Is it possible to replace the Shoulder Pain and Disability Index (SPADI) with a single substitute question for people with shoulder pain, when measuring disability and how well does this substitute question perform as a predictor for recovery.A prospective cohort study.A total of 356 patients with shoulder pain in primary care.Convergent, divergent, and “known” groups validity were assessed by using hypotheses testing. Responsiveness was assessed using the Receiver Operating Curve and hypothesis testing. In addition, we performed multivariate regression to assess if the substitute question showed similar properties as the SPADI and if it affected the model itself, using recovery as an outcome.The Spearman correlation coefficient between the total SPADI score and the substitute question was high, and moderate with the Shoulder Disability Questionnaire. The correlation between the substitute question and the EQ-5D-3L was low and the responsiveness was acceptable. The substitute question did not significantly contribute to both prognostic prediction models as opposed to the SPADI. Regardless all models showed poor to fair discrimination.The single question is a reasonable substitute for the SPADI and can be used as a screening instrument for shoulder disability in primary clinical practice. It has slightly poorer predictive power and should therefore not be used for prognosis. Activity limitations are one of the most important health consequences for patients with shoulder pain . ActivitBoth the Shoulder Pain and Disability Index (SPADI) as the Shoulder Disability Questionnaire (SDQ) are PROMs focusing on activity limitations. Several (systematic) reviews have encouraged the use of the SPADI in both clinical and research settings –7.A survey among physical therapists (PTs) concluded that PROMs are most often used to ensure quality of care, to communicate with other health care providers, and to determine progress (outcomes) of individual patients . These fNevertheless, PROMs are not (fully) integrated into clinical practice yet. A survey among nearly 500 PTs concluded that only half of them regularly used a PROM during their work ; this isSeveral initiatives have been started as a response to these concerns to facilitate the integration of PROMs in clinical care. Clinicians prefer PROMs that can be completed quickly (70%) . TherefoWe therefore aimed to develop and evaluate the validity, responsiveness, and predictive power of a single substitute question for the SPADI as this might be helpful to integrate a PROM into clinical practice.This is a secondary analysis of a prospective cohort study (ShoCoDiP-study), including patients with shoulder pain in physiotherapy setting. Aims of the ShoCoDiP-study were e.g., to evaluate physiotherapy care and prognostic factors in patients with shoulder pain and investigate whether Musculoskeletal ultrasound and the working alliance are related to patient recovery. Details of the design are presented elsewhere . The MedPatients were recruited from primary care physical therapy clinics between November 2011 and December 2012. Patients with shoulder pain were eligible for inclusion if they were at least 18 years old and adequately understood the Dutch language. Patients with serious pathology , previous surgery or diagnostic imaging techniques of the shoulder, such as Magnetic Resonance Imaging or Ultrasound in the previous 3 months, were excluded .In a focus meeting with the ShoCoDiP-project team , various items were discussed that could act as a substitute question to cover the entire domain of the SPADI questionnaire. The final substitute question was chosen based on consensus within the research team: “Please state the amount of limitation in daily activity you experience due to your shoulder pain.” This question could be answered on an 11-point scale, where 0 = no limitation at all and 10 = completely disabled.Participating patients received an online questionnaire that included items focused on demographic characteristics, pain intensity [Numeric Rating Scale (NRS)], disability , and health-related quality of life (EQ-5D-3L).The 11-point NRS was used to capture the patient’s pain intensity. The scale is anchored from “no pain” to “worst imaginable pain.” Patients rate their current level of pain and their worst and least amount of pain in the last 24 h. The NRS has shown to be valid, reliable, and responsive in patients with shoulder pain [The SPADI is a self-administered questionnaire designed to measure pain and disability associated with shoulder pain. It consists of 13 items and each question refers to the past week. Five items measure severity/intensity of pain, and eight items measure disability. Items can be scored on a scale ranging from 0 to 10, where 0 represents “no pain/no difficulty” and 10 “worst pain imaginable/so difficult it requires help” [es help” , 19. Thees help” . The Dutes help” , 21.The SDQ is a pain-related disability questionnaire developed in Dutch, which consists of 16 items [16 items . All ite16 items . The SDQ16 items .The EQ-5D-3L is a health-related quality of life questionnaire covering five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [pression . Responspression .All patients received the SPADI-D, the SDQ, the substitute question, and the Global Perceived Effect (GPE)-scale 26 weeks after initial presentation. Within this period, the patient received individualized physical therapy treatment for 1 or more sessions. Outcome measure was perceived recovery by the patient, measuring with the GPE-scale. The GPE-scale is a 7-point scale scoring whether the patient’s condition has improved or deteriorated. This scale ranges from “completely recovered” to “worse than ever.” The GPE-scale has good test–retest reliability and correlates well with changes in pain and disability .All statistical analyses were performed with SPSS 23. For this study, all patients that did not answer the substitute question were excluded. Handling of missing items for the SPADI and SDQ was performed as described by the original authors , 23. ThiAll data were checked on normality, using a Stem-and-leaf Plot, Q-Plot and Whisker box. Non-parametric tests were used if data were not normally distributed. Descriptive statistics were used to calculate frequencies.r < 0.30 as low (a negligible correlation); 0.30 ≤ r < 0.45 as moderate; 0.45 ≤ r < 0.60 as substantial and r ≥ 0.60 as high [Correlations were calculated using the Pearson correlation coefficient in case of a normal distribution of the data, otherwise a Spearman correlation coefficient was used. Correlations were rated as follows:  as high .Convergent validity relates to the extent to which a particular instrument corresponds to the construct  of shoulder pain and function [r ≥ 0.60). We also measured the correlation between the substitute question and the SDQ, as the instruments are based on a similar construct, we expected a high correlation as well, but lower than the correlation with the SPADI (as the substitute question is designed to replace the SPADI). The SDQ has a different type of answering option and the focus of the SDQ lies on “pain during an activity,” as opposed to the SPADI of which the majority of questions is focussed on “difficulties with performing an activity due to pain.” We therefore expected the substitute question to be highly correlated (r > 0.60) with the SPADI and substantially correlated (r between 0.45 and 0.60) with the SDQ [function . As the  the SDQ .Divergent validity relates to the extent to which a particular instrument does not correspond to the construct  of shoulder pain and function. As two items of the EQ-5D-3L and the substitute question are based on different constructs (the mobility-item and the item anxiety/depression), we expect the correlation coefficient between both to be low (r < 0.30) [ < 0.30) .Known groups validity We assumed that patients with high initial pain  and work absence would have a higher level of perceived disability. Both groups had been chosen a priory. The independent sample Mann–Whitney U test was used to test the difference between known groups.Responsiveness was assessed using the area under the ROC curve (AUC) and hypothesis testing. Patients were selected if they completed the SPADI-D and the substitute question at baseline and follow-up and the GPE-scale at follow-up at 26 weeks.We calculated the AUC to assess the ability of the substitute question to discriminate between patients who are considered improved and not importantly changed according to the GPE, using a frequently used anchor and considered patients as recovered when they answered they were ‘completely recovered’ or ‘much improved’ and as not importantly improved when they answered ‘slightly improved,’ ‘no change,’ or ‘slightly worse’ –30.A benchmark that has been previously used to establish that outcome measures are useful in discriminating improved and unimproved patients has been set at 0.70 AUC .r between 0.45 and 0.60) was also expected between the change score of substitute question and the change score of the SPDQ and the GPE-scale. Correlations between the change score of the substitute question and the change score of EQ-5D-3L mobility as well as the anxiety/depression item were expected to be low (r < 0.30).Hypothesis testing for responsiveness was based on the concept that the correlation between the change score of related constructs (SPADI) must be high. Hypothesis testing was quantified by the Pearson correlation coefficient in case of a normal distribution of the data and otherwise a Spearman correlation coefficient was used. Correlation coefficients between the substitute change score and the SPADI change score were expected to be above 0.50 . A substMultivariate logistic regression analysis was used to predict recovery after 26 weeks. All assumptions (linearity between independent variables and log odds and multicollinearity (>0.80) for continuous variables) were checked before model building. We included no more than one independent variable per ten events  in the multivariable analysis .A systematic review concluded that there was moderate to strong evidence that high pain intensity, increasing age, a longer duration of complaints, and high disability at baseline predict a poorer outcome in patients with shoulder pain . AnotherPatients were selected if they completed the GPE-scale at follow-up at 26 weeks and all items of interest at baseline . We checked if there were significant differences in the relevant characteristics between the patients selected in this analysis and those excluded.Initially, three different models were built. The first model included all predictors  retrieved from the systematic reviews , 34. In A sensitivity analysis (model 4) was performed by adding relevant prognostic factors as found in our own analysis in the total cohort  and not R2), the discriminative ability (AUC), and the reliability of the models (Hosmer and Lemeshow). We considered a comparable (<15% difference) overall correct percentage and Nagelkerke R2 in model 2 and 3, as an indication that it might be valid to replace the questionnaire by its substitute question in predicting outcome. An AUC can be categorized into four categories: poor discrimination (between 0.5 and 0.7), fair discrimination (between 0.7 and 0.8), acceptable discrimination (AUC > 0.8), whereas an AUC of 1.0 indicates perfect discrimination [We assessed the prognostic power , using the We repeated this process for the sensitivity analysis with different predictors (model 4–6).A total of 389 patients responded in our cohort study, 19 of them did not return the SPADI at baseline. We excluded another 14 patients due to too many missing data on the SPADI or SDQ. Of these 356 patients, all answered the substitute question and were therefore included in this study. Demographic characteristics are presented in Table The data of the substitute question were not normally distributed. The median score of the substitute question was 4 points with an interquartile range (IQR) from 2 to 6. The SPADI was normally distributed and had a mean of 46.7 (21.3).As it is unusual to compare data presented in different ways, we also presented the median of the SPADI  in order to facilitate a swift visual inspection of the score of the question of interest (the substitute question) and the score of the total SPADI.The Spearman correlation coefficient between the substitute question and the total SPADI score was 0.74 and with the SDQ 0.59. Our hypotheses were confirmed as the substitute question showed a high correlation with the SPADI and a substantial correlation with the SDQ.The spearman correlation between the substitute question and the mobility-item of the EQ-5D-3L was 0.23 and with the item anxiety/depression 0.20. Our hypotheses were hereby confirmed as the correlation was low between the instruments that measure a different construct and the substitute question.Differences between “known groups” were statistically significant Table .Table 2KThe AUC was 0.76 with a 95% confidence interval ranging from 0.70 to 0.83. Figure Hypothesis testing for responsiveness resulted in a Spearman correlation between the SPADI-D change score and the substitute change score of 0.71 and 0.60 with the SDQ change score. The spearman correlation between the GPE and the substitute question was 0.47. The Spearman correlation between the substitute question and both the mobility as the anxiety/depression item of the EQ-5D-3L was 0.10.Based on the AUC values and confirmation of the hypothesis, we consider the substitute question to be a responsive measurement instrument.n = 250) and those excluded (n = 106) .Model 2 consisted of the following variables: age, pain, duration of complaints, and the SPADI. The Chi-Square test for adding the SPADI was significant (χ2 test for adding the substitute question was not significant (p = 0.193).Model 3 consisted of the following variables: age, pain, duration of complaints, and the substitute question. The All three models showed poor discrimination and the AUC values were within the 95% CI intervals of each other. Differences between both models were small Table . The larR2 was 0.127.The basic model (model 4) consisting of age, duration of complaints, pain, employment and not being depressed and was based on 241 patients, as nine patients had a missing value regarding employment or depression. The correct overall percentage was 63.9% and the Nagelkerke χ2 Omnibus test for adding the SPADI was significant (p = 0.039).Model 5 included all predictors plus the SPADI. The χ2 test for adding the substitute question was not significant (p = 0.501) Table Model 6 included all predictors plus the substitute question. The All models showed poor discrimination, with small differences. The largest differences were found between the Hosmer and Lemeshow goodness of fit of model 4 and 5; however, both were non-significant. The odds of the SPADI and the substitute question were again quite exchangeable; however, the confidence interval of the substitute question was wider.Measurement with the single question can be completed in a shorter amount of time as compared with the SPADI, which takes about 3 min to complete. This could have impact on the use of the instrument in clinical practice and increase the integration of patient-reported outcome measures (PROMs), as the most common reasons for not using them are that they are too time consuming for patients to complete and too time consuming for clinicians to analyze. Quality of life research revealed that both single questions and multi-item scales have a high potential as well as some disadvantages at the same time . They stHowever, the predictive power of the substitute question is not entirely equal to the SPADI as the substitute question did not significantly contribute to both models according to the Chi-Square test, as opposed to the SPADI. Regardless, switching between the SPADI and the substitute question did not have a great impact on the AUC, as all models (with the SPADI and the substitute question) showed poor discrimination. The predictive power of the model including the substitute question for predicting recovery was slightly lower (10%) compared to the model with the SPADI (13%), which are both poor. As these prediction models should be used carefully, this especially applies to using the substitute question as a predictor.Not many studies have been published regarding a substitute question. One study reported that a single self-reported question to assess habitual physical activity is valid and responsive to change and thus useful for epidemiological research in community-dwelling older people, also in follow-up studies. They found correlations between self-reported habitual physical activity and mobility and accelerometer-based physical activity variables . AnotherThis is a new type of research, which is focused on a very pragmatic solution regarding the disuse of PROMs. The population consisted of patients from primary care, a population that is very important within the health care system and where pain-related disability is a relevant issue. We had a relatively high number of included patients, although this could have been higher if we had chosen to use imputation techniques instead of excluding patients due to the missing item criteria. We chose to respect these criteria, as our aim was to assess whether or not the substitute question might be feasible to replace the SPADI, and the criteria of the PROMs itself are therefore more important than to use imputation techniques, in order to make a more steady prediction model due to the higher number of included patients. As the demographic characteristics of the included and excluded patients did not differ, it seems unlikely that there is selection bias regarding the inclusion of patients in the responsiveness and predictive power analyses. There were no remarkable deviations with regard to the patient characteristics of the complete study population compared to the target population (patients with shoulder pain in primary care) as far as we could discern, e.g., the number of participating females was higher than the number of participating males, which is in line with the gender-specific incidence , as was Patients were asked to answer if their shoulder pain had changed since the beginning of treatment. The time between baseline and follow-up was 26 weeks, which might have influenced their recollection of their shoulder problem at the beginning. Although this is common practice, this could have an impact on the results.Although the SPADI is designed as if it consists of two parts (pain and disability), we chose to only formulate one substitute question and to assess the correlation with the total SPADI. The theoretical deviation into two separate parts has not been confirmed in our earlier study . As the It is important to test the content validity of the substitute question, with patients, clinicians, and experts together. Besides, the reliability, validity, responsiveness, and predictive value should be further assessed before this question can be used in clinical practice.The correlation between the substitute question and the full SPADI was relatively high. Combined with acceptable responsiveness, the substitute question can potentially be used as a screening instrument for shoulder disability in primary clinical practice. The single question has slightly poorer predictive power than the complete SPADI, and should therefore not be used for prognosis at this moment.


Cancer has become increasingly prevalent in China over the past few decades. Among the factors that determine the quality of life of cancer patients, pain has commonly been recognized as a most critical one; it could also lead to the ineffective treatment of the cancer. Driven by the need for better pain management for cancer patients, our research team developed a mobile-based Intelligent Pain Management System (IPMS).Our objective was to design, develop, and test the IPMS to facilitate real-time pain recording and timely intervention among cancer patients with pain. The system’s usability, feasibility, compliance, and satisfaction were also assessed.A sample of 46 patients with cancer pain symptoms were recruited at the Oncology Center of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch (hereinafter referred to as “the Oncology Center”). In a pretest, participants completed a pain management knowledge questionnaire and were evaluated using the baseline cancer pain assessment and Karnofsky Performance Status (KPS) evaluation. The participants were then randomly assigned into two groups . After a 14-day trial period, another round of cancer pain assessment, KPS evaluation and pain management knowledge assessment were repeated. In the trial group, the data were fully automatically collected by the IPMS. In the control group, the data were collected using conventional methods, such as phone interviews or door-to-door visits by physicians. The participants were also asked to complete a satisfaction questionnaire on the use of the IPMS.P<.001). The ending KPS score of the trial group was significantly higher than of the control group (P<.001). The improvement of pain management knowledge score in the trial group was more pronounced than that in the control group (P<.001).All participants successfully completed the trial. First, the feasibility of IPMS by observing the number of daily pain assessments recorded among patients was assessed. Second, the users’ satisfaction, effectiveness of pain management, and changes in the quality of their lives were evaluated. All the participants gave high satisfaction score after they used IMPS. Both groups reported similar pain scores and KPS scores at the baseline. At the end of the trial, the mean pain score of the trial group was significantly lower than of the control group  Cancer has become a leading cause of human death globally. The World Health Organization (WHO) estimated that cancer resulted in 8.2 million deaths in 2012 . Due to Research indicates that over one-third of cancer patients experience cancer pain, and this is known to be a major reason for lower quality of life for the patients ,6. The uAnother problem that China is facing is a wide resource gap across age groups and geographical areas. China is on its way to an aged and eventually super-aged nation in an accelerated pace on account of its economic growth and longstanding population policy. An increasing number of elderly people in cities and rural areas are in need of medical attention. Unlike many developed countries in the western hemisphere, China has very limited medical resources to cure and care for cancer patients in the underdeveloped rural areas. There is a critical shortage of medical doctors, nurses, and other medical professionals in China. A 2011 study shows that China has the doctor-to-resident ratio of 2.8 doctors per 1000 urban residents, whereas in the rural areas such ratio declines to 0.95 doctors per 1000 rural residents . TherefoIntelligent Pain Management System (IPMS) is a low cost, conveniently implemented system to facilitate real-time pain recording and timely intervention among Chinese cancer patients. This system has multiple features relying on mobile phones to evaluate real-time pain and KPS scores  for qualThe IPMS used in our research was designed to operate on the Android mobile operating system, in order to provide an affordable, portable, and easy to use environment for patients. The system design was performed by the Xinhua Translational Institute for Cancer Pain in Shanghai, China . The design team adopted a modularity approach consisting of several functional subsystems to facilitate speedy development by multiple teams. The core system consisted of four modules: Life Quality Self-evaluation, Cancer Pain Self-evaluation, Real-time Messaging, and Standard Medication . After sThis module consisted of two questionnaires. A KPS questionnaire was used to obtain the KPS score  and anotThis core module of IPMS was designed to track patients’ self-reported pain data. It contained two submodules: a daily pain assessment submodule and an instant pain assessment submodule. The daily pain assessment submodule  displayeIn addition, a list of pain medications was displayed to allow the patients to report their medications and their effectiveness. Lastly, a final pain assessment questionnaire consisted of 8 aspects (14 questions) to investigate other influences of cancer pain in their daily life, such as movement, hobbies, and relationships with family members, was administered. In the instant pain assessment submodule , NRS wasThis module was designed to assist patients to initiate a real-time consultation session on pain management with the doctors .This module was designed to remind patients of their medication schedule  so that An experiment was designed to test the effectiveness of IPMS on cancer pain management. The experiment involved two groups: an IMPS trial group and a control group.The participants in the trial group were asked to complete a first day’s pain assessment questionnaire and the quality of life questionnaire on the mobile phones provided to them. Participants were then encouraged to use the IPMS as much as possible to record their pain status at least once every day for 14 days. They were asked to report the pain scores through the IPMS only. All other measurements were conducted by self-report questionnaires without face-to-face assessments.The control group was reached through conventional telephone calls or door-to-door visits to collect pain assessment data on a daily basis for 14 days.The primary objective was to assess the feasibility of the IPMS by observing the number of daily pain assessments recorded among the cancer patients.The secondary objective was to evaluate the effectiveness of pain management, changes in the quality of their lives, and users’ satisfaction with IPMS app.The IPMS satisfaction evaluation questionnaire was completed by participants at the end of the study. Each questionnaire involved multiple 5-point Likert scores with ratings associated with the options “extremely like it” (5 points), “like it” (4 points), “okay” (3 points), “dislike it” (2 points), and “extremely dislike it” (1 point). The data generated after the survey were used to evaluate the satisfaction of IPMS usage. The questionnaire also contained an open-ended question where participants were encouraged to give any other suggestions about IPMS they felt needed improvement.A baseline pain assessment and a KPS evaluation were conducted using numerical rating scale (NRS) in both groups. After obtaining the consent, nurses conducted a standardized education session using a booklet to teach the participants proper pain-related and rating system knowledge. At the end of the trial, the pain assessment and KPS evaluation were repeated in both groups.All participates were asked to complete a general information questionnaire on pain management containing five questions  upon regThis study was registered online at ClinicalTrials.gov . With ethical review approved by the Medical Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, a randomized, controlled IPMS trial was conducted at the Oncology Center of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch (hereinafter referred to as “the Oncology Center”). The study lasted from April 2016 to May 2016 in the Oncology Center with no changes to the study design and methods. The random allocation processes, how to enroll participants, as well as how to assign participants to intervention, were determined by physicians.An original sample of 60 patients was recruited at office visits or in hospital visits in the center by physicians. The participating patients met the following screening criteria: (1) the patient was able to read Chinese and use a mobile phone; (2) the patient was aged between 45 and 70 years; (3) the patient was diagnosed with cancer and had self-reported cancer pain within a month prior to the study; (4) the patient was being seen on a regular basis by the oncology team; (5) the patient was under standard analgesia treatments; (6) the patient was estimated to have over 3 months survival time. Patients who self-reported to have severe cognitive impairments or major comorbid illnesses that would interfere with pain assessment were excluded from the experiment. For example, patients who received radiation therapy were excluded due to possible burning pain from the therapy. In April 2016, a total of 46 qualified cancer patients  were finally included in this study.Included participants were randomly allocated on a 1 to 1 ratio to either the IMPS trial group or the control group. Random allocation (simple randomization) of the participants was automatically performed using the random number table.All participants were then randomly assigned into two groups: an IPMS trial group (25) and a control group (21). The trial group had 6 (24%) females and the control group had 8 (38%) females. The participants’ demographic information as well as their disease characteristics were summarized in Each participant in the trial group was provided an Android mobile phone with the IPMS loaded free of charge. They were given a demonstration and training by nurses and physicians on how to operate the smart phone and the IPMS app.t-test and the Chi-square (χ2) test were used to analyze the differences  in pain controlled duration and breakthrough pain between the trial group and the control group. The significant difference was determined by P<.05.The outcome assessor was blinded to the data collection. The collected data were analyzed using the R Statistical Software Package 3.1.3. Independent Student’s P>.05). Further analyses showed that the total number of pain assessments between the day times and the night times was 1.82 (SD 0.43) vs 0.56 (SD 0.18), respectively. In addition, there was no significant difference between the usage times of weekdays and weekends .The compliance rate was consistently high over the course of the trial with no statistical difference in total number of daily pain assessment between week 1 and week 2  between the two groups. Over the 14-day trial period, the average pain score of the trial group was 2.53 (SD 0.42), compared with 2.81 (SD 0.47) of the control group with a significant difference (P<.001). At the end of the trial period, the average pain score of the trial group was 2.20 (SD 0.50), compared with 2.95 (SD 0.59) of control group with a significant difference between the two groups, P<.001 . Although both groups demonstrated increased pain management knowledge, the IPMS trial group indicated a higher score increase in pain management knowledge than did the control group.As to the evaluation of the acquired pain management knowledge after 14 day’s IPMS interaction, there was a 2.96 (SD 0.61) increase in the knowledge score of the trial group after using the IPMS for two weeks, compared with a 0.81 (SD 0.67) increase of the control group (P=.94) before the participants had entered into the trial. At the end of the trial, the KPS was re-evaluated in the two groups . Both groups increased mean KPS significantly from the baseline, but the mean increase in the IPMS trial group was significantly larger than the mean increase in the control group .Another application of the IPMS was the education and evaluation of quality of life through KPS scores. The baseline KPS scores in the IPMS trial group were no different than those of the control group  indicated “very much like it (the IPMS)” and 16 (64%) indicated “like it (the IPMS).” No participant indicated dislike of the IPMS. On the helpfulness of the IPMS, 20 (80%) responded “very helpful” and 5 (20%) responded “helpful.” On the software technical support, 18 (72%) indicated “very much like it” and 7 (28%) indicated “like it.” On the consultant and training course, a majority of participants 18 (72%) reported “very much like it” and (7) 28% reported “like it.” On the prompt response for help, 7 (28%) indicated “very much like it,” 11 (44%) indicated “like it,” and 7 (28%) indicated “okay.” The average score of each question is shown in This research involved a cohort of cancer patients with cancer pain in a study of the usability and effectiveness of an IPMS system designed for this study. We presented data on the compliance, satisfaction, evaluation of pain management in a 2-week clinical trial. Overall, the study demonstrated that the IPMS gained a high rate of compliance and satisfaction among the participants. With little or no additional clinical intervention, IPMS had the potential to improve pain management and quality of life for cancer patients with cancer pain.To the best of our knowledge, this study could be the first to report on the development, usability testing, and evaluation of cancer pain and KPS with an intelligent pain management system through mobile applications in China. A search of the literature has yielded several reports on the assessment of usability of technology-based interventions on cancer pain. However, majority of past research were based on telephone interventions to connect patients with health providers ,24. StinThis study implemented the telephone-based intervention as the control group to compare with the mobile Internet-based IPMS. The IPMS was developed as a multidimensional tool not only for real-time pain assessment but also for KPS evaluation, medication reminder, real-time messaging consultation, and pain management education. Such mechanism was able to convey clinical assistance and intervention between the health providers and the patients in an efficient and effective way. It was the real-time messaging that mattered to the patients’ pain management. The IPMS allowed patients to be able to instantaneously assess and report pain, thus the doctors were able to provide prompt advice on the dosage change of pain control medication, which was not possible in traditional ways. The rapid adoption of mobile devices in China provided a promising future of the IPMS in cities and rural areas. We are expecting that the IPMS will become a popular communicating vehicle between physicians and cancer patients in the near future.The clinical trial yielded a perfect compliance rate (100%) of the IPMS use regardless of time—day times or night times, weekdays, or weekends. The compliance rate was consistent over the course of the trial with no significant difference between week 1 and week 2. The slightly heavier usage at the night times highlighted the potential of IPMS, as obtaining the pain data at night times was always a challenge through conventional methods. Real-time pain satisfaction assessment data have been valuable for researchers and care providers. With a powerful tool as the IPMS, we may be able to better understand the pain burst out patterns and provide timely response to the patients’ need, allowing for improved pain management and higher quality of pain treatment.Through the usability test, we were able to test the user interface and the basic functions of the IPMS. The patient satisfaction rate was high for its easy use, as well as being helpful for the consultant and training courses. However, there was still room for improvement in terms of prompt response for help. As this is the first smart phone app for pain management for both patients and healthcare professionals to use, it may take time for both parties to get used to the system. A clinical study of longer duration will be conducted to address this question in the near future.In this study, the improvement of cancer pain management was more pronounced in the IPMS trial group than in the control group, which suggests that IPMS is beneficial. Testing data also revealed that the knowledge of pain management and quality of life were all significantly increased in the IPMS group compared with the control group. Patients in both groups were exposed to same levels of clinical care, educational program, and pain management knowledge training. The reason the IPMS group had more benefit, may be due to the interactive-feedback learning mechanism that gave the trial group patients more confidence and knowledge to deal with pain management. A similar phenomenon has been observed and reported by Liu LF group in the literature .This study had several limitations that may tamper our results. First, the duration of the trial period was relatively short and the sample size was relatively small. Due to the limited sample size, the distribution of cancers types was not balanced between groups as certain types of cancer had only 1 patient in the sample. The clinical trial group was drawn from a patient pool with different stages of cancer, which may limit the generalizability of this study. Future study is warranted to test the effectiveness of IPMS with a larger sample of participants and longer time period with improved randomization and balance.In conclusion, this study underscored the feasibility and acceptability of IPMS as a novel and effective pain assessment tool for patients with cancer pain. Participants found the system easy to use and helpful. IPMS was found to be beneficial for pain management, quality of life, and pain management education in a 14 days’ clinical trial. It is believed that IPMS has the potential to change the current atlas of pain management in China, especially in underdeveloped rural areas with improved efficiency and effectiveness of pain management and interactions between cancer patients and health professionals.


The aim of this study was to investigate the effects of preemptive analgesia on the inflammatory response and rehabilitation in TKA. 75 patients with unilateral primary knee osteoarthritis were conducted in this prospective study. All patients were randomly divided into two groups . The following parameters were used to evaluate analgesic efficacy: knee flexion, pain at rest and walking, functional walking capacity (2 MWT and 6 MWT), WOMAC score, and hs-CRP level. Patients in MMA with preemptive analgesia group had lower hs-CRP level and less pain at rest and walking during the first week postoperatively (P < 0.05). The 2 MWT was significantly better in MMA with preemptive analgesia group . The 6 MWT scores and WOMAC scores increased significantly within Groups , but no difference between groups postoperatively (P > 0.05). Less cumulative consumption of morphine was found in MMA with preemptive analgesia group at 48 h , but no difference at total requirement (P = 0.113). Preemptive analgesia added to a multimodal analgesic regime improved analgesia, reduced inflammatory reaction and accelerated functional recovery at the first week postoperatively, but not improved long-term function. Although each method has been considered effectively in relieving postoperative pain, side effects can hardly be avoided. Multimodal approaches (MMA) provides a better choice with minimizing side effectset al. found that C-reactive protein considerablly increased in patients with total knee arthroplastyet al. found that elevated levels of CRP was correlated with symptoms of pain, stiffness, and radiographic grading in OAInflammatory reaction is a major component of surgical stress responseThe aim of this study was to investigate the effects of preemptive analgesia on the inflammatory response in patients with or without preemptive analgesia. In addition, we investigated whether preemptive analgesia leaded to low postoperative pain and better rehabilitation.The study protocol was approved by the Ethics Review Committee of Changzhou Traditional Chinese Medical Hospital, affiliated to Nanjing University of Traditional Chinese Medicine. Verbal and written informed consents were obtained before all study. The study was carried out in accordance with the approved guidelines.From February 2013 to February 2014, seventy-five patients, ASA I–III, aged 54–76  years, diagnosed with unilateral primary knee osteoarthritis were conducted in this prospective study. All enrolled patients were randomly allocated using a random-number table to receive MMA with/without preemptive analgesia. Exclusion criteria included inflammatory arthritis, alcohol or medical abuses, autoimmune disorder used steroid medication, and neurologic or psychiatric diseases potentially influencing pain perception.All surgeries were done by one experienced orthopaedic surgeon with a specialist interest in arthroplasty. Prostheses were rotating platform for artificial knee joint . The routine anaesthesia method were lumbar spinal anaesthesia  or general Anaesthesia . The tourniquet and wound drain were used in each case, and the drain was removed after 48 h postoperatively. Low Molecular Weight Heparin Sodium  was used for thromboprophylaxis once daily post- operatively until discharge. The hospital stay was 14 days postoperatively. Mobilization started from the day of surgery with the same rehabilitation scheme by one physiotherapist. After satisfactory radiograph, patients would leave the bed ambulating with walking aids. While on the bed, they would sit on the edge of the bed dependent on their tolerance. On the following days, patients attended rehabilitation twice a day to perform exercises. According to the patient’s tolerance, the distance increased gradually.Follow-up duration was defined as the date of operation to the date of last visit. Range of motion (ROM), pain at rest, pain at walking were measured at 8:30 a.m. during hospitalization. Hospital narcotic analgesic use, side-effects and complications were also recorded during hospitalization. After discharge, pain, ROM and functional results were evaluated at each follow-up. All parameters were measured before operation.A preemptive oral analgesic regimen of celecoxib  was administered to each patient within 1 hour before operation without any other premedication121314A standardized, multimodal analgesic regime with cocktail injection was administrated. The cocktail  was administered pre- and post-cementation. The first injection was administered to posterior capsule, posteromedial structures and periarticular synovium. The second injection was administered to extensor mechanism, pes anserinus, anteromedial capsule, periosteum, iliotibial band and subcutaneous planeAs a primary analgesic, celecoxib (200 mg PO) was administered twice daily starting 12 hours postoperatively and continued throughout their hospital staySystemic inflammation was measured by high-sensitivity C-reactive protein (hs-CRP) in venous blood before operation, daily at the first week, 2 weeks, 1, 3, 6 months after surgery. Venous blood sample was taken from each patient at 7 a.m.Hs-CRP was tested by Simens BN II analyser  according to the manufacturer’s instructions. The normal range for Hs-CRP values: Low risk ≤1 mg/L. Normal = 1–3 mg/L. High risk ≥3 mg/L.Knee flexion was measured in supine lying using a goniometerThe quality of postoperative pain relief was measured by morphine consumption and the visual analogue scale. Patients were asked to mark their level of pain on a 10 cm visual analogue scaleThe 2 min walk test (2 MWT) and 6 min walk test (6 MWT) were used to evaluate functional walking capacityThe Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was administered to assess the knee function2 test or Wilcoxon’s rank sum test.The normality of distribution for continuous numeric variables was assessed by Kolmogorov–Smirnov test. According to normally distributed or not, the variables are presented as means with SD, and otherwise as medians with inter-quartile ranges . Student’s t-test for normally distributed continuous variables, while others using Pearson’s χContinuous data with repeated measures were analysed using repeated-measures regressions for general linear models. Bivariate analysis was used to analysis the relation of different studied variables.The SPSS statistical package  was used for statistical analyses. P < 0.05 was considered as a positive significance.Seventy-five patients were assessed for eligibility in this study and randomly divided into two groups . Baseline pre- and perioperative was similar in both groups .Patients in MMA with preemptive analgesia group had lower hs-CRP level during the first week postoperatively , but negatively correlated with ROM .Less pain at rest and walking were found in MMA with preemptive analgesia group (P < 0.05), but no difference after the first week. No significance was found about severe pain at rest or during walking on the further follow-up .On the follow-up of three months, one patient in MMA with preemptive analgesia group and two patients in MMA without preemptive analgesia group reported moderate pain during walking and recovered by celecoxib.Less cumulative consumption of morphine was found in the MMA with preemptive analgesia group from 0 to 48 h , but no differences on day 7 and week 2 . When repeated 1, 3, 6 months postoperatively, the 6 MWT scores increased significantly within groups (P = 0.020), but no difference was found in both groups .Similarly, the changes in WOMAC scores were statistically significant (P = 0.000), with no difference between groups  could reduce the overall pain for the first 48 h after TKA, and improve analgesia and immediate recovery postoperativelyet al. concluded that a certain amount of glucocorticoid was necessary for reducing opioid consumption and postoperative painet al. studied the relationship between inflammatory responses and functional recovery in hip arthroplasty, and concluded that the inflammatory response was related with immediate functional recovery. And attenuation of the inflammatory meant less pain and better functional recoveryThe pain was significantly reduced in the first week postoperatively in MMA with preemptive analgesia group. No difference was found after 1week postoperatively. Despite we prolonged the assessment of pain upon rest and walking, no prolonged analgesic effect was observed. Lunn TH, et al. found that amide local anesthetics could suppress markedly the metabolic activation and secretory function of leukocytes in a dose-dependent mannerCelecoxib could effectively attenuate the hyperalgesia of afferent and efferent fibers by attenuating inflammatory response. Previous study had concluded that local anesthetics could modulate the inflammatory response in mice systemically or locallyThe nerve fibers around surgical area of the knee covers: the femoral nerve (anterior), the obturator nerve , the lateral femoral cutaneous nerve  and the sciatic nerve (posterior). Periarticular infiltration of local anaesthetics may provide good analgesia locally and improve walking capacityBecause of less use of opioids in both groups, PONV was not a serious clinical problemOur study did not supply a more detailed explanation for the preemptive analgesic benefit. However, suppressing the system inflammatory response (hs-CRP) means less inflammatory mediators in nociceptive processingOur study had several strengths: this was a prospective controlled study. All patients were screened and followed at one single centre and received standardized pre-, peri-, and postoperative regime. The detailed assessment of outcomes was collected by one single data collector, resulting in few missing data.However, there were also limitations to our study, including a relatively small sample size. Nevertheless the small number of patients illustrated the importance of preemptive analgesia on inflammatory response and postoperative functional outcome.In conclusion, preemptive analgesia oral analgesic regimen added to a multimodal analgesic regime improved analgesia, reduced inflammatory reaction and accelerated functional recovery atthe first postoperative week, but not improved long-term function. Therefore, these outcomes are important to determine optimal pain management after TKA.How to cite this article: Jianda, X. et al. Impact of Preemptive Analgesia on inflammatory responses and Rehabilitation after Primary Total Knee Arthroplasty: A Controlled Clinical Study. Sci. Rep.6, 30354; doi: 10.1038/srep30354 (2016).


Objective: Previous research indicates that pain treatment may improve sleep among nursing home patients. We aimed to investigate the long-term effect of pain treatment on 24-h sleep patterns in patients with comorbid depression and dementia.Design: A 13-week, multicenter, parallel-group, double-blind, placebo-controlled randomized clinical trial conducted between August 2014 and September 2016.Setting: Long-term patients from 47 nursing homes in Norway.Participants: We included 106 patients with comorbid dementia and depression according to the Mini Mental Status Examination (MMSE) and the Cornell Scale for Depression in Dementia (CSDD).Intervention: Patients who were not using analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets. Those who already received pain treatment were randomized to buprenorphine transdermal system (maximum 10 μg/h/7 days) or placebo transdermal patches.Measurements: Sleep was assessed continuously for 7 days by actigraphy, at baseline and in week 13. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset (WASO), early morning awakening (EMA), and number of wake bouts (NoW) were evaluated. In addition, daytime total sleep time (DTS) was estimated. Pain was assessed with Mobilization-Observation-Behavior-Intensity-Dementia-2 Pain Scale (MOBID-2).Results: The linear mixed model analyses for TST, SE, SOL, WASO, EMA, NoW and DTS showed no statistically significant differences between patients who received active pain treatment and those who received placebo. Post hoc subgroup analyses showed that there were no statistically significant differences between active treatment and placebo from baseline to week 13 in patients who were in pain (MOBID-2 ≥ 3) at baseline, or in patients who had poor sleep (defined as SE < 85%) at baseline. Patients who received active buprenorphine showed an increase in TST and SE compared to those who received active paracetamol.Conclusion: The main analyses showed that long-term pain treatment did not improve sleep as measured with actigraphy. Compared to paracetamol, TST and SE increased among patients who received buprenorphine. This could indicate that some patients had beneficial effects from the most potent pain treatment. However, based on the present findings, long-term pain treatment is not recommended as a strategy to improve sleep. Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02267057. Approximately 46.8 million people worldwide suffer from dementia – a number estimated to reach 131.5 million by 2050 . In nursSeveral factors contribute to sleep disturbances among NH patients, including pain  and deprNeuropsychiatric Inventory – Nursing Home version (NPI-NH), in people with advanced dementia and agitation. Furthermore, in a recently published randomized controlled trial, based on the same dataset and respondents as the present work, we found that compared to placebo, pain treatment improved sleep after 1 week of treatment  score ≥ 3, than in those who were not. In addition, we aimed to investigate the effects of pain treatment on different sleep outcomes for patients with poor sleep at baseline, defined as sleep efficiency (SE) < 85%. In the last analysis, we aimed to examine if there were any differences within the active treatment group, i.e., between patients receiving active buprenorphine and active placebo, respectively.In additional Efficacy of Pain Treatment on Depression in Patients with Dementia – A Randomized Clinical Trial of Efficacy: DEP.PAIN.DEM.” The study was conducted from August 2014 to September 2016, in Norway. We included 47 NHs from 11 municipalities, located in both urban and rural areas in Norway. In the present study, we used sleep data collected in the week before treatment commenced (baseline) and in week 13 of the treatment/placebo period.The study is based on an actigraphy subproject in the 13-week, multicentre, parallel-group, double-blind, placebo-controlled randomized trial “Mini Mental State Examination (MMSE ≤ 20) and depression as indicated by the Cornell Scale for Depression in Dementia (CSDD ≥ 8). Patients were excluded from the study if they had severe medical disease that could interfere with study participation, were using any opioid analgesic (except buprenorphine 5 mcg/h), did not want to wear an actigraph, were immobile or had involuntary movements. Inclusion and exclusion criteria are covered extensively in Figure 1 for an overview of enrolment and reasons for exclusion). We assessed the patients with the same measurements at baseline and in week 13 of the treatment period.Data collection was led by two researchers who enrolled NHs through direct contact with NH management. If the management agreed to be part of the project, the researchers were given access to patient medical journals to perform a pre-screening review. If there were no recent blood analyses  available, new were requisitioned. In order to be included, patients had to be ≥60 years, long term NH patients with >4 weeks of stay, dementia as indicated by Table 1). Patients were allocated either to a paracetamol group or to a buprenorphine group and randomized to receive active treatment or placebo. If a patient showed any signs of not tolerating the treatment , needed to change medical treatment, or there was anything else conflicting with the patient taking part in the study, the patient was withdrawn from the study and the reason was recorded. During the study period, all patients continued their usual medical treatment.A stepwise protocol, with a fixed-dose regimen, for treating pain was used in the study period (see Actiwatch Spectrum (Philips Respironics). Activity was assessed continuously for 7 days at baseline and for 7 days in week 13 of the treatment period. The intervention started on day 8. Actigraphs were placed on the dominant/mobile wrist. As of today, there is no standard regarding the placement of the actigraph (Actiware 6 (Respironics) was used for sleep scoring. The actigraph’s sensitivity to detect motion was set to medium. Furthermore, sleep/waking status was determined for each one-minute epoch. A qualified technician scored all the activity protocols. A standardized ranked approach was applied to set rest intervals for the actigraphy data, using: event markers when possible, light and activity data, or light or activity data.Sleep-related outcomes were measured with ctigraph . Howeverctigraph . This isActiware 6 software.The scoring protocol generated data on the following outcome variables: total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset (WASO), early morning awakening (EMA), and number of wake bouts (NoW). These parameters were estimated in the time window between lights off in the evening and lights on in the morning. In addition, daytime total sleep time (DTS) was estimated in the time window from lights on to lights off using the Pain was measured by MOBID-2 , a validSymptoms of depression during the last week were assessed using the validated CSDD, an instrument that consists of 19 items measuring five domains related to depression . In line with previous research, which has demonstrated that a score of 8/9 complies with the diagnosis of depression according to ICD-10 criteria, the patient had to get a CSDD score ≥ 8 to be included in the study . The CSDMMSE was used to evaluate cognitive function. MMSE is a brief, cognitive screening test with a 30-point scale that consists of 20 tasks. It was developed to distinguish potential dementia from normal functioning . Scores Figure 1 for the reasons for inclusion/exclusion). The randomization ratio in the actigraphy subproject was therefore not 1:1. The statistician provided the research team with a blinded, sequential list of pack identification numbers, in which patients were consecutively assigned to the next pack number in the list upon inclusion. The study was double-blinded, which implied that all researchers, patients and NH staff were masked with regard to group allocation.Initially, 162 patients were included. By means of computer-generated random numbers, these patients were randomly allocated to each arm in a 1:1 ratio. A statistician produced the randomization list without any involvement from the research team. Stratification factors were not used. However, not all of the patients from the main study were included in the actigraphy subproject  approved the study, and the study’s Clinical Trial number is NCT02267057.The patient’s medical decision-making capacity was deliberated with the patient’s primary nurse. For patients who had reduced capacity to give consent (MMSE scores from 16 to 19), attempts were made to modify the information. Also, the researchers contacted all of the legal guardians of eligible patients. Legal guardians who gave presumed consent on behalf of the patient received written and oral information together with a consent form to sign and mail back. The n = 106) was conducted with no covariates, with baseline as the time reference point, and with random intercept. In addition, we conducted a 2 × 2 ANOVA analysis in which we included only data from the 58 patients who completed week 13. This was done to investigate if the different analyses provided similar results.Descriptive statistics  were calculated and compared across the experimental groups both at baseline (week 0) and post-treatment (week 13). In order to investigate the effect of pain treatment after 13 weeks, linear mixed models were conducted. Mixed models allow for regression-based analyses of treatment effects even in the case of considerable attrition, as long as data are missing at random . Thus, ipost hoc sub-group analyses were carried out. Linear mixed model analyses were conducted for the sub-group of patients with MOBID-2 score ≥ 3 (n = 46) at baseline and the sub-group of patients with poor sleep at baseline, defined as sleep efficiency < 85% (n = 90). Finally, linear mixed model analyses were conducted to compare patients receiving active paracetamol and active buprenorphine treatment, respectively (n = 57). The statistical analyses were conducted using IBM SPSS Statistics 24.In addition to the mixed model for the main effect, several cy < 85%  (n = 90)Figure 1). Mean age was 85.5 years and 76% of the patients were female. Mean scores for MMSE, MOBID-2 and CSDD were 7.6, 2.8, and 11.2, respectively (see Table 2). From baseline to week 13, 48 patients dropped out of the study (reasons for dropout are listed in Table 3). There were no statistically significant differences in relevant baseline characteristics  between the patients who dropped out (n = 48) and the patients who completed treatment through week 13 (n = 58) (see Table 4). This supports the assumption that the data were missing at random. Nine patients were using buprenorphine 5 μg/h prior to inclusion and stayed on this treatment and were then randomized to receive either an additional 5 μg/h (5 patients) or placebo patch (4 patients).Two thousand three hundred and twenty three patients were screened for potential inclusion and 106 patients were included in the actigraphy subproject (see flow chart in Table 5). Similarly, in the 2 × 2 ANOVA analyses with only the 58 patients who had complete data in week 13, there were no significant differences between active pain treatment and placebo. Table 5 also shows descriptive statistics of sleep characteristics for both the placebo group and the active group, as measured at baseline and in week 13 of the treatment period.The main linear mixed model analyses for sleep outcomes showed no statistically significant differences between patients who received active pain treatment compared to those who received placebo  at baseline. There were no statistically significant differences between the patients who received active treatment and those who received placebo. Table 7 shows analyses for the subgroup of patients with sleep efficiency < 85% at baseline. Again, there were no statistically significant differences between the patients who received active treatment and those who received placebo.Table 8 reports analyses for the subgroup of patients receiving the two different types of active pain treatment – paracetamol and buprenorphine, respectively. In this linear mixed model, there were significant effects on TST (p < 0.01) and SE (p < 0.05), which revealed that TST and SE were both improved after 13 weeks for patients who received active buprenorphine compared with patients who received active paracetamol.This is the first placebo-controlled trial to investigate the long-term efficacy of paracetamol and buprenorphine on sleep in patients with comorbid dementia and depression. Previous studies have found that depression among NH patients with dementia may be related to untreated pain . Moreovepost hoc sub-group analyses: TST improved for patients who received active buprenorphine, compared to those who received active paracetamol. In the active paracetamol group, TST was reduced by about 10 min, while it increased by more than one hour in the active buprenorphine group. Furthermore, we found that SE was reduced in the group who received active paracetamol, while it increased by about 9% in the group who received active buprenorphine. Thus, patients who received active buprenorphine seemed to benefit from the treatment. These results are in line with There were, however, interesting significant effects in one of the Sedation is a frequently reported opioid-associated side effect . Usuallyn = 46), and we cannot exclude type 2 errors.Importantly, we found no clear causal effect on the active group with clinically significant pain (MOBID-2 score ≥ 3), compared to placebo. This is contrary to previous studies on older people, in which sleep disturbances have been linked to untreated pain . In addiDue to the considerable attrition of patients at week 13, we conducted linear mixed model analyses. These analyses are appropriate to handle missing data and can take into account the dependency of the observations .Table 3). This large drop-out may have hindered our ability to detect a positive effect from the active treatment compared to placebo. Furthermore, it should be noted that the assignment to paracetamol or buprenorphine was not a result of randomization, but of whether the patients qualified for allocation to either paracetamol or buprenorphine at baseline (and then were randomized to either active or placebo treatment). This may produce bias by indication, since the choice of drug might be related to the outcome.There was a drop-out of 22 patients in the group who received active buprenorphine, suggesting that many patients did not tolerate such treatment (see In addition, during the last decade, there has been a change in the prescription of pain medication for NH patients. Measuring sleep with actigraphy has its limitations. Actigraphy only records movement, and a lack of movement would therefore be assessed as sleep. The study population had low SE, and previous studies show that actigraphy is less accurate in distinguishing sleep from wakefulness when SE is reduced . Actigraa priori power analyses. The lack of this renders us unable to assess whether the statistical analyses had sufficient power. It is, however, noteworthy that our sample of patients with actigraphy was similar or larger than samples in comparable studies (An additional limitation of the study was that we did not conduct  studies .Compared to placebo, pain treatment did not improve sleep in the full sample of patients, as measured with actigraphy. However, we found a significant effect on TST and SE, when we compared the different types of active pain treatment. These results indicate that some patients may experience beneficial effects of pain treatment. However, the underlying mechanisms are unclear. The results could be an indication that some of the patients in fact experience pain, and hence had a positive effect of more potent pain treatment. Future research should investigate this further, with a larger sample size and including patients with clinically significant pain.KB designed the study, analyzed the data, and wrote the paper. BB, EF, and BH designed the study, helped with the analysis of the data, and wrote the paper.Mundipharma International supplied the study medication, but the company did not influence the study design, data collection, analyses and interpretation of data, or final publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JV declared a past co-authorship with one of the authors BH.


The first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.A total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.0–24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS.The ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3–4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3–4 AEs. High AUCTwo-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC.NCT02090153The online version of this article (doi:10.1007/s00280-016-3209-1) contains supplementary material, which is available to authorized users. A globally accepted standard regimen for advanced gastric cancer (AGC) has not been established. S-1, a fourth-generation oral fluorouracil (5-FU), has opened new perspectives with simplicity and convenience over the traditional backbone of chemotherapy for AGC, 5-FU.S-1 contains tegafur/gimeracil/oteracil. Gimeracil reduces the degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), and oteracil improves its gastrointestinal tolerability by inhibiting orotate phosphoribosyltransferase (OPRT). S-1 plus cisplatin is recommended as standard treatment by the Japanese Gastric Cancer Association and has been approved in Asian and European countries .One of the potential partners of S-1 is leucovorin (LV), known to enhance the efficacy of 5-FU by forming a ternary complex with 5-FU metabolite and thymidylate synthase (TS) which prolongs the inhibition of TS and blocks DNA synthesis. It was proved UFT, a third-generation oral 5-FU, had favorable activity and tolerability when combined with LV in AGC patients . A phasePreclinical studies have highlighted the importance of TS, the cellular target of 5-FU–folinic acid mechanism of action . Low TS This current phase II study of S-1/LV is deemed necessary to explore its efficacy and safety as first-line chemotherapy for AGC patients. Considering the frequent grade 3 toxicities, dose reduction, and period prolongation in that previous trial of mCRC , the 4-wAs a one-arm, single-center, open phase II clinical trial, it is approved by the independent Institute Research Ethics Committee at the Sun Yat-sen University Cancer Center and conducted in accordance with the Declaration of Helsinki.The eligibility criteria included (1) histologically confirmed metastatic or recurrent gastric cancer; (2) at least one measurable lesion; (3) an age of ≥18; (4) adequate oral intake; (5) no previous antitumor therapy within 5 years ; (6) an Eastern Cooperative Oncology Group performance status <2; and (7) adequate bone marrow, hepatic, and renal function.The exclusion criteria included (1) known hypersensitivity to any of the study drugs, or usage of drugs interacting with S-1; (2) serious concomitant conditions; (3) extensive bone, brain, or meningeal metastasis; (4) another synchronous cancer; (5) surgery within 3 months; (6) participating in other clinical studies; (7) pregnant women; (8) subjects with reproductive potential who were unwilling to use an effective method of contraception.2), 50 mg (1.25 ≤ BSA < 1.50 m2) and 60 mg (BSA ≥ 1.50 m2) b.i.d. in combination with LV given simultaneously at a fixed dose of 25 mg b.i.d. on days 1–7, followed by a 7-day rest.S-1 (20-mg capsules) and LV (25-mg tablets) were provided by DaPeng Co., Ltd, Japan. All patients were orally treated with S-1 in doses of 40 mg (body surface area (BSA) < 1.25 mClinical and laboratory examinations were carried out within 7 days before enrollment and each cycle of chemotherapy afterward. Tumor measurement was conducted on the basis of computed tomographic scans, within 15 days before enrollment and every 3 cycles afterward, according to Response Evaluation Criteria in Solid Tumors guidelines (version 1.1). Patients were considered response-assessable if they had overt clinical or radiological evidence of early PD within the first three cycles. All treatment-related adverse events (AEs) were categorized according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0).Peripheral blood was prospectively, anonymously sampled for each patient on the first day of the first cycle at 0 h (pre-dose) and 0.5, 1, 2, 4, 8, 24 h post-S-1/LV morning dosing. The 2 ml plasma at 0 h was separated for measuring baseline protein expression level of DPD, OPRT, TS, and TP. The 4-ml blood cells at 0 h were separated for CYP2A6 gene polymorphism. The 2 ml plasma at 0, 0.5, 1, 2, 4, 8, 24 h was separated for plasma concentrations of 5-FU.The plasmic protein expression level of DPD, OPRT, TS, and TP was determined by an enzyme-linked immunosorbent assay (ELISA), as described by Cui et al. .Polymerase chain reaction (PCR)–restriction fragment length polymorphism were used to determine common variant alleles that affect CYP2A6 activity or expression in Asian population , *13, and the wild-type allele (CYP2A6*1), as previously described .0–24h), maximum concentration (Cmax), time taken to reach maximum concentration (Tmax), half-time (T1/2), area under the first moment curve (AUMC0–24h), mean resistance time (MRT0–24h), and plasma clearance (CL) were derived with non-compartmental methods using WinNonlin version 3.1  was independently predictive of grade 3–4 AEs. The rates of grade 3–4 AEs differed between patients with high OPRT/DPD and low OPRT/DPD . Figure Thirteen patients experienced grade 3–4 AEs and 26 patients did not. By univariate logistic regression analysis, high OPRT (accuracy 79.0%), high OPRT/DPD (80.8%), high OPRT/TP (77.8%), high OPRT/TS (71.0%), high OPRT/DPD + TP + TS (78.7%), high OPRT/DPD + TS (77.8%), high OPRT/TP + TS (77.2%), and high OPRT/DPD + TP (80.1%) were all associated with grade 3–4 AEs. OPRT/DPD exhibited the highest accuracy (80.8%). By multivariate logistic regression analysis, high OPRT/DPD [>0.754 vs. ≤0.754, OR 15.566 (1.490–162.605), 0–24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) were significant predictors of prolonged PFS (supplementary Table S5). Similarly, multivariate analysis demonstrated high AUC0–24h of 5-FU was borderline significant predictor of prolonged TTF (supplementary Table S6).Multivariate analysis with a Cox proportional hazards model demonstrated that high AUC0–24h of 5-FU  2.931 1.155–7.433), 33, P = 00–24h of 5-FU, low DPD , and other 35 patients .To integrate the above predictors, we classified 39 patients into 4 patients with high OPRT/TS, high AUCTo our knowledge, the current study is the first one-arm and the second phase II trial to evaluate efficacy and toxicity of S-1/LV chemotherapy in AGC patients, which is the first to predict outcomes using S-1 pharmacogenetic pathway approach, on the basis that LV is but a cofactor entering the 5-FU metabolism. The enrollment was between July 2011 and July 2012, which was similar to between October 2011 and December 2012 of that randomized phase II study of S-1/LV versus SOL versus SP for AGC [We reported S-1/LV regimen yielded promising ORR, PFS, TTF, and OS, without combination with platinum, taxane, irinotecan, or trastuzumab as first-line treatment. In previous phase II studies of S-1 monotherapy in AGC and previous S-1 monotherapy arms of phase III JCOG9912 study, SPIRITS study, SC-101 study, GC0301/TOP-002 study, and START study, conventional dose for 4 weeks followed by 2-week rest was usually given –22. The To reduce the duration of effective drug concentration and keeping an appropriate rest period could be effective method of improving safety. So we modified the schedule as 1-week S-1/LV, followed by 1-week rest period, the same as S-1/LV group in that randomized phase II study. The efficacy S-1/LV here was quite comparable with S-1/LV group in that randomized phase II study, in terms of ORR (41.0 vs. 43%), PFS (4.13 vs. 4.2 m), and TTF (3.70 vs. 4.1 m) . Fewer pJapan Gastric Cancer Association guideline states that S-1 alone could be considered for patient who is not suitable for S-1 plus cisplatin therapy . PreviouGenotyping the peripheral blood for CYP2A6 polymorphism, quantifying plasmic protein expression of DPD, TS, TP, and OPRT with ELISA, is more optimal, convenient, quicker than evaluating genes, mRNAs, or proteins in tumor tissue, especially when 5-FU plasmic pharmacokinetics were to be integrated at the same time. Thus, there may be more clinical accessibility and prospects. What is more, the cutoff levels were determined by standard statistic analysis, not the simple median or mean. The plasmic expression of DPD in this study was consistent with previously reported with ELISA; however, no report for plasmic OPRT, TP, or TS was available . The freIn clinical setting, numerous studies have reported a low TS, low TP, or a high OPRT expression contributed to a high sensitivity to UFT, S-1, or S-1-based treatment in gastric cancer patients, with or without influencing the PFS or OS –38. TherIn this current study, low baseline plasmic DPD was not related to response; however, it was related to long OS, compatible with previous study that high intratumoral DPD mRNA was predictor of poor OS, not ORR or PFS . PreviouP = 0.024), TS (P = 0.044) expression significantly inversely, while DPD (P = 0.073), TP (P = 0.080) borderline inversely correlated with AUC0–24h of 5-FU. The number of CYP2A6 gene variants (P = 0.889) did not correlate with AUC0–24h. This was consistent with that CYP2A6 gene correlated with tegafur pharmacokinetics, but not with 5-FU pharmacokinetics [0–24h of 5-FU, not OPRT/TS, was predictive of PFS revealed that other factors may also influence PFS by AUC0–24h of 5-FU. We did not demonstrate the number of CYP2A6 gene variants correlated with efficacy. Although some studies demonstrated patients having fewer CYP2A6 variants had better PFS in AGC patients with S-1 plus cisplatin, or S-1 plus docetaxel [We found plasmic OPRT Mean plasma concentration–time curve of 5-FU for the entire population. 5-FU: fluorouracil, AUCSupplementary material 2 (DOCX 19 kb)Below is the link to the electronic supplementary material.


DETECT questionnaire (SPDQ) and its short-form version (SF-SPDQ), by modifying the Japanese version of the painDETECT questionnaire (PDQ-J), and to validate these tools.To develop screening tools for neuropathic pain caused by spinal disorders, the Spine painUsing data from patients with neuropathic pain caused by spinal disorders (NeP-SD) and patients with nociceptive pain caused by joint disorders (NocP) as controls, we devised a scoring system for the SPDQ by calculating weighting coefficients for nine PDQ-J items. Simultaneously, we selected some items for the SF-SPDQ. Next, we conducted the validation study primarily using patients with a confirmed diagnosis (a multicenter study) and general patients (a web-based survey). Sensitivity, specificity, and the area under the receiver-operating characteristic curve (AUC), along with additional positive/negative predictive values and positive/negative likelihood ratios, were calculated to assess the diagnostic utility of these tools in each population.Data for 85 patients with NeP-SD and 45 patients with NocP were analyzed to develop the SPDQ/SF-SPDQ. The SPDQ had sensitivity of 78.8% and specificity of 75.6% (AUC = 0.77). The SF-SPDQ had 82.4% sensitivity and 66.7% specificity (AUC = 0.75). In the multicenter study (n = 45), both tools had diagnostic utility almost comparable with that demonstrated at development: the SPDQ had sensitivity of 83.3% and specificity of 69.2%, with the SF-SPDQ having 86.2% sensitivity and 68.8% specificity. In the web-based survey (n = 500), while the SPDQ had slightly low sensitivity (74.0%), the SF-SPDQ maintained high sensitivity (84.4%), although specificity was relatively low (61.2%).We developed the SPDQ and SF-SPDQ as valid screening tools for neuropathic pain caused by spinal disorders. Both have moderate utility as screening tools, with the SF-SPDQ perhaps being preferable for clinical use. However, physicians should be vigilant about possible false-positive diagnoses. Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory nervous system” , and is Because a different treatment approach is required for a different type of pain , early iDETECT questionnaire (PD-Q), one of the available screening tools for neuropathic pain [The painhic pain , allows hic pain . The valhic pain ; howeverhic pain . A natiohic pain . This hiDETECT questionnaire, SPDQ) along with a brief, simplified version of the tool ; and 2) to validate these tools in two different sample populations.Our aims, therefore, were: 1) to develop a screening tool for neuropathic pain caused by spinal disorders  and two items on pain course pattern and radiating pain, respectively, with three additional numerical rating scales (NRSs) to assess the intensity of pain  . A totalIn the development study of the SPDQ, we recruited patients aged 20 years or older with neuropathic pain caused by spinal disorders (NeP-SD) persisting for ≥3 months and with a pain NRS score of ≥1. The diagnosis of neuropathic pain due to spinal disorders  was confirmed by certificated orthopedic spine surgeons, on the basis of the International Association for the Study of Pain (IASP) neuropathic pain diagnostic grading system . As a coFirst, to devise a scoring scale for the SPDQ, we computed weighting coefficients for the nine items of the PDQ-J other than three NRSs, using canonical discriminant analysis. We then conducted receiver-operating characteristic (ROC) analyses to determine the cutoff point, which was defined as the point at which the sum of sensitivity plus specificity becomes the maximum value. In addition, to create a simplified version we selected items to be included in the SF-SPDQ using a stepwise method, and computed weighting coefficients and identified the cutoff point in the same manner as described for the SPDQ. Using the devised scoring of the SPDQ and SF-SPDQ, we calculated sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR−), positive predictive value (PPV), negative predictive value (NPV), and the area under the ROC curve (AUC) (to discriminate patients with NeP-SD from those with NocP) for the SPDQ and SF-SPDQ.To validate the SPDQ and SF-SPDQ for clinical use, we assessed the diagnostic utility of these tools using patients with a confirmed diagnosis in a multicenter study. For extended evaluation, we additionally conducted a web-based survey to assess the diagnostic utility of these tools in a more general population. Both the multicenter study and the web-based survey were approved by the ethics committee at Fukushima Medical University School of Medicine  in April 2016.For the multicenter study to validate the SPDQ and SF-SPDQ, we recruited patients with either NeP-SD or NocP (as a control) who were 20 years or older and had a pain NRS score of ≥3, and whose treatment was not scheduled to be changed. Patients with NeP-SD were defined as having neuropathic pain defined by the IASP , due to Eligible patients were identified by physicians at 10 hospitals located in or near Fukushima, Japan from May 2016 to March 2017. After physicians adequately explained the study, written informed consent was obtained from patients who agreed to participate. Physicians collected data of patients’ characteristics and asked patients to complete the first questionnaire, which included the PDQ-J and other self-report assessment measures for pain and HRQoL. No personal information was collected in the questionnaire. Among patients who visited hospitals within 2 to 4 weeks from the first questionnaire administration, patients whose symptoms had not changed since the time of the first questionnaire according to their physicians’ judgment were asked to complete the PDQ-J again (second questionnaire administration) for the assessment of repeatability of the SPDQ.The other measures for the assessment of pain included the pain interference scale of the Brief Pain Inventory (BPI) ,17 and tThe EuroQol 5 Dimension (EQ-5D) ,21 was iTo assess the use of the SPDQ and SF-SPDQ in a more general patient population, we recruited patients with either NeP-SD or NocP (as a control) online using an Internet research company, Rakuten Research Inc. , which had approximately 2.27 million registered individuals. Patients were eligible if they were 20 years or older, had pain in the upper or lower limb, and regularly received medical care for NeP-SD or NocP. Thus, patients with only low back pain or neck pain and without spinal or joint disorders were ineligible. Patients who regularly received medical care for any reason caused by an act by a third party and those who were incapable of completing a questionnaire by themselves were excluded.An invitation with a screening questionnaire, whose purpose was to ascertain the presence of the target pain diseases , was sent electronically to potential participants with spinal disorders or joint disorders. As one of several questions to check individuals’ eligibility for participation, a question to screen out patients who have both spinal disorders and joint disorders was included in the screening questionnaire. Eligible patients who had passed the screening questionnaire and agreed to participate in the survey then proceeded to the survey questionnaire, which included questions about patients’ characteristics, the PDQ-J, BPI pain interference scale, NPSI, and EQ-5D. No personal information was collected in the survey questionnaire. The survey was conducted in July to August 2016.The demographic and clinical characteristics of patients and scores of self-report assessment measures were summarized descriptively for each pain group (NeP-SD or NocP group).The SPDQ and SF-SPDQ were scored using the scoring method devised in the development study. To assess the diagnostic utility of the SPDQ and SF-SPDQ in both the multicenter study and the web-based survey, we calculated sensitivity, specificity, LR+, LR−, PPV, NPV, and the AUC, using data obtained from the respective populations.To assess the repeatability of the SPDQ, the agreements between the results of the first and the second administrations of the SPDQ were evaluated using Cohen’s kappa. The kappa coefficient was interpreted as follows: <0.20 as poor, 0.21–0.40 as fair, 0.41–0.60 as moderate, 0.61–0.80 as good, and 0.81–1.00 as very good ,23.All statistical analyses were performed using SAS release 9.4 . Data management and statistical analyses were independently conducted by Clinical Study Support, Inc. .Data for 130 patients (85 patients with NeP-SD and 45 patients with NocP) were analyzed in the development study. In the NeP-SD group, mean  age and BMI were 63.5 (14.5) years and 22.8 (3.5), and 49.4% of patients were male. In the NocP group, mean (SD) age and BMI were 60.1 (17.6) years and 23.5 (4.8), and 80.0% were male. Spinal disorders in patients with NeP-SD were mainly lumbar spinal stenosis (65 patients) and lumbar disc herniation (17 patients). Joint disorders in patients with NocP were mainly hip osteoarthritis (20 patients) and knee osteoarthritis (19 patients).The canonical discriminant analysis yielded the weighting coefficients for nine items of the PDQ-J . To defiFor the SF-SPDQ, two items on electric shock-like pain and numbness were selected, and weighting coefficients for these items were obtained . Again, For the SPDQ, the sensitivity for detecting NeP-SD was 78.8% (67/85 patients) and specificity for screening out NocP was 75.6% (34/45 patients) . The AUCWe obtained completed questionnaires from 29 patients with NeP-SD and 16 patients with NocP. The demographic and clinical characteristics of these patients and scores of self-report assessment measures are summarized for each group in Of these 45 patients, 24 patients with NeP-SD and 13 with NocP answered all items of the SPDQ; thus, the diagnostic utility of the SPDQ was analyzed using the data of these 37 patients. The mean (SD) SPDQ scores were 7.3 (9.2) in the NeP-SD group and −5.4 (8.5) in the NocP group. The SPDQ had sensitivity of 83.3% (20/24 patients) and specificity of 69.2% (9/13 patients), and the AUC was 0.76 .The diagnostic utility of the SF-SPDQ was analyzed using the data of all 45 patients (no missing responses). The mean (SD) SF-SPDQ scores were 9.2 (8.7) in the NeP-SD group and −3.9 (9.4) in the NocP group. The sensitivity was 86.2% (25/29 patients), the specificity was 68.8% (11/16 patients), and the AUC was 0.77.To investigate the results of the SPDQ in each group in more detail, we examined the frequency distribution by response category for each item of the SPDQ . For graA screening questionnaire was sent to 9,572 potential participants among the registered volunteers, and responses were obtained from 500 patients (250 patients for each group). The demographic and clinical characteristics of patients and scores of self-report assessment measures in each group are summarized in The mean (SD) SPDQ scores were 6.7 (10.4) in the NeP-SD group and −5.4 (9.0) in the NocP group. The SPDQ had sensitivity of 74.0% (185/250 patients) and specificity of 72.8% (182/250 patients), and the AUC was 0.73 . The meaWe calculated Cohen’s kappa coefficients to assess the agreements between the results of the first and the second questionnaire administrations, using the data of 21 patients with NeP-SD and 8 patients with NocP who completed the SPDQ twice in the multicenter study. Similarly, the kappa coefficients for the SF-SPDQ were calculated using the data of 25 patients with NeP-SD and 11 patients with NocP who completed the SF-SPDQ twice. The kappa coefficient was 0.5 for both the SPDQ and the SF-SPDQ, indicating that the agreement was moderate.We developed a screening tool to help detect patients with neuropathic pain caused by spinal disorders and also a brief, simplified version, both of which had moderate utility as screening tools. Subsequently we assessed the diagnostic utility of these tools using two different populations, and the multicenter study using patients with a confirmed diagnosis showed that both the SPDQ and SF-SPDQ had moderate diagnostic utility also in this population. Furthermore, the SF-SPDQ maintained reasonably high sensitivity in our extended evaluation using general patients, supporting its preferable use in clinical settings.In the multicenter study, the SPDQ had sensitivity and specificity almost comparable with those demonstrated in the development study . The SF-SPDQ had sensitivity and specificity that were close to those at development . The PPV and NPV of each tool were also similar to those in the development study, where the prevalence of the target pain was almost the same as that in this population. These comparable results support the idea that both the SPDQ and SF-SPDQ may have equivalent diagnostic utility in similar clinical settings . Although the PPV of 83.3% for both tools implies that positive results are likely to be reliable in this population, the relatively low specificity still suggests that physicians should be mindful of the potential false-positive diagnoses. The LR+ of <3 was not high enough: LR+ of ≥10 is considered to indicate that a positive test result would be good at “ruling in” the disease , which aIn the web-based survey, we collaterally evaluated the use of these tools in a more general patient population. Compared with the results of the multicenter study, the SPDQ had low sensitivity (74.0%) in this population. This may be attributed to the mild pain conditions, as shown by the low mean scores for pain NRS and the NPSI. Indeed, many patients with NeP-SD reported having had no pain, or hardly noticed their pain, for most symptoms see ; as a reThe examination of the response distribution to each SPDQ item revealed that more patients with NeP-SD reported numbness in comparison with control patients. This was not surprising because the item for numbness is weighted the most in the SPDQ and SF-SPDQ. However, the fact that conspicuous distributions were observed in both populations may suggest that numbness can be one clue to the probable presence of neuropathic components in Japanese patients with pain, although it does not necessarily deny other types of pain such as nociceptive pain. For the remaining items, the response distribution did not greatly differ between the two pain groups, even for the item for electric shock-like pain, which is weighted the second most in the SPDQ and SF-SPDQ. As discussed above, these similarities—more precisely, less frequent manifestation of these pain symptoms—probably reflect the mild conditions of patients. Because the SPDQ is based on patients’ description of pain symptoms, it would be more suitable for patients with pain of a certain level of severity.The item for electric shock-like pain is given the largest negative coefficient in both tools, meaning that the possibility of neuropathic pain decreases if patients have stronger electric shock-like pain. Considering that the term “electric shock-like pain” is one descriptor of neuropathic pain , this seFor repeatability, the agreement was moderate for both the SPDQ and SF-SPDQ. One possible reason for this may be attributed to changes in patients’ symptoms, although patients included in the second questionnaire administration were supposed to be those without changes in symptoms as judged by physicians. Because patients were required to describe their symptoms in detail in the SPDQ, rather than their overall condition, possible changes in patients’ perception of their symptoms might have resulted in different responses to the SPDQ. One might also think that it would reflect the fluctuation of symptoms. However, because the mean disease duration was relatively long (2.5 years in the NeP-SD group and 1.5 years in the NocP group), it is more likely that their diseases were formed by the time of the questionnaire administration, which was confirmed by the physicians’ judgment of stable symptom conditions. Thus, we consider that the possible changes in responses probably reflected a more subjective level of change rather than the fluctuation of symptoms.There are some limitations to this study. First, because the SPDQ and SF-SPDQ were developed using a statistical model, the resulting tools were highly dependent on the characteristics of the sample population. Therefore we conducted the validation study using patients with a confirmed diagnosis, and the results showed that both tools had equivalent diagnostic utility also in a different population. Second, patients in our multicenter study were recruited from a limited area of Japan, which may limit generalization to patients across the nation. However, the results were comparable with those of the development study of the SPDQ, for which patients were enrolled from various regions of Japan. The generalizability of the results of our web-based survey may also be limited because some groups of patients may have been under-represented. For example, patients suffering severe pain might not have been able to or willing to participate, which may have resulted in the inclusion of patients with less severe symptoms. Third, recruiting a feasible number of patients for our multicenter study resulted in a small sample size, meaning that one patient’s data largely influenced the results of the study. In addition, our validation study relied on patients’ self-reporting in the questionnaires, which may have resulted in misclassification. In particular, inclusion of patients in our web-based survey according to their self-reported diseases may have resulted in improper inclusion or misclassification of patients, despite our best efforts to screen out inappropriate patients by using a screening questionnaire. Given these limitations, the results of this study need to be interpreted with caution.We developed a valid screening tool for neuropathic pain caused by spinal disorders, the SPDQ, and a simplified version, the SF-SPDQ. Both the SPDQ and SF-SPDQ demonstrated moderate diagnostic utility in patients attending the orthopedic department, but the SF-SPDQ may be more suitable for use in clinical settings because although it is a 2-item short tool it consistently demonstrated high sensitivity in two different populations. However, physicians should be aware of the possibility of false-positive diagnoses. Additional examinations of patients evaluated as positive may help to more accurately detect patients with neuropathic pain caused by spinal disorders.