A number of studies have demonstrated an association of neuropathic pain and chronic low back pain (CLBP), but the outcome difference in each medical management is poorly understood. This study is aimed to investigate treatment patterns of neuropathic pain in CLBP patients and to explore patient-reported outcomes (PROs) including quality of life (QoL) and functional disability by treatment patterns.Data were extracted from the neuropathic low back pain (NLBP) outcomes research. It was a multicenter and cross-sectional study in which 1200 patients were enrolled at 27 general hospitals, from 2014 to 2015. Of total, 478 patients classified as neuropathic pain were used for this subgroup analysis. The patients were divided into 2 groups according to treatment patterns (with vs. without the targeted therapy [TT] of neuropathic pain). Demographic and clinical features were collected by chart reviews and PROs were measured by patient's survey. QoL was assessed by EuroQoL 5-dimension (EQ-5D) questionnaire. Functional disability was measured by the Quebec Back Pain Disability Scale (QBPDS). Multiple linear regression analyses were conducted to compare the PROs between TT group and non-targeted therapy (nTT) group.P < 0.01) and EQ-VAS  than the nTT group. The TT group's QBPDS score was lower than the nTT group, although its statistical significance still has not been reached .Among the NLBP patients , EQ-5D index, EuroQoL-Visual Analog Scale (EQ-VAS), and QBPDS Scores (mean ± standard deviation) were 0.40 ± 0.28, 54.98 ± 19.98, and 46.03 ± 21.24, respectively. Only 142 (29.7%) patients had pharmacological TT of neuropathic pain. Univariate analyses revealed no significant mean differences between TT group and nTT group in the EQ-5D index (0.41 ± 0.27 and 0.39 ± 0.28), EQ-VAS (56.43 ± 18.17 and 54.37 ± 20.69), and QBPDS (45.31 ± 21.32 and 46.31 ± 21.24). After adjustment with covariates, TT group had higher scores of EQ-5D index (β = 0.07; We found that considerable proportion of the NLBP patients remains untreated or undertreated. Although TT group had significantly better QoL than nTT group, only 29.7% of NLBP patients had pharmacological TT. Therefore, clinicians should consider using TT for better QoL of neuropathic pain patients. Thus, NLBP may require to be considered as an important clinical problem.Low back pain (LBP) is one of the most common musculoskeletal disorders, resulting in significant personal, social, and economic burden. Mechanical conditions of the spine, including disk disease, disk herniation, spondylosis, spinal stenosis, and fractures, account for up to 98% of LBP cases. Neuropathic pain in chronic LBP was reported to be highly prevalent and neuropathic pain affects the social and psychological well-being of LBP patients. Hiyama et al reported that NLBP patients had significantly higher visual analog scale (VAS) scores and lower the scores of short form 36 (SF-36) and Japanese Orthopedic Association Back Pain Evaluation Questionnaire than LBP patients with nociceptive pain. This result suggests that NLBP affects the physical, social, and psychological well-being compared to nociceptive LBP patients. Hence, it is significant to identify the involvement of neuropathic pain in LBP patients and to effectively manage NLBP.Neuropathic pain profoundly decreased the quality of life (QoL).However, there was no multicenter cohort study not only for the prevalence of NLBP patients but also for the treatment pattern in Korean NLBP patients. Although treatment pattern and outcome could be different in each different country and health care system, it would be valuable to understand relationship between the pattern and the outcome of NLBP treatment. Serotonin noradrenaline reuptake inhibitors and topical lidocaine were recommended as second-line therapies. Third-line therapies included tramadol and controlled release opioid analgesics. Recommended forth-line treatments were cannabinoids, methadone, and anticonvulsants. The special interest group of the international association for the study of neuropathic pain recently suggested guidelines of pharmacological management of neuropathic pain. According to their guidelines, tricyclic antidepressants (TCAs), gabapentin, pregabalin, and topical lidocaine were recommended as first-line treatment options and second-line treatments included opioid analgesics and tramadol.Pharmacotherapy is the primary clinical approach for managing NLBP. Canadian pain society provided guidelines of pharmacological management of chronic neuropathic pain as follows: first-line treatments were specific antidepressants (tricyclics) and anticonvulsants .Although these guidelines for neuropathic pain management were provided, there was still a lack of available data on treatment patterns of NLBP patients and outcome by treatment pattern.Therefore, the purpose of this study was to investigate the treatment patterns of NLBP in Korea and to explore the patient-reported outcomes (PROs) including QoL and functional disability by the treatment patterns.22.1This was a subgroup analysis of chronic low back pain (CLBP) patients with neuropathic pain derived from the NLBP outcome research (OR) that was multicentered, cross-sectional study. Data were collected between December 2014 and May 2015 from 27 nationwide general hospitals of South Korea. This study was approved by the all participated centers’ Institutional Review Board. We included CLBP patients who have moderate degree of LBP at least (VAS > 4) and received “minimally adequate treatment” with a medication trial lasting at least 4 weeks. Patients judged by physicians to meet the following criteria were included: age 20 years; CLBP at least 3 months; patients diagnosed with LBP owing to herniated disc, stenosis, spondylosis, spondylolysis, spondylolisthesis, or degenerative disc disease, according to magnetic resonance imaging or computed tomography findings; VAS at least 4; pain medication at least 4 weeks before the enrollment; and patients who were able to understand and willing to complete the subject information sheet and informed consent form. If the patients had following criteria, they were excluded: cancer, sprain, infection, fracture, ankylosing spondylitis, myofascial pain, or sacroiliitis; surgery within 3 months; current participation in other interventional studies; or patients with a critical or unstable health condition. The patients were clearly informed about the aim of our study, and their informed consents were obtained. With a significance level of 0.05 and an estimated error rate of 2.8%, the required number of patients to be enrolled was calculated to be approximately 1200: A target sample size was estimated based on the assumption that the prevalence of NLBP is 37%.Among the total 1200 patients enrolled in NLBP OR, NLBP patients whose scores were at least 4/10 in Douleur Neuropathique 4 (DN4) questionnaire were included in this subgroup analysis  were measured by the patient's survey. Age, sex, height, and body weight were included in demographic information. Clinical variables contained diagnosis of LBP, comorbidities, symptom period, pain VAS scores, DN4 score, Quebec Task Force Classification for Spinal Disorders (QTFC-SD), and pain control state (pharmacotherapy and surgery). As one of clinical characteristics, QTFC-SD was used to categorize patients’ spinal disorders on the basis of clinical examination and pain localization.2.2.2,27Treatment patterns were divided into 2 groups according to whether patients received targeted therapy (TT) of neuropathic pain or not. The TT group included anticonvulsants, TCAs, and topical lidocaine, whereas non-targeted therapy (nTT) group included opioid analgesics, nonopioid analgesics, and muscle relaxants.2.2.3 = 1 – (0.165 + 0.003 × M2 + 0.274 × M3 + 0.058 × SC2 + 0.078 × SC3 + 0.045 × UA2 + 0.133 × UA3 + 0.048 × PD2 + 0.130 × PD3 + 0.043 × AD2 + 0.103 × AD3 + 0.347 × N3 + 0.014 × I2sq)Final EQ-5D index's scoreQoL was assessed by generic EuroQoL 5-dimension (EQ-5D) questionnaire. EQ-5D is made up of 2 parts: a descriptive system, which could be converted into a single index, and a EuroQoL Visual Analogue Scale (EQ-VAS). The descriptive measurement consists of 5 dimensions: “mobility,” “self-care,” “usual activities,” “pain/discomfort,” and “anxiety/depression.” Each dimension has 3 levels: no problems, some problems, and severe problems, coded as numbers of 1, 2, and 3 in order. These scores, measured by descriptive part, were converted into scores of a single index (EQ-5D index) with a range from −0.229 to 1 point by applying the equation as follows:The EQ-VAS with a range from 0 to 100 points was used for subjective evaluation of patient's current health state. The ends of the scale were marked “best imaginable health state” and “worst imaginable health.” In these 2 measurements, a higher score means a higher QoL.Quebec Back Pain Disability Scale (QBPDS) was used for measuring functional disability. The QBPDS consists of 20 questions and has a scale of 0 to 5 for each question with a range from 0 to 100 points. A higher score of this tool indicates a more severe disability of function.2.3This investigation was designed as multicenter cross-sectional observational study of LBP patients. The patients  were provided with all study-related information, and they signed an informed consent form. All participating medical institutions obtained approval from their respective institutional review boards.2.4χ2 test, as appropriate. Mean differences of patient's QoL measured by EQ-5D index and EQ-VAS scores as well as their functional disability measured by QBPDS were also examined using the independent t test. An appropriateness of a use of the test was examined by histogram and normal probability plot for each of numerical variables. For variables with positively skewed data, a logarithmic transformation was performed before the t test. Multiple linear regression analyses were performed to compare scores of EQ-5D index, EQ-VAS, and QBPDS between 2 groups after adjusting potential confounders. Variables with P < .1 from bivariate analyses were selected as the potential confounders. Degree of performance of the regression model was measured by its coefficient of determination (R2). Collinearity among explanatory variables has also been checked, and no noticeable problem found in the multiple regression models used in this study. All statistical analyses were performed using the SAS software, version 9.4 , and a 2-tailed P value <.05 was considered as statistically significant.Patient's demographic and clinical characteristics were summarized as mean ± standard deviation (SD) for continuous variables or frequency (percentage) for categorical variables. Comparisons of patient's characteristics between the TT group and nTT group were made by Student 2 independent sample t test or 33.1P < .0001). In the TT group, the most frequent pain type was pain with distal extremity radiation (49.3%) followed by spinal stenosis (16.2%) and spinal nerve root compression (14.8%). pain with distal extremity radiation (50.0%) showed the highest proportion in the nTT group as in the TT group. However, unlike the TT group, pain with proximal extremity radiation (17.6%) was the secondly highest, followed by pain with radiation and neurologic finding (11.3%).Demographic and clinical features of NLBP patients are presented in Table P < .0001).Our data also showed that the subject's severity of LBP measured by QBPDS was associated with their anxiety/depression which was the fifth dimension of EQ-5D index measured as “none,” “some/moderate,” and “extreme.” Specifically, patient having more severe anxiety/depression showed significantly higher mean QBPDS score , there were no differences in the EQ-5D index (0.41 ± 0.27 and 0.39 ± 0.28), EQ-VAS (56.43 ± 18.17 and 54.37 ± 20.69), and QBPDS (45.31 ± 21.32 and 46.31 ± 21.24)    , the patients managed by the TT showed higher scores of EQ-5D index (1) Table  and EQ-V5) Table  than the4neuropathic pain is often undertreated or treated with ineffective or untested modalities.This study showed the mismatch between diagnosis and treatment pattern of NLBP patients. Although 39.8% of LBP patients met the DN4 criteria for neuropathic pain, only 29.7% were receiving pharmacological treatment with proven efficacy in neuropathic pain. The literature reveals that  NLBP results from a primary lesion or a malfunction within the somatosensory system, whereas nociceptive LBP is caused by tissue injury and/or inflammatory process. The general clinical diagnosis of neuropathic pain was based on the evidence of a lesion or a disease of the nervous system, which was ascertained by interviewing the patients and performing clinical examinations. However, it is complex and difficult methods to detect neuropathic pain in LBP patients.A reason for the low proportion of patients having TT would be difficulty in distinguishing the certain clinical difference between NLBP and nociceptive LBP. Identifying the underlying mechanism of chronic pain allows the use of pharmacological agents targeting specific pain mechanisms.Some clinicians used screening tools of neuropathic pain as a simpler means. However, there were various standardized screening measurements incurring wide variation in diagnosis of neuropathic pain and no consensus on the diagnosis of neuropathic pain.In addition, although there were many evidence-based guidelines in the pharmacological management of neuropathic pain due to the attempts for developing a therapeutic approach of related societies, neuropathic pain treatment guideline for LBP was absent. Serotonin noradrenaline reuptake inhibitors and topical lidocaine were recommended as second-line therapies. Third-line therapies included tramadol and controlled release opioid analgesics. Recommended forth-line treatments were cannabinoids, methadone, and anticonvulsants. The special interest group of the international association for the study of neuropathic pain recently suggested guidelines of pharmacological management of neuropathic pain. According to their guidelines, TCAs, gabapentin, pregabalin, and topical lidocaine were recommended as first-line treatment options and second-line treatments included opioid analgesics and tramadol.Canadian pain society provided guidelines of pharmacological management of chronic neuropathic pain as follows: first-line treatments were specific antidepressants (tricyclics) and anticonvulsants .We defined the TT and nTT based on these 2 references. Target therapy included TCAs, gabapentin, pregabalin, and topical lidocaine, which are recommended as first- or second-line medical treatment because their efficacy in neuropathic pain has been established in multiple randomized controlled trials (RCTs).,32 QoL measured by EQ-5D scores of patients with neuropathic pain (0.40 ± 0.28) was considerably lower in this study than those of other chronic diseases reported in the previous study , which showed the negative impact of the neuropathic pain in CLBP patients. After adjustment with covariates, the patients managed by pharmacological TT showed higher EQ-5D index and EQ-VAS scores than the nTT group, which suggested that the neuropathic pain patients who received the TT showed significantly better outcome in terms of pain control and QoL than the nTT group. In many RCTs, medications included in TT group of our study were proven in terms of efficacy of neuropathic pain therapy. Two studies of antidepressants in neuropathic pain reported that TCAs provided the identical efficacy in the neuropathic pain management.,40 Gabapentin and pregabalin have shown the efficacy in the studies on comparison between anticonvulsants and placebo in patients with several neuropathic pain conditions.,42 The 5% lidocaine patch has shown excellent efficacy and tolerability in allodynia patients due to various types of peripheral neuropathic pain.,42Neuropathic pain patients had severe and chronic symptoms that impaired their QoL.This study has several limitations. First, some of the well-known risk factors for NLBP include advanced age, female sex, and diabetes with or without hypertension, obesity, smoking, and psychological factors such as depression. Although these data demonstrated that neuropathic LBP and depression are significantly correlated with each other, the relationship between neuropathic LBP and other risk factors was not examined in this study because the aim of this study was to investigate treatment patterns of NLBP patients and to explore PRO including QoL and functional disability by treatment patterns.Second limitation of this study stems from the differential diagnosis of neuropathic pain. This study used DN4 questionnaire to diagnose a neuropathic pain in LBP patients based on a more reliable identification and qualification of a neuropathic pain. Despite the good sensitivity and specificity of the DN4 questionnaire, the question remains whether the distinction between neuropathic and nociceptive symptom profiles truly represents the biological background of pain, or whether it may be an artificial effect. Moreover, these categories of pain overlap to some degree. Although screening tools may give guidance to clinicians by selecting patients that need further diagnostic evaluation and pain management by specialists, they clearly do not replace clinical judgment. In this regard, the evaluation method using the questionnaire that was employed in this study is also a limitation.In addition, it should be noted that because other pain measures were not part of the study, no comparisons can be made between the DN4 questionnaire and other neuropathic pain screening scales.The third limitation of this study results from the subject population because it was mostly performed at a tertiary care university hospital. The spectrum of presenting patients obviously differs between primary care clinics and community hospitals. Fourth, this subgroup analysis has the limitation on the sample size, not calculated to investigate this subgroup. Thus, it is difficult to generalize the study results. Lastly, we could use only measured variables in this study as the potential confounders.Despite these limitations, there have been no other similar studies to compare the treatment outcome between TT and nTT in the NLBP population and this study showed that TT could be associated with a better QoL of NLBP patients. There were, however, relatively low numbers of patients having pharmacological TT of neuropathic pain in this study. These results could suggest that in cases with neuropathic pain, appropriate pharmacological treatments for the neuropathic component should be considered to have better QoL. Further studies are required to explore effects of TT on the improvement of QoL and functional ability in larger population with NLBP.Conceptualization: Bo-Jeong Seo, Young-Joo Kim.Data curation: Jae Taek Hong, Jin-Hwan Kim, Keun-Su Kim, Chong-Suh Lee, Hyun-Chul Shin, Woo-Kyung Kim, Joo-Han Kim, Jung-Kil Lee, In-Soo Kim, Yoon Ha, Soo-Bin Im, Sang Woo Kim, In-Ho Han, Jun-Jae Shin, ByeongCheol Rim, Kyung-Soo Suk, Jin-Hyok Kim, Ye-Soo Park Park, Bong-Soon Chang, Deuk Soo Jun, Young-Hoon Kim, Jung-Hee Lee, Woo-Kie Min, Jung Sub Lee, Si-Young Park, In-Soo Oh, Jae-Young Hong.Formal analysis: Juneyoung Lee.Investigation: Jae Taek Hong, Hyun-Chul Shin, Woo-Kyung Kim, Joo-Han Kim, Jung-Kil Lee, In-Soo Kim, Yoon Ha, Soo-Bin Im, In-Ho Han, Jun-Jae Shin, ByeongCheol Rim, Kyung-Soo Suk, Jin-Hyok Kim, Ye-Soo Park Park, Bong-Soon Chang, Deuk Soo Jun, Young-Hoon Kim, Jung-Hee Lee, Woo-Kie Min, Jung Sub Lee, Si-Young Park, In-Soo Oh, Jae-Young Hong.Methodology: Jae Taek Hong, Bo-Jeong Seo.Project administration: Bo-Jeong Seo.Supervision: Keun-Su Kim, Chong-Suh Lee, Bo-Jeong Seo, Young-Joo Kim.Validation: Jae Taek Hong, Jin-Hwan Kim, Bo-Jeong Seo.Visualization: Bo-Jeong Seo.Writing – original draft: Jae Taek Hong, Jin-Hwan Kim.Writing – review & editing: Keun-Su Kim, Chong-Suh Lee, Bo-Jeong Seo, Young-Joo Kim, Juneyoung Lee.


To decrease the morbidity burden of cardiovascular disease and to avoid the development of potentially preventable complications, early assessment and treatment of acute coronary syndrome (ACS) are important. The aim of this study has therefore been to explore the possible association between patients’ estimated intensity of chest pain when first seen by the ambulance crew in suspected ACS, and the subsequent outcome before and after arrival in hospital.Data was collected both prospectively and retrospectively. The inclusion criteria were chest pain raising suspicion of ACS and a reported intensity of pain ≥4 on the visual analogue scale.All in all, 1603 patients were included in the study. Increased intensity of chest pain was related to: 1) more heart-related complications before hospital admission; 2) a higher proportion of heart failure, anxiety and chest pain after hospital admission; 3) a higher proportion of acute myocardial infarction and 4) a prolonged hospitalisation. However, there was no significant association with mortality neither in 30 days nor in three years. Adjustment for possible confounders including age, a history of smoking and heart failure showed similar results.The estimated intensity of chest pain reported by the patients on admission by the ambulance team was associated with the risk of complications prior to hospital admission, heart failure, anxiety and chest pain after hospital admission, the final diagnosis and the number of days in hospital.ClinicalTrials.gov 151:2008/4564 Identifier: NCT00792181. Registred 17 November 2008 ‘retrospectively registered’. Early assessment and treatment of acute coronary syndrome (ACS) are major contributors to decreasing the morbidity burden of cardiovascular disease and to avoiding the development of potentially preventable complications . In SwedContradictory suggestions are reported about symptoms that could predict the severity of ACS. European guidelines declare that severe or ongoing chest pain lasting 20 min or more is a symptom indicating high risk of ACS . HoweverEarlier studies on patients with acute myocardial infarction have reported a variety of emotional reactions  and largThese conditions underline the importance of additional and deepened knowledge about early assessment and clinical decisions concerning patients suffering suspected ACS. Reducing time from onset of ACS symptoms to arrival in the coronary care unit at the hospital continues to be a challenge to the healthcare system . For exaExperiences from Sweden suggest that more than half of all patients with a final diagnosis of ACS dial 112 for transport by ambulance to hospital. Among these patients a very large proportion has an electrocardiogram (ECG) recorded on scene that often is sent directly to the nearest cardiology department for further evaluation. Among patients with ECG signs of myocardial ischaemia a direct transport to the catheterisation laboratory or coronary care unit is today a routine procedure .The pathophysiology behind the chest pain and the variability in patients’ experiences of chest pain when suffering from ischaemic heart diseases remains obscure. However, in a retrospective study on chest pain in patients admitted to hospital, ambulance patients received the final diagnosis of acute myocardial infarction more often than patients not transported by ambulance . In a reHowever, not much is known on the subject of symptoms such as chest pain, discomfort, anxiety and various other clinical findings from the prehospital setting regarding the predictable severity of ischaemic heart diseases including the risk of complications. Here, there is a gap in knowledge and therefore the aim of this study has been to explore the possible connection between one aspect of chest pain, i.e. the patients’ estimated intensity of chest pain when first seen by the ambulance crew in suspected ACS, and clinical findings and complications before and after arrival in hospital.The data for the present study was collected from a Randomised Clinical Trial (RCT no. NCT00792181), here called the main study, which has previously been reported –21. The The present study had a prospective randomised and a retrospective observational design. The intensity of chest pain as well as the occurrence of various complications in the prehospital setting were all prospectively reported, whereas data from hospital records was retrospectively reported. All the data was collected in Western Sweden (1.5 million inhabitants) with five ambulance care services, involving 500 ANs, 60 ambulances and one ambulance boat. All the ambulance services participating in the study were staffed with at least one AN. Data collection started in May 2008 and ended in December 2010.The VAS has been found to be valid, reliable and appropriate for use in clinical practice, using black lines and a numeric scale . Based oAll patients were transported by ambulance care services in Western Sweden and participated in the RCT (see above). The intensity of pain (VAS ≥4) was an inclusion criterion for receiving pain treatment in the main study . The incThe exclusion criteria were: 1/ Systolic blood pressure < 100 mmHg, 2/ age < 18 years, 3/ under the influence of alcohol, 4/ under the influence of drugs, 5/ benzodiazepine abuse, 6/ dementia, disorientation, 7/ communication problems, 8/ symptoms assessed as being caused by trauma and 9/ secondary transports .Patients were instructed by the AN to use the CAS ruler as follows: “I want you to show your chest pain or discomfort on this scale. The bottom of the scale corresponds to no pain or discomfort. The top corresponds to the most severe pain or discomfort you can imagine. I will move the red line along the scale from the bottom until you say stop”. The CAS ruler was then placed in a vertical position. There were no figures on the side of the instrument that were shown to the patient. By turning the CAS ruler the AN could observe a numeral VAS indicating the level of the patient’s estimated chest pain or discomfort.The following complications before and after arrival in hospital were considered as clinical endpoints: heart failure, hypotension, AV-block, bradyarrythmias, supraventricular arrhythmias and ventricular arrhythmias, all requiring treatment. Before arrival in hospital was defined as time from arrival of the ambulance on scene until the time when the ambulance arrived at the hospital whereas after arrival in hospital was defined as time on admission to hospital until time of leaving hospital.Further clinical endpoints were anxiety and chest pain requiring treatment after hospital admission; mortality before hospital discharge and in 30-days; and final diagnosis and the duration of hospitalisation.The complications that took place before arrival in hospital were reported prospectively by the AN on duty, whereas complications and other findings that took place after arrival in hospital were reported retrospectively by a few research nurses who collected the information from the hospital records. These records included notes made both by the responsible physician and by the nurse. Information on anxiety was also collected from these notes.The final diagnosis was assessed according to the ICD code given by the responsible physician and 30-days mortality was assessed according to the Swedish population registry. All deaths in Sweden reach this registry within two weeks after the event.P-value calculations were based on the actual values.For descriptive purposes patients were divided into three groups according to their subjective assessment of chest pain on the arrival of the AN according to the initial value of VAS: 1). 4.00–5.99; 2). 6.00–7.99; 3). ≥8.00. p-value calculations, using the Mann-Whitney U test for dichotomous variables and Spearman’s rank correlation statistic for continuous variables. For calculation of odds ratios with corresponding 95% confidence intervals and p-values, logistic regression was used, both unadjusted and when adjusting for potential confounders, defined as baseline characteristics with p < 0.20 for association with VAS value. Correspondingly, Spearman’s partial rank correlation was used for adjusted correlation coefficient regarding length of hospitalisation. Thirty days and 3 years mortality was estimated by the Kaplan-Meier method and Cox proportional hazards model was used for calculation of hazard ratios with corresponding confidence intervals and p-values. All tests are two-sided and p-values below 0.05 were considered statistically significant. SAS for Windows version 9.4 was used for the analysis.For the univariate analyses of association between initial severity of chest pain and clinical findings as well as baseline characteristics, the actual VAS value was used in All in all, 1836 patients were included in the main study . Of thesPatients with the most severe chest pain tended to be younger and more frequently to be smokers. Otherwise the estimated intensity of chest pain on the arrival of the ambulance clinicians was not significantly associated with characteristics in terms of distribution of gender and previous history of various diseases Table .Table 1AThere was an association between the severity of chest pain and the proportion of hypotension as well as AV-block/bradyarrhythmia requiring treatment. Thus, the risk of these complications increased with increasing severity of pain. Among the patients with the most severe pain the absolute risk was still low, only 2.0% (95% CI 0.8–4.2%) for hypotension and 1.7% (95% CI 0.6–3.8%) for AV- block / bradyarrhythmia. The absolute difference in risk between moderate pain (4–6) and severe pain (> 8) regarding these two complications was 1.4 and 1.6%, respectively. There was no significant association between the estimated intensity of chest pain and other complications before arrival in hospital  and of symptoms of chest pain requiring treatment 42% (95% CI 37–48%). The absolute difference in risk between moderate pain and severe pain regarding these two findings were 5 and 10%, respectively.There was also an association between the estimated intensity of chest pain and the proportion of patients who received a final diagnosis of acute myocardial infarction. Among patients with the most severe pain the absolute risk was 33% (95% CI 28–39%), with an absolute difference in risk between moderate pain and severe pain of 11%.Additionally, more severe chest pain was associated with an increase in the number of days that the patients spent in hospital Table .Table 4CThe strength of the association is shown in Table p = 0.25; adjusted for confounders 0.96 , p = 0.73) nor to 3-year mortality , p = 0.27; adjusted 0.98 , p = 0.65).In Fig. This is to the best of our knowledge the largest study reporting on the connection between the intensity of chest pain according to subjective assessment on ambulance arrival and clinical findings before and after arrival in hospital among patients with acute chest pain raising suspicion of ACS.The principal research question being addressed is the degree of association between the patient-reported intensity of an acute symptom at an early assessment and the subsequent outcome. We found significant but mostly weak associations between the patients’ estimated severity of chest pain on admission of the ambulance clinicians and a number of indicators reflecting the severity of the disease. These findings are new and suggest that the severity of chest pain as assessed by patients using the VAS may give some indirect indications of the severity of the disease underlying the symptom presentation in prehospital assessments. Some of the study’s outcomes are strictly time dependent conditions  and some are not (e.g. angina pectoris). Our findings could be related to a Norwegian study showing that a majority of ambulance patients with chest pain were admitted for further assessment in hospital, but only a quarter were assessed in the prehospital setting as having a severe illness . These fThe present results show a connection between estimated intensity of chest pain and AV block/bradyarrhythmias in the prehospital setting. In general, the proportion of various complications prior to hospital admission was very low, contributing to the failure of finding any significant association between the reported intensity of chest pain and the majority of complications prior to arrival to hospital. The ambulance care organisation is affected by an ambition to reduce time delay, which may lead to stress with a detrimental effect on patient care . HoweverAfter admission to hospital, the proportion of various haemodynamic complications as well as supraventricular arrhythmias increased, whereas ventricular arrhythmias and bradyarrhythmias remained infrequent. No significant association between the early assessment of the intensity of chest pain in the prehospital setting and these complications was found with exception for heart failure. Hence this may indicate a weak association between the early intensity of chest pain prior to arrival to hospital and the severity of the disease. Galinski et al. found no significant difference regarding the severity of pain between ambulance transported patients with acute myocardial infarction and no myocardial infarction . They arThe present finding of a significant association between estimated intensity of chest pain and the duration of hospitalisation may be explained by a higher proportion of acute myocardial infarction with increasing severity of pain. This is in line with an earlier study by Goodacre et al., showing pain as a predictor of acute myocardial infarction and ACS in patients with normal or non-diagnostic ECG . PatientOur results showed an association between the reported initial intensity of chest pain and anxiety as well as chest pain after admission to hospital. This may correspond to myocardial infarction patients’ vulnerability due to lacking control of the situation, experiencing anxiety  and fearThis is a study with a very large sample size, which must be seen as a strength. The pain was prospectively reported based on the patients’ subjective assessment. The measurement was made early in the course before the administration of pain treatment. Furthermore, in the statistical analyses adjustment were made for possible confounders in terms of age and previous history.However, this method for estimation of the intensity of chest pain has several limitations. The data received via VAS is at an ordinal level dependent on the patients’ subjective pain assessment. However, the fact that VAS does not collect information about the pain quality, duration or localisation, must be regarded as a limitation. This study only included patients with an estimated initial VAS of ≥4. Therefore the full spectrum of patients’ chest pain experience was not included in the analyses, which may have led to missed cases and potential selection bias error. This fact might underscore the true association between the intensity of chest pain and the subsequent outcome. One cannot exclude the possibility that other types of symptoms, e.g. dyspnea, nausea and vomiting might be equally important in the evaluation of the association between the initial intensity of chest pain and the subsequent outcome. This emphasises the importance of studying and developing methods for chest pain assessments that include other symptoms as well, such as pain quality, duration and localisation.Furthermore, patients with a systolic blood pressure of < 100 mmHg were also excluded from participation. Such patients often have indications of a compromised circulation with an unstable clinical condition. Thus, the study cohort focuses on patients with a more stable clinical condition. We report on the intensity of symptoms at the time of admission by the ambulance clinicians and not at the time of symptom onset when symptoms are most probably even more severe.All the patients included in these analyses participated in a randomised study which has been reported earlier –21. HencThere was no external monitor who validated the quality of the data with regard to clinical endpoints such as heart failure and arrhythmias. However, since only conditions that required treatment were considered we assume a high validity. In Swedish healthcare, all medications that are given by healthcare providers must be carefully recorded.The lack of association between the intensity pain and the risk of death particularly during long term must be interpreted with caution. A number of unmeasured confounders are likely to affect this association, of which revascularization may be the most important one. Furthermore may the inclusion of patients with less time dependent conditions such as chronic angina pectoris be a confounder. In such conditions may the association between the intensity of pain an outcome be different as compared with myocardial infarction.Finally, the last patient was included in the study seven years ago. However, during these seven years there has been no major change in the prehospital assessment of care among patients with chest pain either with regard to treatment or care in the region in which this study took place.In patients with chest pain raising suspicion of ACS on admission by the ambulance clinicians and then transported by ambulance, the estimated intensity of chest pain was associated with complications prior to hospital admission, heart failure, anxiety and chest pain after arrival in hospital, final diagnosis and the number of days in hospital. One implication of this study might be that when ANs suspect ACS the likelihood of an underlying acute myocardial infarction is somewhat higher if the patient in addition scores high on VAS.However, the association between early assessment and the subsequent outcome was relatively weak as patients with lower intensity (VAS < 4) of chest pain were not included in the study and therefore cannot be commented on. Hence, this study provides knowledge about patients reporting prehospital chest pain measuring VAS 4 or higher. In order to generate a wider picture of the association between reported intensity of prehospital chest pain and the subsequent outcome, studies on patients reporting lower intensity of pain are important as a complement to the present study. In addition, risk scores for patients with acute chest pain might be developed specifically for the prehospital setting in which the intensity of the initial chest pain could be one of a number of different aspects of the clinical picture.Ethical considerations were taken into account in line with the Declaration of Helsinki . The pat


In rotator cuff tears, some cases become asymptomatic with nonsurgical treatment, others remain symptomatic. The purpose of this study was to identify factors associated with pain in nonsurgically treated rotator cuff tears using magnetic resonance imaging (MRI).In total, 108 shoulders diagnosed with supraspinatus (SSP) tendon tears using MRI were nonsurgically treated, and MRI was repeated after more than a year. The patients were divided into pain or improvement group according to whether the pain persisted or disappeared. Bursal fluid accumulation; SSP tendon retraction; subscapularis (SSC) tendon tears; infraspinatus (ISP) tendon tears; and Goutallier classification into SSC, SSP, and ISP were included as evaluation factors. Predictive factors for persistent pain on initial MRI and factors associated with persisting pain after nonsurgical treatment on repeat MRI were statistically analyzed using multivariate logistic regression analysis.The improvement group showed a significant decrease in bursal fluid accumulation compared with the pain group (p < 0.01). SSC tendon tears  on initial MRI were significantly associated with persistent pain. Bursal fluid accumulation  and SSC tendon tears  on repeat MRI were significantly associated with persistent pain.Bursal fluid accumulation decreased when pain improved. The involvement of SSC tendon tears can serve as a predictive factor for persistent pain. Pain may persist although patients with rotator cuff tears including SSC tendon tears are nonsurgically treated.Level IV case-control study A rotator cuff tear is a common cause of pain and disability of the shoulder among adults. Some rotator cuff tears are symptomatic, whereas others are asymptomatic , 2. TreaFrom 2010 to 2014, all symptomatic patients diagnosed with full-thickness SSP tendon tears, regardless of whether infraspinatus (ISP) and subscapularis (SSC) tendon tears existed or not on MRI, were nonsurgically treated using steroids or hyaluronic acid injections and anti-inflammatory analgesics. Patients were recommended for surgery when symptoms persisted after nonsurgical treatment for at least 3 months. Patients who rejected to undergoing surgery were continued to be nonsurgically treated. The treatment was terminated if subjective symptoms disappeared by nonsurgical treatment, and the patients were regularly followed-up. Patients were reexamined using MRI at more than 1 year after the initial MRI. Patients who underwent surgery; patients who could not be followed-up; and patients with a history of surgery, fracture, osteoarthritis, or purulent arthritis of ipsilateral shoulder joints; patients with rheumatoid arthritis; and patients suspected to have neurological disease or cervical spine disease, such as cervical spondylotic amyotrophy, were excluded from this study. In total, 97 patients (108 shoulders), including 49 males (55 shoulders) and 48 females 53 shoulders), with a mean age of 68.9 ± 8.1  years, were enrolled. Mean follow-up period was 22.6 ± 12.4  months. The patients were divided into pain group and improvement group. Pain group consisted of patients that pain persisted until repeat MRI and required continued nonsurgical treatments such as steroids, hyaluronic acid injections, and/or anti-inflammatory analgesics. Improvement group consisted of patients that became asymptomatic and the treatment was terminated before repeat MRI. Finally, 63 patients  were included in the pain group and 38 patients  were included in the improvement group.MRI examinations were performed using a 1.5 Tesla scanner . The patients were rested in a supine position with the affected arm toward the side of the body, with the palm of the hands facing upward, for the imaging of the shoulder joints. The imaging protocol included the following sequences (Sigma/EXCELART Vantage): oblique coronal T2-weighted imaging ; axial T2-weighted imaging ; oblique sagittal T1-weighted imaging ; and oblique sagittal T2-weighted imaging . The same MRI scanner that was initially used was used for the repeat MRI.Bursal fluid accumulation; SSP tendon retraction; SSC tendon tears; ISP tendon tears; and Goutallier classification in SSC, SSP, and ISP were included as evaluation factors. Subcoracoid–subacromial–subdeltoid bursal fluid accumulation was evaluated. The volume of fluid was graded as follows: grade 0, bursal fluid not detected; grade 1, the thickness of bursal fluid < 5 mm; and grade 2, the thickness of bursal fluid ≥ 5 mm. SSP tendon tear retraction was measured from the torn SSP tendon stump to the lateral aspect of the greater tuberosity on an oblique coronal MRI (T2-weighted imaging). SSC tendon tears were diagnosed on the basis of the axial and oblique sagittal T2-weighted MRI. A partial tear was diagnosed if high signal intensity was detected in the most proximal portion of the SSC tendon but did not involve the full thickness of the tendon. A complete tear was diagnosed if a detachment of SSC tendon insertion was detected. Cuff tears spreading to the middle facet on the oblique sagittal MRI (T2-weighted imaging) were defined as ISP tendon tears. The fatty infiltration of the SSC, SSP, and ISP muscles was assessed on an oblique sagittal MRI (T1-weighted imaging) according to the modified Goutallier classification using a slice of the outermost edge touching the spine and the body of the scapula , 14. ChaU tests were used to investigate differences in the progression of SSP tendon retraction between the two groups. Logistic regression analysis was performed to investigate predictive factors for persistent pain on the initial MRI and factors associated with persisting pain after nonsurgical treatment on the repeat MRI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. From the univariate logistic regression analysis, the variables that had a P value of < 0.05 were considered as potential variables. Multivariate logistic regression was performed in the next phase. A P value of < 0.05 was considered statistically significant.Chi-squared test was used to evaluate differences in the decreasing rate in bursal fluid accumulation and the progression rates of SSC, ISP tendon tears, and Goutallier classification in SSC, SSP, and ISP between the two groups. Mann–Whitney P < 0.01). SSP tendon tear retraction progressed from 24.4 ± 13.5 mm to 28.5 ± 14.1 mm in pain group and from 17.1 ± 13.8 mm to 21.2 ± 14.4 mm in improvement group. The average progression of SSP tendon tear retraction was 4.1 ± 5.4 mm in the pain group and 4.1 ± 5.2 mm in the improvement group, and there was no significant difference between the two groups (P = 0.90). With regard to SSC tendon tears, in the pain group, the progression rate of SSC tendon tears was 11.9%. In the improvement group, the progression rate of SSC tendon tears was 2.4%. There was no significant difference in progression rate of SSC tendon tears between the two groups (P = 0.08). For ISP tendon tears, the progression rate of ISP tendon tears was 11.9% in the pain group, while in the improvement the progression rate was 7.3%. There was no significant difference in progression rate of ISP tendon tears between the two groups (P = 0.44). In the Goutallier classification in SSC, the progression rate of the Goutallier classification for SSC was 3.0% in the pain group, while in the improvement group it was 7.3%. No significant differences were seen for this parameter between the two groups (P = 0.30). The progression rate according to the Goutallier classification for SSP in the pain group was 14.9%, while in the improvement group it was 14.6%. No significant difference in progression rate of Goutallier classification in SSP between the two groups was noted (P = 0.97). With regards to the Goutallier classification for ISP, in the pain group, the progression rate was 17.9%, and in the improvement group, it was 12.2%. No significant differences in the progression rate of the Goutallier classification in ISP between the two groups was noted (P = 0.43).The changes in each factor are shown in Table P < 0.05 in univariate models were selected (Table P = 0.03) on initial MRI were considered as predictive factor for persistent pain  and SSC tendon tears  on repeat MRI were significantly associated with persistent pain (Table Multivariate logistic regression analysis was employed to investigate the factors associated with persisting pain after the nonsurgical treatment in repeat MRI. Variables with ed Table . TherefoThere are several reports of predictors of outcome of nonsurgical treatment for rotator cuff tears , 11, 12.There are a few reports comparing MRI findings in symptomatic and asymptomatic rotator cuff tears. Some reports showed that there was no difference , 16, othThe balance between the SSC muscle and the ISP and teres minor muscles is often referred to as the rotator cuff “transversal force couple.” It generates stability in the glenohumeral joint by an antagonistic balance between the forces exerted in an anterior and posterior part . This anThe SSC has other crucial functions in the shoulder joint. The SSC stabilizes the long head of the biceps tendon. It was reported that most SSC tendon tears occurred on the most superior part and the articular side of the attachment of the humerus , 30. IdeFor the reasons stated above, in this study, SSC tendon tears may be associated with persistent pain for nonsurgically treated rotator cuff tears. Arthroscopic repair with use of a suture anchor technique has been reported to be a safe and effective procedure for the treatment of combined rotator cuff tears involving the SSC tendon . It has There were several limitations to this study. First, the number of cases included is small. Second, nonsurgical treatment was not standardized as the frequency of injection varied. Third, there is no scale for pain evaluation. Conditions requiring continued nonsurgical treatments such as steroids, hyaluronic acid injections, and/or anti-inflammatory analgesics were defined as persistent pain. Fourth, interpretations of MRI are not always accurate , 38. HowWe evaluated the factors associated with pain in nonsurgically treated rotator cuff tears by MRI. Bursal fluid accumulation decreased when pain improved, but the bursal fluid is not a reliable predictive factor for persistent pain in initial MRI. On the other hand, SSC tendon tears on initial and repeat MRI were significantly associated with persistent pain. Therefore, the involvement of SSC tendon tears may serve as a predictive factor in persistent pain. SSC function may be important since SSC contributes to “transversal force couple” and stabilizes the long head of the biceps tendon. When patients with rotator cuff tears including SSC tendon tears are treated nonsurgically, attention to the possibility of persistent pain should be given.


Patients after total knee arthroplasty (TKA) often develop moderate to severe pain. This study compared the analgesic effect of low-dose epidural morphine vs. a comparable saline injection in patients following TKA surgery.This randomized, double-blinded, and placebo-controlled trial was conducted in a tertiary hospital in Beijing between July 1, 2017 and May 30, 2018. One hundred and ten patients following TKA under combined spinal-epidural anesthesia were randomized to receive either epidural morphine  or placebo . For all patients, single-injection femoral nerve block was performed, and a supplementary patient-controlled intravenous analgesia pump was provided. The severity of pain was assessed with the numerical rating scale  at 6, 12, 24, 36, and 48 hours after surgery. The primary endpoint was moderate to severe pain (NRS pain score ≥4) within 48 hours after surgery.The percentage with moderate to severe pain within 48 hours was lower in the epidural morphine group than in the placebo group . Furthermore, the cumulative morphine consumption within 48 hours was lower  whereas the mental component summary score of 30-day quality of life was higher  in the epidural morphine group than in the placebo group.For patients following TKA, the addition of epidural morphine to single-injection femoral nerve block improves the quality of analgesia within 48 hours, without increasing adverse events.NCT03203967.ClinicalTrials.gov  Total knee arthroplasty (TKA) is an important therapy for patients with later-stage knee osteoarthritis to relieve pain and improve quality of life. However, many patients suffer from moderate to severe postoperative pain that impede them from participating early physical therapy and recovering joint function. In addition, severe postoperative pain also contributes to immobility-related complications like deep vein thrombosis and delay hospital discharge –5. AlthoLow-dose epidural morphine is commonly used for analgesia after cesarean section. The effect of single dose morphine lasts more than 20 hours, with low incidences of itching, nausea, vomiting, and respiratory depression ,18. We hhttp://dx.doi.org/10.17504/protocols.io. [dx.doi.org/10.17504/protocols.io.wanfade]. Written informed consent obtained from each patient.This was a randomized, double-blind, and placebo-controlled one-center trial with a two-arm parallel-group design to prove the superiority hypothesis. The study protocol  was apprPotential participants were screened the day before surgery. The inclusion criteria were adult patients (age of 18 years or older) who were scheduled to undergo unilateral TKA under combined spinal-epidural anesthesia. Patients who met any of the following criteria were excluded: (1) age higher than 90 years; (2) presence of any contraindication to neuraxial anesthesia or peripheral nerve block; (3) use of opioid analgesics during the last month; (4) unable to understand Numeric Rating Scale for pain evaluation or existence of language barrier; (5) severe renal insufficiency ; (6) history of asthma; or (7) American Society of Anesthesiologists (ASA) classification of grade IV or higher.After obtaining the written informed consents, investigators responsible for patient recruitment collected detailed baseline data including demographic characteristics, diagnosis, comorbidities, current medication, NYHA classification, American Society of Anesthesiologists (ASA) classification, history of previous surgery and anesthesia, as well as important laboratory test results.The random numbers were generated in a 1:1 ratio with a block size of 4 by an independent biostatistician using the SAS statistical package version 9.3 . The results of randomization were sealed in sequentially numbered envelops and stored at the site of investigation until the end of the study.During the study period, each enrolled patient was assigned a recruitment number. The study drugs, either 2 mg morphine in 5 mL normal saline or 5 mL normal saline, were prepared according to the randomization sequence by a study coordinator (JTT) who did not participate in the rest of the study. The prepared drugs were contained in 5 mL syringes with same appearance, labeled with the recruitment numbers, and provided to the anesthesiologists taking care of the enrolled patients. All patients, health-care team members, and investigators responsible for data collection and postoperative follow-up were masked from group allocation throughout the study period.Combined spinal (with 0.5% hyperbaric bupivacaine) and epidural (with 2% lidocaine) anesthesia was performed for all patients. The dosage of local anesthetics  was determined by the anesthesiologists. Intraoperative sedation was provided with dexmedetomidine infusion  which was started once patients were hemodynamically stable after spinal anesthesia, and stopped before the end of surgery. The study drugs  was administered at the end of surgery through the indwelling epidural catheter which was removed afterwards.Patients were transferred to the post-anesthetic care unit (PACU), where single-injection femoral nerve block was performed with 20 mL of 0.5% ropivacaine under the guidance of ultrasonography and a nerve stimulator. A patient-controlled intravenous analgesia (PCIA) pump was also provided, which was established with 100 mL of 0.5 mg/mL morphine and programmed to deliver a 2 mL bolus with a lockout interval of 8–10 min and a background infusion of 0.5 mL/h. The PCIA pump was stopped at 48 hours after surgery. If the morphine solution in the pump was exhausted before that time, supplemental morphine of same concentration was provided to ensure a 48-hour postoperative patient-controlled analgesia.Intraoperative data including duration of anesthesia and surgery, name of surgery, types and doses of anesthetic drugs, and fluid balance were recorded. After surgery, patients were monitored in PACU for at least 30 minutes. Motor blockade of the lower limbs was estimated using a modified Bromage scale  at PACU arrival and 30 minutes.After surgery, two investigators (MZT and CF) visited patients at 6, 12, 24, 36, and 48 hours after surgery . The severity of pain at rest and with movement was assessed with the numerical rating scale . Motor blockade of the lower limbs was estimated using a modified Bromage scale. The numbers of required and given bolus injections by the PCIA pumps between the neighbouring time-points were counted. The occurrence of side effects , the uses and dosages of other analgesics, the volume of drainage, and the requirement of blood transfusion within 48 hours were recorded. The score of patients’ satisfactions  was evaluated at 48 hours after surgery. Other postoperative date including time to ambulation, length of postoperative hospital stays, occurrence of complications within 30 days, and 30-day mortality after surgery were documented.At 30 days after surgery, the quality of life was assessed with 12-item short-form ; the severity of arthritic symptoms was assessed with WOMAC osteoarthritis index . 30-day followed-up was performed by face-to-face interview, when patients came back to the hospital for a re-examination.The primary endpoint was moderate to severe pain (NRS pain score ≥4) within 48 hours after surgery. Secondary endpoints included the cumulative morphine consumption and supplemental analgesics within 48 hours, the percentage with satisfied analgesia at 48 hours, time to ambulation, length of stay in hospital after surgery, the incidence of complications within 30 days after surgery, all cause 30-day mortality, as well as the quality of life (SF-12) and WOMAC Osteoarthritis Index at 30 days after surgery. Other predefined endpoints included the NRS pain scores (at rest and with movement), the percentage with moderate to severe pain and bolus of PCIA pump at various time-points after surgery.A study comparing continuous femoral nerve block vs. continuous femoral nerve block plus mini-dose spinal morphine for analgesia after TKA showed that, at 12 hours after surgery, the percentage with moderate to severe pain was 69.7% vs. 42.9%, respectively . We assuAll data were entered into database using the EpiData software package  with a double-entry method. Continuous variables  were analyzed using the unpaired t-test, with mean differences calculated with the covariance analysis. Ordinal data  were analyzed with Mann-Whitney U test, with median differences calculated with the Hodges-Lehmann estimator. Categorical variables  were analyzed using the Chi-squared test or Fisher exact test, with odds ratio (OR) calculated by logistic analysis. Time-to-event results  were analyzed using the Kaplan-Meier survival analysis, with the difference between groups tested by the log-rank test and hazard ratio (HR) calculated by Cox regression analysis. Data collected from the pain diaries  were analyzed using nonlinear mixed effects models. A two-sided P value of less than 0.05 was considered statistically significant. Outcome and safety data were analyzed in the intent-to-treat population. We also did per protocol analysis for the primary endpoint. No interim analysis was performed. The statistical analysis was performed with SPSS 19.0 statistical package  and STATA9.0 .From July 1, 2017 to May 30, 2018, 266 patients were screened for eligibility; 143 patients met the inclusion/exclusion criteria; 110 patients gave consents and were randomized into the study, among them 55 in the epidural morphine group and 55 in the placebo group. During the study period, 2 patients in the epidural morphine group discontinued the PCIA pump because of nausea and vomiting; 3 patients in the epidural morphine group were lost to follow up at postoperative day 30 . The lasThe percentage of patients with moderate to severe pain (NRS pain score ≥4) within 48 hours was significantly lower in the epidural morphine group than in the placebo group  . Per-proFurthermore, the cumulative morphine consumption within 48 hours was significantly lower , whereas the mental component summary score of quality of life (SF-12) at 30 days was significantly higher  in the epidural morphine group than in the placebo group . Among oIn all patients, motor blockage of lower limbs recovered completely within 6 hours after surgery. There were no significant differences between the two groups regarding the incidence of adverse events .Our results showed that, for patients following TKA, the addition of low-dose epidural morphine to single-injection femoral nerve block reduced the percentage with moderate to severe pain within 48 hours. It also decreased the cumulative morphine consumption within 48 hours and improved the mental health-related quality of life at 30 days. This intervention did not increase the incidence of side effects.In the present study, TKA was performed under combined spinal-epidural anesthesia. Within 6 hours after surgery, no patient developed moderate to severe pain and bolus injection of PCIA pump was seldom required. These could be attributed to the residual effect of spinal anesthesia which was also confirmed by the existence of lower-limb motor blockage. From 6 to 12 hours after surgery, only a few patients had moderate to severe pain and bolus injections of PCA pump was occasionally required. One reason was that patients seldom move the surgical leg and, therefore, pain with movement was not induced; another reason was that the effect of single femoral nerve block and epidural morphine were satisfactory during this period. Studies showed that the mean duration of a single femoral nerve block (with 20 ml of 0.5% ropivacaine) lasts 799±364 minutes . From 12In the placebo group of the present study, the effect of spinal anesthesia completely disappeared at 12 hours after surgery; even though single femoral nerve block combined with intravenous PCA pump were used for postoperative analgesia, up to 76.4% of patients suffered from moderate to severe pain within 48 hours. Additional sciatic nerve block can improve postoperative analgesia by covering the popliteal area, but means more intervention, time and costs ,24. AddiThere were several limitations in our study. The update of the information in the trial registry does not affect the initial planning, but it should be noted that the sample size calculation is based on an approximation, which does not hold in small samples. The calculation results in 53 patients per group using nQuery Advisor for the Chi-Square test and 60 per group using Fisher exact test. Further taking our planned sample size of 102 with our initially planned 10% dropout rate, it results a corrected sample size of 113. Thus, the trial is slightly underpowered. Secondly, as a single-center study, the generalizability of our results may be limited. Thirdly, the difference of percentage with moderate to severe pain between the two groups used to calculate the sample size was 26.8%, whereas the actual difference in our results was 18.2%. This might have decreased the power of our study to detect the difference between groups. However, we do find that low-dose epidural morphine improved postoperative analgesia .For patients undergoing TKA, the addition of low-dose epidural morphine to single femoral nerve block reduces the percentage with moderate to severe pain within 48 hours; it also lowers the consumption of intravenous opioids within 48 hours and improves the mental health-related quality of life at 30 days after surgery, without increasing adverse events.S1 Checklist(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


To investigate the current dosing regimens of gabapentinoids in Pakistani patients with neuropathic pain and to compare their clinical efficacy and tolerability in terms of pain relief and adverse effects using difference in pain score as a treatment outcome.This observational, prospective study was conducted in 320 patients with neuropathic pain from August 2016 to March 2018 at Basic Medical Sciences Institute (BMSI), Karachi in collaboration with Shifa International Hospital and Benazir Bhutto Hospital, Islamabad. Demographic data, treatment-related adverse effects and pain intensity was documented at recruitment and follow up visits at two, four and eight weeks. Discontinuation due to adverse effects and lack of efficacy were also recorded. Data was entered and analyzed using SPSS version 22.Mean age of patients was 52.57±12.47 and the most common ethnicity were Punjabi speaking population (66%). Diabetic neuropathy (51%) was the most common etiology followed by radicular pain (25%). Mean dosages of pregabalin and gabapentin were 114mg and 470mg respectively. Mean pain score was significantly reduced by gabapentinoids (<0.001). Dizziness, drowsiness and somnolence were frequent adverse effects. Common dosages for pregabalin and gabapentin were 75 mg/day and 300 mg/day respectively.Current dosing regimens of gabapentinoids in Pakistani patients with neuropathic pain were found to be efficacious at low dosages in comparison to international recommended dosages. Gabapentin and pregabalin were both similar in terms of reducing pain score but onset of pain relief was relatively faster with pregabalin. Dizziness, drowsiness and somnolence were frequently reported with both gabapentinoids; however, visual blurring, ataxia and weight gain were observed only with the use of pregabalin. Adverse effects are frequently observed with gabapentinoids which necessitates reverting back to low dosages or switching to other drugs for pain relief. Neuropathic pain (NeP) is defined as pain caused by a lesion or disease of the somatosensory system.92-δsubunit of voltage-dependent calcium channels which leads to reduced neurotransmitter release resulting in attenuation of post-synaptic excitability.10The first line treatment options for the management of NeP include gabapentinoids, tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors and opioids. Pregabalin and gabapentin are the two gabapentinoids which have been approved and widely prescribed for NeP. These are derivatives of the inhibitory neurotransmitter gamma-aminobutyric and bind to presynaptic αPregabalin has been approved for the treatment of neuropathic pain syndromes with considerable efficacy in dosages range from 150mg up to 600 mg/day depending on patients’ therapeutic response and tolerability. On the other hand, gabapentin is prescribed with starting dose of 300mg and it is then titrated up to 1800-3600mg/day divided in three doses in patients with normal renal function.13Most of the clinical studies involving administration of gabapentinoids have reported dizziness, drowsiness and somnolence as the most frequent dose-dependent adverse effects which occur in about every fourth patient. Other common adverse effects include nervousness, headache, blurred vision, dry mouth, peripheral edema, weight gain, constipation, blurred vision, decreased motor coordination and ataxia in 1-10% of patients.15Multiple factors make NeP difficult to manage including heterogeneous diagnostic criteria, inadequate response to existing treatment options and variable efficacy of the available drugs. Current clinical practices are based on randomized clinical trials and clear recommendations on dosages are not available.With this background, aim of this study was to explore the current dosing regimens of pregabalin and gabapentin in patients with neuropathic pain. Furthermore, our study also compared the efficacy and tolerability of gabapentinoids in terms of pain relief and adverse effects using difference in pain score as a treatment outcome.This observational, prospective study was carried out in outpatient pain clinics over a period of 20 months from August 2016 to March 2018 at Shifa International Hospital, Islamabad, Benazir Bhutto Hospital, Rawalpindi in collaboration with Basic Medical Sciences Institute, Karachi. Study protocol was approved by Institutional Review Board & Ethics Committee. Three hundred and twenty patients of either gender, aged ≥ 18 years were included after obtaining written and verbal informed consent with established diagnosis of neuropathic pain due to heterogeneous etiologies. Patients’ pain scores at the time of recruitment were ≥ 40mm on the 100mm Visual Analog Scale (VAS) of the Short Form-McGill Pain Questionnaire and an average pain score ≥4 on an 11-point Numeric Rating Scale. Patients with creatinine clearance less than 60ml/min or any other renal insufficiency and gastrointestinal diseases that could interfere with the absorption of drugs were excluded from the study. Patients’ demographic data, clinical history and all relevant information related to neuropathic pain were recorded in a detailed structured questionnaire.The patients who were receiving different dosages of pregabalin or gabapentin in QD, BID and TID regimen by prescribing clinicians were placed into dosing groups of pregabalin  and gabapentin . The patients were followed for primary efficacy outcomes by measuring pain scores by VAS and NRS at baseline and later at 2-, 4- and 8 weeks’ follow-up visits. All the clinical progress and adverse effects since the commencement of these medications were recorded for the full duration of study. Discontinuation of gabapentinoids due to lack of efficacy, inadequate response and adverse effects were also recorded. For this study we estimated the sample size using a previously published paperp-value less than 0.05.Exposure to gabapentinoids and outcomes  were recorded for all those patients who continued the treatment till 8-weeks of the study. Clinical efficacy was defined as a change in mean pain score from baseline to a clinically meaningful reduction of ≥30% or ≥50%.Three hundred and twenty patients were enrolled in the study out of which sixty-eight patients could not complete the study due to various reasons. Sixteen of these patients were lost to follow up during the study whereas twenty-four patients showed inadequate response to gabapentinoids and were switched to other drugs. Twenty-eight patients developed severe dizziness or drowsiness and could not tolerate these adverse effects. Two hundred and fifty-two patients completed the study and were evaluated for efficacy and tolerability measures.Mean age of these study participants was 52.57±12.47. Most common ethnic group among our study participants were Punjabi speaking population (66%) followed by Pathan (28%) and Urdu speaking participants (6%). Number of females was almost twice as the number of male participants. Results of the demographic data are summarized in Two hundred and six study participants (81.74%) received pregabalin whereas forty six (18%) patients received gabapentin for different types of neuropathic pain. The most common etiologies for neuropathic pain were diabetic neuropathy and radicular pain with prevalence of 51% and 24% respectively. Frequencies of etiologies, mean dosages and dosage arms of both gabapentinoids are summarized in Mean dosages of pregabalin in all patients was114.25±59.58 mg whereas mean dosages required by Urdu speaking, Punjabi and Pathan for all etiologies were 101.79±71.03, 114.24±59.58 and 116.56±54.72mg respectively with a p value of 0.293. Furthermore, mean dosage requirements of gabapentin were 470.48±277.45mg in all patients. Mean dosages of gabapentin were 486.96±268.83mg in Punjabi speaking and 555.56±292.02mg in Pushto speaking population with a p value of <0.001.Dizziness, drowsiness and somnolence were the most frequent adverse effects reported with both pregabalin and gabapentin. Frequencies of adverse effects reported are summarized in The mean pain score for all etiologies using the NRS scale after approximately two weeks’ duration was reduced to 1.92 in patients taking pregabalin and 1.93 in patients receiving gabapentin. These results are summarized in In our study, majority of the participants belonged to Punjabi and Pushto speaking ethnic groups as these groups represent majority of population of Rawalpindi and Islamabad where this study was conducted. Number of female patients was almost twice than males and consistent with other studies conducted to compare prevalence of chronic pain in both genders concluding females have greater pain sensitivity, report pain more frequently and have a lower threshold for most types of pain including neuropathic pain.17The mean dosages of pregabalin and gabapentin for all etiologies were 114.2±59.6 and 470.5±277.45 respectively. Furthermore, pregabalin frequency of administration was more which could be due to discrete pharmacokinetic advantages of pregabalin over gabapentin.20Our results showed that patients taking gabapentin and pregabalin for neuropathic pain showed a significant decrease in pain from a mean pain score of 6.2 to 1.9 and 5.9 to 1.9 after a mean duration of 18.28 and 13.73 days, respectively. These results of our study are in accordance with different studies where both drugs resulted in a mean decrease of pain intensity of approximately 30-50% in majority of the patients.21Pregabalin was most commonly prescribed for diabetic neuropathy and the results of our study are consistent with other researches proving pregabalin as better choice as monotherapy in 75 to 300 mg/day in early reduction of pain.23Neuropsychiatric adverse effects such as severe dizziness, drowsiness and somnolence were reported in 23% and 4% of patients receiving pregabalin and gabapentin, respectively. In our study, mean doses of patients with adverse effects were significantly less compared to the average doses in patients who did not report such adverse effects. Moreover, sixty-eight patients were not included for final analysis and main reasons for drop out were non-compliance due to severe adverse effects. Mean dosages of pregabalin and gabapentin were not similar in different ethnic population though not statistically significant. Some studies have suggested role of distinct genetic polymorphism for regulation of proteins for absorption, metabolism, and excretion and as transporter molecule at the site of action in different population which might result in variation of clinical response to these drugs.25To our knowledge, there have been no studies from Pakistan to evaluate efficacy and tolerability of gabapentinoids in chronic NeP. We acknowledge potential limitations of the study as it was observational, time-bound and conducted in running OPDs hence it was not possible to categorize patients in equal groups for head to head comparison as the drugs and doses were selected by clinicians according to type and severity of NeP. However, potential strengths of our study were adjustment of other variables such as detailed documentation, regular follow-up and close monitoring of adverse effects.In summary, effective dosing range of pregabalin and gabapentin was 114.2±59.6 ad 470.5±277.45mg/d, respectively. Mean time in onset of relief of pain was less for pregabalin as compared to gabapentin (<0.001). Pregabalin prescription rate was higher as compared to gabapentin. Majority of patients experienced dizziness, drowsiness and somnolence at low doses. Our study findings conclude that Pakistani patients respond to neuropathic pain at low dosages in comparison to international recommendations. Given routine clinical use of gabapentinoids, future clinical trials are required to define appropriate dosing regimens and molecular studies are needed to explore the role of polymorphism in Pakistani population and occurrence of adverse effects at low dosages.AS conceived, designed, collected data, did statistical analysis and drafted manuscript.SMA and MK drafted manuscript, reviewed and did final approval of manuscript.AA conceived and designed study, collected data and reviewed manuscript.


Knowledge: Pain Management of the Nursing Outcomes Classification (NOC) in patients with chronic pain, defined as extent of understanding conveyed about causes, symptoms, and treatment of pain. A three-stage study was designed: (1) translation and cultural adaptation through an expert panel, (2) content validation, (3) clinical validation. This study provides nurses with a Spanish version of this scale adapted to their context, as well as a set of structured indicators to measure patients’ knowledge about chronic pain. The results indicated that the culturally adapted Spanish version of the outcome Knowledge: Pain Management had a high level of content validity (CVI = 0.92), with 27 indicators being distributed between two factors. This version has been shown to be reliable in terms of inter-observer agreement (κ = 0.79) and internal consistency (α = 0.95). In conclusion, Knowledge: Pain Management has been shown to be reliable and valid to measure knowledge of chronic pain.Pain has a major impact on health and quality of life. Since the level of knowledge of painful conditions can influence how these are addressed and managed, assessing this knowledge in patients becomes crucial. As a result, it is necessary to have culturally adapted and validated instruments that specifically measure patients’ knowledge of chronic pain management. The objective of this study was to carry out the Spanish cultural adaptation and the validation of the outcome  Pain is a health issue that affects a large number of individuals ,2. In acHealthcare professionals’ knowledge of pain management and treatment has attracted considerable attention ,8. ConveIn this sense, there is evidence that knowledge about analgesic drugs is associated with adherence to analgesic therapy . CaregivAn association has been found between the satisfaction with pain treatment and patients’ knowledge about the disease and some treatment-specific topics; this association persisted up to 12 months after receiving the education . ParticiImproving patient empowerment requires, first, exploring their beliefs, level of understanding about pain and pain management. Beliefs about pain may influence the behavior of the patients in pain management . MeasuriKnowledge: Pain Management , which is oriented towards measuring the extent of understanding conveyed about causes, symptoms, and treatment of pain. This outcome has 41 indicators  which are used to measure the overall KPN concept. It is measured with a five-point Likert scale . The indicators facilitate the monitoring of progress in knowledge of pain in a given episode of care and in different care settings [The Nursing Outcomes Classification (NOC)  includessettings .The research of the NOC project were carried out in the United States. Subsequently, further studies have been carried out in other countries to increase the knowledge and applicability of the NOC outcomes, although each outcome has undergone its own research and development process. Validation by an expert panel has been used in certain nursing diagnoses ,27, as wKnowledge: Pain Management and to assess its psychometric properties and sensitivity to change in patients with chronic pain.The objective of this study was to provide the Spanish translation and cultural adaptation of the English version (5th edition) of the NOC outcome Knowledge: Pain management: (1) Spanish translation and cultural adaptation; (2) content validation; and (3) clinical validation.A three-stage validation design was used for the outcome Stage 1: The translation/back-translation method ,30 was aStage 2: A panel of 21 pain experts of Spanish nationality (19 nurses and two physiotherapists) assessed the content validity of the first Spanish version in two rounds of consensus using the Delphi technique . The memThe CVI-indicator (CVI-i) was determined for each indicator, taking into consideration that, for six or more experts, this value should not be below 0.78 . The modStage 3: An observational-longitudinal study was carried out to establish the reliability, validity, and sensitivity to change of the Spanish version of the KPM.The study was conducted from March 2013 to April 2014 in 9 settings  in the Andalusian Health Service in the provinces of Jaén (6) and Granada (3), Spain. Twenty nurses (16 women and four men) participated in the data collection. These nurses were working full time, had been working for more than 6 months in their respective healthcare centres, and had a mean experience of 20.7 years in caring for patients with chronic pain (Standard Deviation = 6.59). The nurses were working in the following units: Primary Care Team (50%), Oncology Impatient Unit (30%), Hospital Case Management (Advanced Practice Nurses) (10%), and Chronic Pain Unit (10%).Data published by the authors of the validation of the NOC for use in people with chronic pain were used to estimate the size of the patient sample . A minimKnowledge: Pain management. The adapted Spanish version of KPM with 30 indicators, which was obtained after validation by experts, was used. These indicators measure the knowledge of how pain appears and is maintained, aspects related to medication and treatment, and various strategies and techniques for appropriate pain management. Twenty eight indicators were taken from the original English version  and a fuPain intensity. The Spanish version of the 11-point Numerical Pain Intensity Scale (NPIS) was used. The reliability and validity of this one-dimensional instrument are well-documented, being widely utilised for pain intensity assessment . The aspPain Coping Questionnaire (reduced version) (PCQ-R). The subscale “Seeking instrumental social support” was considered. This subscale assesses how individuals cope with pain by seeking advice, help, or information (problem-focused coping) on a 5-point Likert scale . The psychometric properties of this questionnaire have been studied in the Spanish population. Internal consistency ranged from α = 0.75 to α = 0.94; test-retest reliability was r = 0.81, and convergent validity with other scales was as expected ,39.Ad hoc questions to patients. Knowledge: Pain Management and in the data collection procedure. Most of the interviews with primary care patients were conducted in the nursing offices of the healthcare centres, although some were conducted in the patients’ homes. Inpatients were interviewed in a private area in the hospitalisation area. Patients in the Chronic Pain Unit were interviewed in the nurses’ office of the unit.The principal investigator trained all collaborating nurses in the measurement of the outcome An ad hoc questionnaire were used by the nurses to record the patients’ demographic and clinical data, as well as their own demographic and professional data. Two assessments were conducted. In the first assessment, patients self-reported the NPIS, the PCQ-R, and the ad hoc questions about their knowledge and satisfaction. Two nurses then independently assessed the KPM, concealing their score from the other nurse (to measure inter-observer agreement). In the second assessment, conducted after a 20–30 day interval (to measure sensitivity to change), patients answered the ad hoc questions again and the KPM was reassessed by one of the nurses who conducted the first measurement.The project was approved by the Research Ethics Committee of Jaén, Spain. Nurses and patients were given detailed information on the project and signed an informed consent form. Participant anonymity and data confidentiality were preserved in compliance with current data protection laws in Spain.® SPSS® statistics 19. IBM, International Business Machines Corporation, Armonk, NY, USA). Descriptive statistics were calculated. For nominal variables, frequencies and percentages were used. For continuous variables, means and standard deviations were used. Additionally, 95% confidence intervals were calculated for continuous variables.The data were collected in a spreadsheet  and analysed with SPSS  was performed using the principal components method with quartimax rotation to study the underlying conceptual structure of KPM. Sample adequacy was estimated with the Kaiser-Meyer-Olkin index and Bartlett’s test of sphericity, with riterion . In the Convergent and divergent validity was analysed using the multitrait-multimethod (MTMM) matrix ,41. In sIn order to assess reliability, internal consistency and inter-observer agreement were determined. Cohen’s kappa coefficient with quadratic weighting was used to determine inter-observer agreement, considering kappa values ≤ 0.20 to reflect poor agreement; values of 0.21–0.40, mild agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; and 0.81–1.00, excellent agreement. Internal consistency was calculated according to Cronbach’s alpha coefficient, considering values > 0.80 to indicate a good level of consistency ,41.p < 0.05.Sensitivity to change. The capacity of KPM to detect change was analysed by administering this outcome at two points in time separated by 20–30 days . Wilcoxon’s rank-sum test was used to evaluate the mean agreement between the measurements, with statistical significance set at A Spanish adaptation of KPM, semantically equivalent to the English version, was obtained. The adapted version has modifications to the label, to 17 indicators, and to the measurement scale, compared to the 5th and 6th Spanish editions of the NOC ,32,33.After review by the panel of experts, a version with 30 indicators was obtained . Overall, the CVI-ua was 0.33 and the CVI-a was 0.92. All indicators were rated as excellent with modified kappa scores ranging from 0.75 to 1.00 . ThirteeThe clinical validation study included 84 pain patients. n = 84), and 44 patients had a second measurement . The mean interval between the initial and final measurements was 42.84 (SD = 19.35) days.The most frequent nursing diagnoses (NANDA-I) were Chronic pain (42.9%) and Acute pain (11.9%). Patients were using different types of drugs , with scheduled non-opioid analgesics being more frequent . All 84 patients underwent a first (baseline) measurement . Pain was mainly located in the back (54.8%), lower extremities (48.8%), and pelvis (45.2%). The mean score obtained in the PCQ-R subscale “Seeking instrumental social support” was 8.73 points (SD = 4.29) (range: 0–16) .Knowledge: Pain Management was 3.24 (SD = 0.87) in the baseline measurement and 3.46 (SD = 0.77) in the final measurement. The lowest mean score was 2.52 (SD = 1.31) for the indicator “Potential medication interactions”, and the highest mean score was 3.98 (SD = 0.88) for “Importance of informing health professional of all current medication”. The scores for the 5 questions to patients about their knowledge and satisfaction with pain management are shown in The overall mean score obtained through the outcome p < 0.0001) showed that the data were suitable for analysis.Construct validity was assessed through an EFA. Taking into consideration the parallel analysis, the 30 indicators can be grouped into two factors. The Kaiser-Meyer-Olkin sample adequacy test (0.806) and Bartlett’s test of sphericity , Effective heat/cold application (variance = 0.353), and Available community resources (variance = 0.279), presented low proportions of explained variance and low factor loading values. As a result, they were eliminated.A second analysis with quartimax rotation showed a structure of 27 indicators distributed between two factors explaining 53.56% of the variance. The matrix of rotated factors shows their composition: (a) Knowledge about pain, made up of 25 indicators explaining 45.73% of the variance; (b) Non-prescription medication, made up of two indicators explaining 7.82% of the remaining variance .p < 0.001); and Q2 How well prepared are you to take care of yourself and to manage and control your painful condition? .Analysis using MTMM makes it possible to assess the convergent and divergent validity of KPM . For conp = 0.16) and with the PCQ-R subscale “Seeking instrumental social support” ; and no correlations with the three questions about satisfaction: Q3 How satisfied are you with the care provided by the nurses in relieving your pain? ; Q4 How satisfied are you with the treatment of your pain? ; and Q5 How much have you managed to improve your pain with the treatment and care provided by professionals? .For divergent validity, weak correlations lacking statistical significance were found with the score for the outcome Client satisfaction: Pain management . Agreement was excellent for 6 indicators and good for 20 indicators ), nor for either of the two ad-hoc questions: How much do you know about the causes, symptoms, and treatment of pain?  and How well prepared are you to take care of yourself and to manage and control your painful condition? . However, in the analysis of indicators, statistically significant differences were observed in six of them between the baseline and final measurements: Strategies for preventive pain management , Effective relaxation techniques , Effective distraction , Effective heat/cold application , Benefits of ongoing self-monitoring of pain , Available community resources .No differences were found between the baseline and final scores for the outcome KPM  of this outcome were tested in a sample of patients with pain. Nurses in Spanish-speaking contexts could use this adapted version of KPM to measure the degree of knowledge that their patients have about the causes, symptoms, and treatment of pain.This article report on the process to translate and adapt to Spanish context and culture the set of indicators included in the nursing outcome Following the principles of good practice ,42, duriThe content validity data suggest that the set of indicators is adequate for the conceptualisation of the KPM outcome in accordance with the recommendations made by Polit et al. , who proThe two-factor structure proposed in the final model for the KPM outcome makes it possible to explain a significant percentage of the overall variance, although a fraction of the variance remains unexplained, so it is likely that other indicators may be added in the future. Further studies are required to verify the suitability of this structure in other clinical settings and types of pain patients. Factor 1, Knowledge about pain, includes a considerable number of indicators addressing various concepts of pain, such as treatment and improvement strategies (13), aspects related to medication (9), and, to a lesser extent, signs and symptoms associated with pain (3), which point to the complexity of this factor. Factor 2, Non-prescription medication, has only two indicators. The correlations of these indicators with the total are the lowest on the whole list, which suggests that factor 2 needs an improved definition of the overall set and/or its indicators. This distribution of outcome indicators into two factors may be useful for nurses when deciding which indicators to use in assessing patients’ knowledge of different aspects related to pain and pain management, in line with other validation studies of other NOC outcomes ,44,45.We found evidence of validity of convergent and divergent criteria for the KPM outcome. Convergent validity was verified drawing on the strong correlations with the specific questions about knowledge and ability to control pain, as well as on each of the two proposed factors. In addition, the KPM outcome is well differentiated from other related yet different concepts, such as satisfaction with pain management and ability to cope, as shown by the divergent validity analysis.A more detailed analysis showed that some of the indicators referring to medication aspects had a weak correlation with the score on the ad hoc question about knowledge. At this point, it is pertinent to wonder whether the question was well configured in terms of content and scope for the population studied, as this suggests that knowledge about medication can be challenging for patients. The level of knowledge is associated with adherence to analgesic therapy , but knoWe found evidence of the reliability of KPM when used by nurses in patients with chronic pain. Inter-observer agreement was high for the overall set and most of the indicators. However, five indicators relating to medication had a low or moderate correlation , which mIt could not be established that KPM showed sensitivity to changes in patient knowledge in the overall score. Patients may not have experienced substantial changes in their knowledge which would explain why no significant changes were observed between the baseline and final scores. However, significant changes were observed in a group of indicators relating to various pain management and treatment strategies. In this study, the mean time interval between measurements was almost 43 days, longer than the interval in the study on the outcome Pain control (code 1605) , with 30Although no validation studies have been identified with which to compare the psychometric tests in this study, the usefulness of KPM has been demonstrated in other studies. As such, KPM has been validated for certain nursing diagnoses, Lucena et al.  validateA comprehension and cognitive equivalence test carried out with nurses, patients, healthy individuals, and even native speakers representing the target population  may improve the cultural adaptation process and provide a better adjustment of the concepts used to the cultural characteristics of the given geographical area ,51.Homogeneity in the training of participating nurses cannot be ensured, as they were included in the study because they were willing to collaborate and this may, therefore, lead to an overestimation of reliability. Attempts have been made to control bias by training participants in the conditions of the study, by diversifying participation , and by seeking the participation of advanced practice nurses .Patients were selected using convenience sampling and the sample size was relatively small. However, the representativeness of the study was improved by sampling at 9 different locations. Broader randomised samples and other additional care settings should be included to further increase knowledge of the psychometric properties of KPM. Some of the indicators included in the English version of this outcome were not included in the two-factor Spanish version, which may require further assessments. Additional studies are also necessary to increase the time between the baseline and the final measurements, seeking significant differences in the sensitivity to change of KPM and its indicators in patients with chronic pain.Knowledge: Pain Management, adapted to a Spanish context, includes 27 indicators. Evidence has been obtained of the reliability and validity of these indicators for use in nursing practice in Spanish-speaking contexts.The final version of the nursing outcome An internal structure of two factors, referred to as Knowledge about pain and Non-prescription medication, can be observed. This structure is novel and thus requires further research with larger patient samples, additional care settings, and acute pain scenarios. Being able to make an appropriate selection of indicators based on this two-factor structure may help nurses in their decision-making, especially the less experienced.The present study highlights an interesting field of research. Improving the definition and conceptual configuration of the outcome KPM, presenting an operational list of indicators, and increasing the input of psychometric testing through further research will not only consolidate the reliability and validity of this outcome, but will also make it more useful in the complex process of caring for individuals with pain.