadiometers were placed against the wall, while participants stood upright without their shoes and their heels and occiput on the stadiometer. For height, measures were to the nearest 0.5 cm while for weight we considered one decimal place. Their hospital medical records were reviewed to collect information on radiologic findings and treatment.Patients’ Work absence due to LBP was denoted “days of work loss” and defined as the number of days of restricted routine activity (inability to carry out your regular activities) or absence at workplace because of CLBP occurring within the 30 days preceding the interview.This study received Ethical Approval from the Faculty of Health Sciences Institutional Review Board (2017/003/UB/SG/IRB/FHS). The components and purpose of the study were explained to all potential study participants and only those who freely gave written consent were included. Patient confidentiality was maintained and the study adhered to the World Medical Association’s Declaration of Helsinki.p < 0.1) in bivariate analysis, were then fitted in a multivariable linear regression model to determine factors independently associated with disability. Prior to fitting the multivariable model, we checked for evidence of multicollinearity in the independent variables via a correlation matrix and then ran collinearity diagnostics to assess their tolerance and variance inflation factors (VIF). All VIFs were less than 2, suggesting absence of any multicollinearity. Statistical significance was set at p < 0.05.Data were analyzed using the Statistical Package for Social Sciences  version 20. Results are summarized as counts and percentages for categorical variables and as means and standard deviation (SD) or median with 25th and 75th percentiles where appropriate for continuous variables. Standard assumptions of parametric tests  were tested; as such, we performed no data transformations. The RMDQ score was analyzed as a continuous outcome variable. We adopted a threshold score of ≥4 to report prevalence of dysfunctional CLBP, based on a previous study conducted among adult LBP patients . BivariaA sample of 136 CLBP  was included. Forty-one percent of participants had non-specific CLBP, 56% CLBP with radiculopathy/stenosis, and 3% had CLBP from a specific spinal cause. The principal specific aetiologies encountered in participants are described in Fig. The median (IQR) duration of CLBP was 33.0 (69) months. The median duration of current pain symptoms was 12 months and median pain intensity was 40 mm (39). The mean disability score was 12.5 ± 6. RMDQ > 4 was found in 88.1% of participants. Average work lost days was 6 ± 10 days in the previous month due to LBP . There were weak positive relationships between duration of the current pain episode , patients age  with disability. However, sleep satisfaction  and psychological wellbeing  negatively correlated with disability scores .As stated we used One-way ANOVA and employed the Tukey post hoc criterion for significance. Our findings indicated that the mean RMDQ was significantly higher in the widowed 16.9 ± 4.6) when compared to the married 12.5 ± 6.1) or single 11.5 ± 6.3); and in persons with no formal education when compared to those with tertiary education (23.0 ± 1.4 vs. 11.3 ± 5.6). Non-consumers of alcohol; persons with BBDS; and those with leg pain equally had higher mean RMDQ scores when compared with counterparts without , days of work absence , psychological wellbeing , alcohol consumption , and bowel/bladder dysfunction , Table In the multivariable linear regression model, the factors that were independently associated disability were; pain intensity , pain intensity was independently predictive of disability in aged adults with LBP . SimilarApproximately one third of LBP patients have been found to have sphincter dysfunction , 41. HowPsychological factors are known to influence disability in LBP , 42, 43.This study had a number of limitations. First, the use of a cross-sectional study design limited the establishment of temporality or causal relationships, which would have been possible with a prospective cohort design. However, our study revealed associations that can serve as benchmark in the design of future studies. Secondly, our study may be prone to selection bias owing to the non-random sampling and hospital-based nature of the study. It is thus likely that our findings may not reflect the situation of CLBP patients at other health facilities across the county. Interpretation of our results in terms of generalizability must therefore be done with caution.Nevertheless, we have used rigorous statistical methods to explore the burden and factors associated with disability in patients with chronic low back pain. Our study to the best of our knowledge is the first in Cameroon to investigate the disability and chronic low back pain relationship and thus may serve as framework for further research.Evidence from this study has confirmed that CLBP is associated with significant disability and work loss. Improved psychological wellbeing was associated with less disability, while longer work absence, BBDS and not consuming alcohol were associated with greater disability. Our findings provided context-specific evidence to guide priority setting in prevention and treatment strategies to reduce the burden of low back pain. Larger and robust population-based studies are warranted to fine-tune our findings.


Background and purpose — Anterior knee pain is common after tibial nailing. Its origin is poorly understood. Injury of the infrapatellar nerve is a possible cause. In this randomized controlled trial we compared changes in knee pain after an infrapatellar nerve block with lidocaine or placebo in patients with persistent knee pain after tibial nailing.Patients and methods — Patients with chronic knee pain after tibial nailing were randomized to an infrapatellar nerve block with 5 ml 2% lidocaine or placebo (sodium chloride 0.9%), after which they performed 8 daily activities. Before and after these activities, pain was recorded using a numeric rating scale . Primary endpoint was the change in pain during kneeling after the infrapatellar nerve block. Secondary outcomes were changes in pain after the nerve block during the other activities.Results — 34 patients (age 18–62 years) were equally randomized. A significant reduction of the NRS for kneeling pain with an infrapatellar nerve block with lidocaine was found compared with placebo . There were no differences between the treatments for the NRS values for pain during other activities.Interpretation — Compared with placebo, an infrapatellar nerve block with lidocaine was more effective in reducing pain during kneeling in patients with chronic knee pain after tibial nailing. Our findings support the contention that kneeling pain after tibial nailing is a peripheral nerve-related problem. The common treatment for tibial shaft fractures is intramedullary nailing. A drawback of this procedure is anterior knee pain  between June 2000 and December 2016, were selected from St Elisabeth Hospital , Gelderse Vallei Hospital , and Erasmus Medical Center . Nailing or nail removal had to be more than 6 months ago. 601 patients with a tibial shaft fracture were treated with an intramedullary nail introduced through a longitudinal infrapatellar incision during the specified period . After application of the exclusion criteria, 407 patients were potentially eligible for trial participation. These patients were sent a numeric rating scale (NRS) to rate knee anterior pain during 8 different daily activities . If the patient did not reply, telephone calls were attempted. Pain scores were returned by 233 patients. Criteria for inclusion in the trial were an NRS of 4–6 (moderate pain) during at least 3 out of 8 activities or an NRS of 7 or higher (severe pain) during 1 or more activities. 79 patients met these criteria, of whom 34 agreed to participate in the study.Eligible patients who agreed to participate in this study were seen at the outpatient clinics of the participating hospitals. Trauma characteristics, data concerning the initial procedure and nail removal were gathered retrospectively. Length of the longitudinal incision was measured on a flexed knee in mm using a tape measure and localization of the incision was noted . Sensory disturbances  in the area of the infrapatellar nerve  were tested using a cotton swab, comparing the non-operated leg with the operated leg and the surrounding dermatomas. Baseline pain (T0) was scored using an NRS during 8 activities, which were all supervised by an examiner (SJMK or MSL). The NRS measures pain severity by asking the patient to select a number (from 0 to 10) to represent how severe the pain is, where 0 represents “no pain” and 10 represents “worst pain possible.” This rating scale has shown to be valid, reliable, and appropriate for use in clinical practice  were used for the nerve blocks. 2 syringes were prepared, marked with number 1 or 2 according to the allocation, and checked by a doctor not involved in the trial. The name and date of birth of the participant were written on the envelope. As both fluids were colorless and odorless, both patient and examiner remained unaware of which treatment was administered.An infrapatellar nerve block was performed freehand by depositing 5 mL of the solution in a fan-like manner subcutaneously between the medial surface of the medial femoral condyle and the medial aspect of the patellar tendon, including the incision. After 5 minutes patients completed the 8 activities under supervision and NRS scores were subsequently obtained (T1). Thereafter, each patient crossed over and was injected with the alternate treatment (T2). Time between injections (wash-out period) was approximately 30 minutes.Kneeling is the most frequently and painful activity reported after tibial nailing . Skewed data are presented as median (range). Differences between the 2 groups were tested using Student’s t-test  or Mann–Whitney U test (skewed distribution) for continuous variables. The method described by Hills and Armitage for two-period cross-over clinical trials was applied . Written informed consent was obtained from all patients. Participants did not receive compensation of any kind. The study was not funded by any source. The authors have no competing interests to declare.Approval was obtained from the central medical research ethics committee and the institutional board of all participating hospitals (NL34510.008.11/P1142 2016/07/20). The study was registered with the Dutch trial registry , after the first nerve block (T1), and after the second nerve block (T2) are displayed in Treatment effects (decline in median pain scores) were significant for kneeling (p = 0.02), squatting (p = 0.03) and sitting with bent knees (p = 0.001). However, a period effect was present for the primary endpoint kneeling , meaningFor kneeling a significant decline in median pain scores remained after a nerve block with lidocaine compared with placebo . There was no statistically difference between the groups during squatting, sitting with bent knees, jumping, walking stairs, running, walking, and rest (data not shown).The purpose of this study was to compare changes in knee pain after a subcutaneous lidocaine block of the infrapatellar nerve or placebo in patients with chronic anterior knee pain after tibial nailing. For kneeling a significant reduction in pain scores was found after an infrapatellar nerve block with lidocaine.The effect of lidocaine usually lasts about 1–2 hours and with a wash-out period of about 30 minutes one can presume that the effect of the lidocaine injection persists during the second treatment period. We expected that pain scores in the lidocaine-first group would reach their utmost lowest levels after injection and only minimal changes would occur after the second injection with saline. Pain scores in the placebo-first group were expected to decline only minimally after the first injection and decline further after lidocaine injection; a difference in change scores would then still be observed. However, data analysis showed a period effect for the primary endpoint, meaning the effect of the treatment was different in the first period (T1–T0) from the effect in the second period (T2–T1). This can easily be explained by the short wash-out period. Also, both the patient and the examiner were blinded to the treatment given. Due to the local effect lidocaine has on the skin, patients may recognize this effect. This affects true blinding and might also have affected the pain scores.Although pain during kneeling was reduced in both groups, pain was not totally diminished and no statistically significant reduction was seen for pain during the other activities . A possible explanation is that not all patients were able or willing to do these activities, which affected the statistical power. Moreover, the starting pain level was lower than in other activities, thus a smaller effect size can be expected. The study could be underpowered for these activities; however, they were not the primary outcome. In some patients pain can be multi-modal and might as well have originated from intra-articular injury  who returned their NRS indicated they had either moderate or severe knee pain during several activities after a median follow-up of 7.1 years (0.5–14). Although there might be some selection bias due to selective response to the initial questionnaire, this percentage is in concordance with the long-term results of Lefaivre et al  and LeliKneeling pain is frequently mentioned to be the most painful activity  in 29/34 of the patients. Iatrogenic injury to the infrapatellar nerve is one of many concepts regarding the origin of anterior knee pain after tibial nailing. The course of the infrapatellar nerve makes it susceptible to iatrogenic injury during nail insertion, especially when longitudinal infrapatellar medial and midline incisions are used (Kerver et al. Although pain scores declined for all activities at the end of the study, actual function and effect on function were not assessed. Sudden improvement of functional outcome was, however, not expected in patients who sustained knee pain for several years. Long-term improvement in function after infrapatellar nerve block has been reported though (Hsu et al. The incidence of persisting anterior knee pain after tibial nailing is high and we provide arguments for the hypothesis that iatrogenic injury to the infrapatellar nerve contributes to this problem. Patients suffering from this complication who response well to an infrapatellar nerve block with lidocaine might benefit from denervation (Dellon et al. In summary, compared with placebo, an infrapatellar nerve block with lidocaine was more effective in reducing pain during kneeling in patients with chronic knee pain after tibial nailing through a longitudinal infrapatellar incision. Our data support the contention that kneeling pain after tibial nailing is a peripheral nerve-related problem.


N-methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent.Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through  The fN-methyl-D-aspartate (NMDA) glutamate receptors follows, with phosphorylation of the GLUN1 and GluN2B subunits being the key molecular drivers [−/− knockout mice showed diminished central sensitization-mediated nociceptive behaviours but retained normal nociceptive processing The consensus of preclinical laboratory studies is that synaptic plasticity in spinal cord neurons, particularly increased glutamatergic excitatory neurotransmission, is thought to be a major mechanism underlying central sensitization that contributes to pain hypersensitivity . This fo drivers . BlockinOur recent preclinical studies have shown that the orally-active Src inhibitor saracatinib  has potential use as an analgesic in cancer-induced bone pain, as it reversed some of the pain behaviours evoked by intra-tibial injection of mammary cancer cells in rats 2Prior to opening for recruitment, the study was registered on the European Clinical Trials database (EudraCT number 2013-00250562). A favourable ethical opinion was obtained from the local office (Yorkshire & The Humber) of the National Research Ethics Committee of the UK Health Research Authority (13/YH/0623) and clinical trial authorization was obtained from the UK Medicines and Healthcare Regulatory Authority (CTA number: 21304/0249/001-001).2.1Participants were recruited from either out-patient clinics in a specialized Oncology Hospital  or from a palliative care Hospice . Potential recruits were identified by screening clinical records to identify patients with bone metastases (primary screen) and then at individual consultations with their Oncologist/Palliative Care physician (secondary screen) to identify patients that had sub-optimal control of bone pain with their existing medication. There were no limits on the type or dose of existing pain relief medications that patients were taking to be eligible for recruitment and patients taking maintenance chemotherapy were also able to participate. Patients that had previous/planned radiotherapy to the site of their pain had to be at least one month post-treatment to be eligible for recruitment and no new treatments/medications were permitted during the study.9/L, platelet count ≥100 × 109/L, bilirubin ≤1.5 x upper limit of normal (ULN), alanine transaminase or aspartate transaminase ≤2.5 x ULN (≤ 5 x ULN if liver metastases), creatinine ≤1.5 x ULN.Inclusion criteria were: (1) cytologically or histologically confirmed solid tumours or multiple myeloma with painful bone metastases and poor control of bone pain in spite of pain medication. Prostate cancer patients without histology or cytology were eligible for recruitment if their prostate specific antigen was >100 ng/mL at diagnosis and a bone scan confirmed skeletal metastases; (2) baseline average pain ≥2 and ≤9 on a 0–10 numerical scale recorded on at least two separate days using the Brief Pain Inventory-Short Form; (3) WHO performance status ≤2; (4) age ≥16 years; (5) ability to take and absorb oral medications; (6) able to give written informed consent and willing to follow the study protocol; (7) adequate baseline haematological, hepatic and renal function, which was defined as: Haemoglobin >9.0 g/dL (including after transfusion), absolute neutrophil count ≥ 1.5 × 10Exclusion criteria were: (1) life expectancy <3 months; (2) previous or planned radiotherapy at site of pain within one month of first dose; (3) unstable cardiac disease in last 3 months; (4) history of interstitial lung disease; (5) unable to discontinue any medication with known moderate or potent inhibitory effect on CYP3A4, or is a substrate of CYP3A4; (6) concomitant cytotoxic chemotherapy unless established on maintenance treatment for > 6 weeks ; (7) unable to understand written or spoken English.2.2The study was a two-centre, parallel group randomised controlled phase II trial designed to assess whether the Src kinase inhibitor saracatinib had efficacy as an analgesic when compared to placebo using cancer patients’ self-reported pain scores. The primary objective was to determine if patients’ self-reported pain scores were significantly lower  after 4 weeks of treatment with saracatinib than with placebo, using questions 3 (worst pain in last 24 h), 4 (least pain in last 24 h), 5 (average pain), and 6 (pain right now) of the Brief Pain Inventory - Short Form BPI-SF . SecondaTo determine if analgesic drug usage decreased when patients took saracatinib, analgesic usage data for the previous 24 h period was collected at screening and each clinic visit. The doses of all opioids were converted to an overall equivalent dose of oral morphine . Oral morphine equivalent at the start of the study was compared to OME at the end to determine whether this changed whilst on treatment, the rationale being that if the study medication provided additional pain relief then patients might reduce their dose of other pain medications. Pain-related symptoms and quality of life at the beginning and end of the study were compared using summary data scores from the QLQ-C30 questionnaire and the painful characteristics and painful sites scores from the QLQ-BM22 questionnaire. Bone turnover was assessed by measuring markers of bone resorption  and bone deposition  in either serum  or urine (uNTX/CR) samples n = 12 is thought to be sufficient n = 12/group and a population standard deviation of 2.6 points in pain scores in patients with cancer pain  with a minimally clinically important difference of 2-points α = 10%, (acceptable as only a reduction in pain scores was desirable and the study was exploratory) gives a power of 72%. By comparison, a two-sided significance level of α = 5% gives only 50% power with the same group size.For an exploratory study such as this, a group size of 2.3Patients that wished to participate in the study were screened to ensure that they satisfied all of the inclusion criteria and none of the exclusion criteria. Screening was done by experienced research nurses 7–14 days prior to randomization, and as well as confirming eligibility criteria, baseline samples for sCTx, PINP and uNTX/CR were taken and the BPI-SF, EORTC QLQ-C30 and BM22 questionnaires administered. To confirm that baseline pain scores were within the eligibility criteria, each potential recruit completed a daily BPI-SF questionnaire for 7 days and mean pain scores calculated using question 5 (pain on average). Patients that were eligible to enter the trial and who wished to participate gave informed written consent and were randomized to either saracatinib or placebo. Patients were randomized on a 1:1 basis using block randomization with a block size of 4; the randomization schedule was created by the company that prepared the treatment kits . Each randomized patient was assigned a unique code that was replicated on individual patient treatment kits; the patient, the Investigator that randomized the patient and the pharmacist that dispensed the treatment kit were all blinded to the treatment assigned. Randomisation codes were assigned strictly sequentially and if a subject withdrew from the study before completion their randomization number could not re-used. At randomization a venous blood sample was taken as a baseline for pharmacokinetic studies.Patients randomized to saracatinib received 125 mg once per day for 28 days in tablet form. This dose of saracatinib is lower than the maximum tolerated dose in patients with advanced solid malignancies (175 mg) and has an emerging safety profile that was considered to be acceptable for testing in this patient population with appropriate safety monitoring during the trial Treatment commenced at randomization (day 1) and patients completed the BPI-SF daily for 7 days after 1 week on study (days 8–14). At a clinic visit on day 15, performance status and haematological/hepatic/renal function were checked to confirm patients were still eligible to participate. Blood and urine samples were taken for sCTX, PINP, uNTX/Cr and pharmacokinetic testing and the BPI, EORTC QLQ-C30 and BM22 questionnaires administered. Analgesic usage was reviewed, any changes since screening documented and OME calculated for the previous 24 h. Adverse events were also documented. Patients remained on treatment for 2 more weeks and completed the BPI-SF daily during the last week of the study (days 22–28). A final clinic visit occurred on day 29; as before performance status and haematological/hepatic/renal function were checked, blood and urine samples were taken for sCTX, PINP and uNTX/Cr analysis, the BPI-SF, QLQ-C30 and BM22 questionnaires administered and analgesic usage was reviewed, any changes since screening documented and OME calculated for the previous 24 h. Adverse events were also documented. A telephone interview 30 days after the last clinic visit was performed to identify any further adverse events that occurred after stopping treatment.2.3.1Blood samples for haematological, hepatic and renal function were analysed immediately after collection for saracatinib safety monitoring; samples for bone biomarker turnover and pharmacokinetic analysis were prepared and frozen at -80 °C then analysed in batches. Serum (for sCTX and PINP measurement) was prepared from venous blood that was allowed to clot at room temperature for at least 30 min, centrifuged at 1300 g for 15 min and aliquots frozen. Plasma (for pharmacokinetic studies) was prepared by centrifuging venous blood collected in lithium heparin tubes at 1000 g for 10 min within 30 min of collection, aliquoted and frozen. Urine samples  were frozen until analyzed.Saracatinib levels were measured in plasma samples using liquid chromatography-mass spectrometry  using an ABI5000 mass spectrometer . The lower limit of the assay was 0.5 ng/mL and the upper limit was 500 ng/mL. Bone biomarkers were analysed as described previously 3During the period September 2014–August 2017, 36 patients were identified that were eligible to participate: 15 of these gave written consent, 13 were randomized and 12 patients completed the study . The comPatients randomized to saracatinib 125 mg/day had plasma concentrations of drug in the range 80–190 ng/ml ; this is comparable with other studies performed on this patient population [3.1Comparison of patients’ self-reported pain scores after 4 weeks of treatment are shown in On the basis of improvement in pain symptoms after 4 weeks of treatment of at least 2 units on a 0–10 scale, 2 patients in the placebo-treated group and 3 patients in the saracatinib-treated group went on to extended use of study medication for up to 5 months. One of the saracatinib-treated patients initially declined extended use, but later requested extended use when her pain increased after the study ended. An unblinded pharmacist ensured that patients on extended use continued to receive the same medication that they were randomized to on day 1.3.2There was wide variation in OME intake across patients, which was due to the diversity of drugs that patients were prescribed for pain management as well as inter-individual differences in dosing. In the placebo-treated group mean OME at randomization was 130 ± 153 μg/day (range 3–340) and 138 ± 167 μg/day at the end of the 4 week study (range 12 – 340). Equivalent figures for the saracatinib treated group were 210 ± 352 μg/day at randomization (range 18–920) and 207 ± 327 μg/day at the completion of the study (range 5–860). The data indicate that 4 weeks of daily saracatinib treatment at a dose of 125 mg/day had no effect on patients’ consumption of regularly prescribed pain medication.3.3Quality of Life was assessed using 4 scores from the QLQ-C30 and QLQ-BM22 questionnaires developed by the European Organisation for Research and Treatment of Cancer ,4: C30 g3.4p < 0.01, Kruskall–Wallis ANOVA). This effect on bone resorption is in keeping with the known action on osteoclasts of Src inhibitors [We studied two biomarkers of bone resorption, sCTX; and uNTX/Cr and one biomarker of bone deposition, PINP. Four patients in the placebo-treated group had a history of anti-resorptive medication treatment (three with bisphosphonates and one with the RANKL inhibitor denosumab) and three of these continued to receive treatment during the study (2 bisphosphate and 1 denosumab); in the saracatinib group 3 patients had a history of bisphosphonate treatment  and two of them continued with bisphosphonate treatment during the study. Patients taking saracatinib showed a significant reduction in levels of serum CTX over time, with a median reduction of 31% below baseline on day 29  and needed observation only and no intervention (CTC grade 1), 14% were grade 2 adverse events and there was one grade 3 event that required hospitalization . In the saracatinib-treated group, the majority of the adverse events (73%) affected the gastrointestinal system, with 13% being neurological and 9% fatigue, in keeping with the known adverse event profile of saracatinib 4The current study showed that 4 weeks of treatment with saracatinib did not have a clinically-significant effect on self-reported bone pain scores in patients with symptomatic skeletal metastases. The lack of analgesic efficacy of saracatinib is unlikely to be due to inadequate dosing, as plasma concentrations of drug were similar to published phase I studies ,40 and iin vivo inhibition of phosphorylation of the GluN1 subunit of the NMDA receptor by saracatinib in a preclinical model of cancer-induced bone pain; saracatinib also inhibited osteoclastic bone resorption without affecting osteoblastic bone formation in vivo, or that central sensitisation was not the dominant pain mechanism in the patients that were recruited. It is known that osteoclastic inhibitors such as bisphosphonates have some analgesic effect e.g. denosumab vs. zoledronic acid was 6 months longer for denosumab Clinical studies support the contention that some of the pain symptoms that are reported by patients with bone metastases are due to changes in sensory processing within the central nervous system ,42. Givesrc gene deleted (Src−/−) show abnormal development of bones and teeth with an osteopetrosis-like phenotype As well as defects in pain processing UK Medical Research Council through the “Mechanisms of Human Disease” initiative (MR/K015052/1), in collaboration with AstraZeneca. AstraZeneca provided placebo and saracatinib tablets and knowledge on saracatinib. We are indebted to the patients that took part in this study.This work was funded by the Sarah Danson: Conceptualization, Funding acquisition, Investigation, Supervision, Writing - review & editing. Matthew R Mulvey: Investigation, Writing - review & editing. Lesley Turner: Data curation, Project administration. Janet Horsman: Data curation, Project administration. KJane Escott: Methodology, Resources, Writing - review & editing. Robert E Coleman: Conceptualization, Funding acquisition, Writing - review & editing. Sam H Ahmedzai: Conceptualization, Funding acquisition, Writing - review & editing. Michael I Bennett: Investigation, Project administration, Supervision, Writing - review & editing. David Andrew: Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing.S Danson has received fees from Amgen for giving lectures.KJ Escott is an employee of AstraZeneca.RE Coleman is co-inventor and patent holder of a bone biomarker under development by Inbiomotion, has received fees for advising on clinical trial protocol development from Amgen, Astellas and Boehringer Ingelheim as well as for independent medical education lectures at symposia supported by Amgen, Genomic Health and Eisai.SH Ahmedzai has received support for undertaking cancer pain studies, giving lectures or for consultancy from Grunenthal, Menarini, Mundipharma and PfizerThe remaining authors have no declaration of interests.


Despite introducing novel analgesics, pain management for spine surgery remains a challenge. Multimodal pain control has recently gained popularity in surgical spine care. We proposed a novel management approach using multimodal cocktail analgesics. Injection to skin surrounding surgical incision site will be given perioperatively. This study evaluates the safety and efficacy of cocktail analgesic injection on pain management following lumbar spinal fusion surgery.Thirty-six patients with degenerative lumbar spinal diseases on the waiting list for lumbar spinal fusion surgery will be recruited. Patients will be randomly assigned to receive either cocktail analgesic injection or sterile saline before surgical wound closure. All patients will routinely receive postoperative intravenous patient-controlled analgesia (IV-PCA) with sufentanil on an as-needed basis without a basal dose. The primary outcome is perceived pain intensity as measured by visual analog pain score. Secondary outcomes include sufentanil consumption, time to first use of IV-PCA, rescue analgesics consumption, and the presence of adverse effects. Findings of this interventional trial will provide novel evidence supporting the superior effect of cocktail analgesic injection during surgery.ChiCTR-IPR-17013094. Peripheral and central sensitization further aggravates postoperative pain. Postoperative pain reduces patients’ satisfaction and substantially affects recovery, increases postoperative morbidities, and prolongs the length of hospital stay.Patients undergone major spine surgery frequently experience severe pain after operation, lasting for more than 3 days. While epidural and intravenous routes of drug administration may achieve analgesia,–8 these costly procedures demand specialized skills and may confer nausea, vomiting, pruritus and urinary retention, respiratory depression, and neuraxial hematoma.–11 In contrary, administration of local wound injection surrounding incision does not require highly trained personnel. This localized injection also facilitates drug delivery to the area of surgical wound and minimize systemic exposure.–14 We propose a novel multimodal analgesic regimen containing several medications, designated cocktail analgesics, which are injected surrounding the surgical incision perioperatively. This study aims to evaluate the efficacy of cocktail analgesics for postoperative pain management amongst patients having 2-levels underwent lumbar spinal fusion surgery. We will determine if cocktail analgesic injection would provide satisfactory postoperative analgesia.Adequate postoperative pain management is essential to improve functional outcome, accelerate early ambulation, shorten the duration of hospital stay, and prevent subsequent development of chronic postsurgical pain. Different postoperative analgesics are available in various forms of administrative routes. Mechanisms contributing to postoperative pain in spine surgery are multifactorial. In this connection, single analgesic may be inadequate to achieve desirable outcomes. Compared with conventional analgesia, multimodal analgesia has recently gained popularity. This therapeutic approach combines different analgesics with multiple routes of administration to better optimize pain relief and minimize undesirable side effects and complications.22.1This is a single-center, prospective, double-blinded, randomized controlled trial. The protocol will be performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Peking Union Medical College Hospital. Written informed consent will be obtained from each patient before enrollment. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-17013094). An overview of the trial design is shown in Figure 2.2Our center is a tertiary referral hospital for spine surgery with the necessary types and volume of clinical cases required for this study. The research team comprises a chief spine surgeon and a team of experienced surgeons, nurses and allied health staff.2.3Patients on the lumbar spinal fusions waiting list at Peking Union Medical College Hospital (PUMCH) will be invited to participate in this study. After initial screening, potentially eligible patients will be given a plain Chinese statement detailing the nature of the study and the commitment required. A trained researcher will obtain informed consent from eligible candidates who are willing to participate. Identified participants will be approached for inclusion in the study according to predefined inclusion and exclusion criteria.2.4(1)Age between 18 and 70 years.(2)On the surgical waiting list for primary 2-level lumbar spinal fusion surgery diagnosed with lumbar spinal stenosis or lumbar disc herniation.(3)American Society of Anesthesiologists physical status I∼II.(4)Understand and comply with the study protocol.2.5(1)History of hypersensitivity to parecoxib, ropivacaine, diprospan, fentanyl, or sulfonamide.(2)Perioperative period of coronary artery bypass surgery.(3)Pregnant, lactating, or probably pregnant.(4)Revision surgery or surgery for neoplastic disease.(5)Inability to provide informed consent due to mental incompetence2.6Random assignment will be performed before surgery using a computer-generated, block random-allocation sequence with a 1:1 ratio. Allocation concealment will be achieved using opaque sequentially numbered sealed envelopes. The research staff will record the patients’ details.2.7The cocktail analgesic or equivalent volume of saline is prepared by pharmacy independent to the trial in an aseptic fashion. Both the attending surgeon and the patients will be blinded to the group allocation. Data will be collected by research staff blinded to group allocation. Upon completion of the study, a biostatistician blinded to group allocation will analyze outcome data.2.8All patients will be randomized using a computer-generated list to 1 of 2 groups, 1 of which will receive subcutaneous injection of cocktail analgesic at final wound closure during surgery (cocktail group). Control group patients will receive equivalent volume of saline. The same surgeon will perform all operations. All patients will undergo 2-level posterior lumbar spinal fusions with pedicle screws and rod fixation.2.9Cocktail solution will contain ropivacaine 1%, 200 mg (20 ml), parecoxib 40 mg, betamethasone 7 mg (1 ml), mixed with normal saline into a total volume of 50 ml.2.10In the cocktail group, cocktail analgesics will be injected surrounding the deep fascia and the muscular layer in the surgical wound before final wound closure. A total of 35 ml trial solution will be used. Postoperative analgesia will be provided by intravenous patient-controlled analgesia (IV-PCA) delivering sufentanil 2 μg in each bolus, with a 15-minute lockout interval. No basal infusion will be used. PCA pump will be removed in 48 hours after surgery.2.11In the control group, an equal volume of saline (35 ml) will be injected to the deep fascia and the muscular layer in the surgical wound in the same fashion as the cocktail group. IV-PCA will be provided in the same mode.2.12Surgery will be performed under general anesthesia with standardized fashion. A standardized intraoperative strategy for fluid management will be applied which consists of 0.9% saline at 5 ml/kg/h and hydroxyethyl starch colloid at 7.5 ml/kg/h. At the end of the surgery, the PCA pump will be started on without a basal dosage, which will be removed 48 hours later. After surgery, patients will be taken to the recovery room and monitored according to standard hospital policy. Patients will be educated with the use of the PCA device and discharged to the ward, once recovery room discharge criteria have been met. Patients will receive supplemental oxygen via nasal cannula at 2 l/min for 24 hours. The time to first mobilization will be recorded and the patient will continue to be monitored until discharge. Any serious adverse events (SAEs) will prompt follow up. Patients will be followed up routinely at 4 weeks after discharge by the spine specialist. Symptoms of nerve damage will be actively sought at this consultation.2.13Patients who require an additional analgesic after PCA removal will be provided with tramadol 50 mg intramuscularly route each time. Usually, the need for supplementary treatment with systemic opioids is a reliable indicator when concerned about postoperative pain control. Having considered that the use of strong or long-term rescue analgesia in both groups may reduce pain too much and “washed out” any differences between the 2 groups. In this study, we use tramadol hydrochloride injection for rescue analgesia, which is a mid-intensity opioid analgesic that will facilitate observing the differences in pain control between groups. The frequency and total dosage during the first 3 postoperative days will be recorded.2.142.14.1Schedule for data collection is shown in Table –17 Postoperative pain at 6, 12, 24, 36, 48, and 72 hours after surgery will be recorded using the VAS pain scores. The VAS consists of a 10-cm horizontal line with 1-cm vertical lines at each end on which a score of 0 indicates no pain and a score of 10 indicates the worst conceivable pain. All data are verified against original documents by individuals who are independent of the trial.The VAS has been used extensively for rating pain intensity in previous studies.2.15The primary outcome was the average pain score over the incision site from the time of surgery up to 3 postoperative days after surgery2.162.16.1Sufentanil consumption of IV-PCA during the first 48 hours postoperatively will be recorded.2.16.2The time to first use of IV-PCA and proportion of the patients during the first 48 hours postoperatively will be recorded.2.16.3The frequency and total dosage of the rescue analgesics (tramadol hydrochloride injection) during the first 72 hours postoperatively will be recorded.2.16.4The presence of side effects during the entire postoperative period will be recorded, including nausea, vomiting, and other adverse events and complications.2.17The sample size calculation was based on the following parameters:(1)alpha value = 0.05, 2-sided;(2)power = 80%.The minimal clinical significance in VAS pain score was defined as the mean difference between current and preceding scores when the subject reported “a little worse” or “a little better” pain. Our pilot study shows that VAS pain scores 72 hours after lumbar spinal fusion surgery were reported to be 2.1 ± 1.6 in patients receiving cocktail analgesic injection and 5.6 ± 1.7 in patients without. Based on these findings, we hypothesized that VAS pain score 72 hours after surgery will be 2.5 for the cocktail group and 5.0 for the control group, with a standard deviation set at 2.5 and a ratio of patients in the cocktail to the control group of 1:1. Calculations showed that a sample size of 14 patients per group to detect a difference in VAS pain score between the 2 groups after treatment. Assuming a 20% dropout rate, 18 patients per group, or a total of 36 patients, are required.It is anticipated that recruitment for this study will take 6 months to complete, using 1 surgeon to reduce surgical variability. Data collection for each patient will occur during the first 72 hours postoperatively and at a routine 4-week follow-up appointment. No further follow up will be routinely arranged. Any patients requiring specific follow up will have this arranged on an individual basis.2.18This is a 6-month study commencing January 2018 and ending June 2019. See Table 2.19Every effort will be made to retain patients in the trial and to minimize withdrawals. However, the trial will be discontinued on condition that any SAEs happen. Additionally, patients may request to be withdrawn from this study at any time without any reason. Intention to treat and “as treated” analyses will be performed.2.20All adverse events will be recorded and discussed at weekly safety meetings by at least 2 investigators. If clinically indicated, the nature of the analgesia administered in the study may be revealed. After assessment by the Principle Investigator, any SAEs will be reported to the Ethics Committee in PUMCH. All SAEs will be also reported to the China Food and Drug Administration by the Ethics Committee.2.21t test and Mann–Whitney U test for parametric and nonparametric data, respectively. Pearson Chi-square will be used for categorical variables. In strata where the expected counts are less than 5, Fisher exact test will be used. Univariate logistic regression and simple linear regression will be performed to determine potential predictors associated with binary outcomes and continuous outcomes, respectively. For predictors significantly associated with the outcomes of interest (P < .1), they will be further examined for co-linearity using Chi-square test, 0-order Pearson product-moment correlation, or Student t test as appropriate. For continuous variables with variable inflation factor greater or equal to 10, only 1 variable will be kept for subsequent analysis. After removing redundant co-variates, multivariate regression models will be built. The goodness-of-fit of the final models will be determined by the Hosmer–Lemeshow test (logistic regression) or R2 (multiple linear regression), respectively. For time-to-event outcomes, multivariate Cox proportional hazard regression models will be built. The cumulative probability of an outcome event over time will be presented in form of Kaplan–Meier curves.Data distribution will be tested for normality using the Shapiro–Wilk test. Skewed data will be corrected by logit-transformation as appropriate and subsequently examined using parametric test in order to preserve statistical power. For data set that cannot be normalized by logit-transformation, nonparametric test will be applied. Group comparison will be done by Student P-value less than .05 will be considered as statistical significance. All statistical analyses will be 2-tailed and performed using Statistical Package for Social Sciences .To determine changes of analgesic consumption and pain score over time between groups, a generalized estimating equation population average regression will be used. To correct for ceiling effect of analgesic consumption on pain score reporting, an empirical logit transformation will be applied in before comparison between groups. For missing data less than 10%, imputation will be performed using median for continuous and ordinal variables. For nominal variables, the most common category will be imputed. If there are more than 10% missing data, multiple imputation will be used. Intention-to-treat and per-protocol analyses will be performed to account for possible missing data. 2.22The study has been approved by the Ethics Committee of Peking Union Medical College Hospital. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-17013094). On completion of the trial, the findings will be analyzed and tabulated. Results of the trial will be submitted for publication in a peer-reviewed journal.3 However, no optimal regimen for pain control after spine surgery has been found. Therefore, we design a novel multimodal analgesic regimen for wound infiltration. Ropivacaine is a propyl analog of bupivacaine with longer duration of action and reversibly inhibits sodium ion influx in nerve fibers. It has lesser proclivity to penetrate large myelinated motor fibers compared with bupivacaine due to its low lipophilic nature. This is responsible for differential sensory blockade of ropivacaine with less central nervous system and cardiac toxicity compared with bupivacaine. Parecoxib is a selective COX-2 inhibitor shown to be as effective as traditional NSAIDs as an analgesic for acute postoperative pain whilst having fewer gastrointestinal side effects than traditional NSAIDs, such as diclofenac and ibuprofen.–21 Moreover, parecoxib has no effects on serum thromboxane and platelet functions, suggesting that it may be an effective postoperative analgesic. Betamethasone produce strong anti-inflammatory action. This study hypothesized that cocktail analgesic injection could provide superior postoperative analgesia after lumbar spinal fusion surgery. In addition, this route of administration is safe, convenient, and general-purpose way in practice. To date; however, no comparative data are available. Therefore, we believe that this study will provide some insight into perioperative multimodal analgesia, which helps to improve perioperative clinical practice.To maximize postoperative pain relief, enhance patient satisfaction, and facilitate rehabilitation after surgery, pain management is indispensably important. Multimodal analgesia for pain management after surgery has been shown effective.Data curation: Zhinan Ren, Lin Sheng, Xin Chen, William Ka Kei Wu, Matthew T.V. Chan, Jeffery Ho.Formal analysis: Derong Xu.Software: Zheng Li.Supervision: Shugang li.Writing – original draft: Zhinan Ren.Writing – review and editing: Shugang li.