Evidence exists for the efficacy of collaborative care (CC) for major depressive disorder (MDD), for the efficacy of the consequent use of pain medication against pain, and for the efficacy of duloxetine against both MDD and neuropathic pain. Their relative effectiveness in comorbid MDD and pain has never been established so far. This study explores the effectiveness of CC with pain medication and duloxetine, and CC with pain medication and placebo, compared with duloxetine alone, on depressive and pain symptoms. This study was prematurely terminated because of massive reorganizations and reimbursement changes in mental health care in the Netherlands during the study period and is therefore of exploratory nature.http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1089; NTR number: NTR1089).Three-armed, randomized, multicenter, placebo-controlled trial at three specialized mental health outpatient clinics with patients who screened positive for MDD. Interventions lasted 12 weeks. Pain medication was administered according to an algorithm that avoids opiate prescription as much as possible, where paracetamol, COX inhibitors, and pregabalin are offered as steps before opiates are considered. Patients who did not show up for three or more sessions were registered as non-compliant. Explorative, intention-to-treat and per protocol, multilevel regression analyses were performed. The trial is listed in the trial registration . Non-compliant patients (n = 31) did not improve over the 12-week period, in contrast to compliant patients (n = 29). Pain outcomes did not differ between the three groups.Sixty patients completed the study. Patients in all treatment groups reported significantly less depressive and pain symptoms after 12 weeks. CC with placebo condition showed the fastest decrease in depressive symptoms compared with the duloxetine alone group (In MDD and pain, patient’s compliance and placebo effects are more important in attaining effect than choice of one of the treatments. Active pain management with COX inhibitors and pregabalin as alternatives to tramadol or other opiates might provide an attractive alternative to the current WHO pain ladder as it avoids opiate prescription as much as possible. The generalizability is limited due to the small sample size. Larger studies are needed. Pain is common among depressive patients –4, with One option for a dual and integrated treatment approach that addresses both depression and pain is collaborative care (CC), which is effective in the treatment of depression –17 and pIn general, the World Health Organization pain ladder is used in pain treatment, which suggests three steps, the second and third steps of which involve opiates, and antidepressants; pregabalin and mood stabilizers have been suggested as adjuvant medication . In the Pain is common in patients with major depressive disorders (MDDs) and has a negative influence on treatment outcome. Furthermore, pain and depression have a bidirectional association: persons with pain symptoms are at increased risk for depression and those with depressive symptoms report more pain symptoms than persons without depressive symptoms . Hence, CC including pain medication treatment, combined with duloxetine;CC, including pain medication treatment, combined with a placebo;duloxetine only.The design of the study has been described in more detail elsewhere  but is sThe allocation of duloxetine/placebo in the CC groups was double-blind and the duloxetine only group was open label.This study was led by the Clinical Centre for Body, Mind, and Health, and performed within this center and two other mental health institutions in the Netherlands: Arkin, and GGZ inGeest. Inclusion took place between December 2011 and May 2014.http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1089; NTR number: NTR1089.This study was carried out in accordance with the recommendations of the scientific committees of the three participating institutions with written informed consent from all subjects in accordance with the Declaration of Helsinki. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the respective scientific committees of the three participating institutions, the medical ethical committee, and by the Central Commission for Human Bound Research . The trial is listed in the trial registration: Consecutive patients presented at three specialized mental health outpatient clinics were screened for MDD and pain; they were asked informed consent and randomly assigned to one of the three treatment groups. Inclusion criteria were a Patient Health Questionnaire depression sub-scale (PHQ9)  score ofEach participating patient received a unique identification number. This number was inserted into a specially designed program for randomization. The randomization number  was digitally sent to the pharmacist of the VU medical center. The pharmacist changed the labels of medication so no information was provided whether the pills were duloxetine or a placebo. The pharmacist could identify the medication by a unique number. After receiving a randomization number, the pharmacist would send four unique medication numbers to the contact of the mental health center where the patient was registered. The contact would ensure the psychiatrist received the correct medication for the included patient. Two people controlled the unique medication numbers assigned to a patient. Study investigators, research coordinators, attending care teams, and the patients were blinded to treatment allocation when randomized into one of the CC groups. Medication in the duloxetine alone group was open label. Randomization in a 1:1:1 fashion was balanced within blocks, in which each treatment arm would occur two times in every six randomizations , 51.The severity of depressive symptoms was measured with the PHQ9, a brief but validated instrument that scores each of the DSM-IV criteria for MDD . Each itTo measure pain symptoms, the item for average pain of the BPI  was usedClassification of nociceptive pain, neuropathic pain, or mixed pain was done using the painDETECT questionnaire that was specifically validated for this purpose . The paiBefore treatment started, all participants completed a baseline self-report questionnaire. During treatment, the patients completed self-report questionnaires BPI, PHQ9, and the Antidepressant Side-Effects Checklist (ASEC-21)  providedIn this study, duloxetine was used as an antidepressant. Patients started with 30 mg every day for the first 2 weeks, which was increased to 60 mg for the following 2 weeks. Dependent on the score on the PHQ9, the dose would then be raised to 90 mg (if the PHQ9 score was not decreased with five points) or would remain 60 mg (if the PHQ9 score decreased by at least five points). When after 12 weeks no response or remission was obtained on the PHQ9, a switch to amitriptyline was suggested.For pain, medication was prescribed according to the nature of pain, for which a distinction was made between nociceptive and neuropathic pain. Figure A comprehensive description of the intervention can be found elsewhere . Here, wIn all three treatment groups, the intervention lasted 12 weeks. All participants completed the painDETECT questionnaire (to assess nociceptive and neuropathic pain), the PHQ9, and the BPI at baseline. During treatment, assessments of PHQ9 and BPI were performed every other week. Patients who did not show up for three or more sessions were registered as non-compliant.Every week, each patient had a session with a psychologist, and every other week a session with a psychiatrist. In case of treatment response , but non-remission, as indicated by a score of >5 on the PHQ9 after 12 weeks of treatment, the patient was referred to the GP with subsequent antidepressant treatment and pain medication advice. If after 12 weeks (after de-blinding the medication code) no treatment response had occurred on severity of depressive symptoms, as indicated as less improvement than 50% on the initial PHQ9 score, the patient was not referred to the GP but referred instead for further specialized mental health care. During the treatment, the patient worked through a self-help manual containing information about depression and pain symptoms, antidepressant medication and relaxation techniques, and was guided by the psychologist. The psychologist treated patients using PST, a brief, structured psychological intervention, consisting of seven stages . PST is In the CC groups, duloxetine or placebo was prescribed, and pain medication was administered according to an algorithm specifically designed for this study. This algorithm avoids opiate prescription as much as possible, which is considered as an alternative to the current WHO pain ladder, with paracetamol, COX inhibitors, and pregabalin as steps before opiates are started.In the CC groups, duloxetine (or placebo) and pain medication were administered by a psychiatrist, using an algorithm that is shown in Figure Collaborative care was simultaneously provided by a team of a care-manager (psychologist) and a psychiatrist. Only patients in the CC groups were treated by all specialists. The care-manager was responsible for PST, a brief, structured psychological intervention.The patients in the duloxetine only group received treatment of the psychiatrist who used a CRF and the duloxetine algorithm in prescribing duloxetine.Patients had to show up at least 80% of the sessions to be considered as compliant to treatment. Patients who did not show up for three or more sessions (20% of the sessions) were registered as non-compliant .n should be 24 patients for each treatment arm. Two other trials, one comparing duloxetine to placebo  were performed to examine whether the number of side effects reported would differ between the treatment groups.Descriptive analyses were performed to describe the sample at baseline, regarding gender, age, compliance, severity of depressive symptoms, and pain severity. Differences between treatment groups and between compliant and non-compliant patients were analyzed regarding baseline characteristics. All linear variables were normally distributed . Although the required sample sizes were not reached, we performed explorative, intention-to-treat, MLAs. We evaluated the effect of time for the whole sample, the effect of the treatment group, and the effect of the treatment group over time in terms of depressive symptoms and in terms of pain symptoms over a 16-week period (from moment of screening to the end of the therapy sessions). Quadratic functions of time were included to examine whether there was an initial increase in outcomes followed by a decrease (negative quadratic function), or the other way around (positive quadratic function). Third, explorative, per-protocol MLAs were used to evaluate the effect in case of compliance. Data from all 60 participants were used in the analyses. In the per-protocol analyses, the compliant and non-compliant patients were separately analyzed to examine differences between these groups. There were no dropouts. The duloxetine only group was used as the reference group in all analyses because we expected the CC groups to be the most effective compared with the duloxetine only group. The number of side effects that were reported on the ASEC-21 is presented for the total sample and for all the treatment groups. Between group analyses , and only five patients reported pain of both a nociceptive and neuropathic nature. No significant differences were found between the three treatment groups regarding gender, age, depressive symptoms, and pain symptoms. The two CC groups did not differ regarding the nature of pain. Table n = 7) and of neuropathic nature (n = 10). No significant differences were found between compliant versus non-compliant patients regarding gender, age, treatment condition, severity of depressive and pain symptoms, and nature of pain.Table b = −0.34; p = < 0.001) and pain  symptoms after therapy , but this effect diminished at the end of treatment . No significant differences were found between the duloxetine alone treatment group and the CC + placebo treatment group.Table We carried out a randomized controlled trial, testing and comparing the effectiveness of three active treatments among patients with moderately severe MDD and comorbid pain. This is a notoriously hard group of patients to engage and treat, and the prognosis of both dimensions of symptoms, when left untreated, is unlikely to be favorable –13. Our A review of 79 studies comparing CC with routine care or alternate treatments found that CC leads to greater improvement than care as usual in depression outcomes in the short term as well as the long term . Our resThe finding that the CC with placebo condition seems to be the most optimal condition in this study is intriguing. A possible explanation might be the placebo effect, which could increase the effect of CC, at least at the beginning of therapy. Patients in both CC groups most likely have an expectation of a reward  and had experience with the use of similar medications, have learned the (positive) effects of these medications, and are therefore more likely to experience a positive effect , which might contribute to less psychological and physical symptoms , 60. ConThis study is a first step to establish an effective treatment for the combination of depression and pain. A major strength of this study is the use of an algorithm for pain medication, which distinguishes nociceptive pain from neuropathic pain. A WHO pain ladder algorithm does exist, but that algorithm focuses mainly on nociceptive pain. An algorithm for neuropathic pain was not yet available. The results indicate that active pain management in CC with COX inhibitors and pregabalin as alternatives to tramadol or other opiates might provide an attractive alternative to the current WHO pain ladder as it avoids opiate prescription as much as possible. Recently, it was suggested that adaptations of the original WHO pain ladder are needed . For exaThis study has several limitations that need to be addressed, however. All treatment groups had some form of active treatment, which makes spontaneous recovery or the natural fluctuation of symptoms hard to address. However, in a large observational study, severity of pain did not change over time, and even increased in those persons with depressive symptoms when compared with healthy persons , so the The findings from this study are better thought of as hypothesis forming rather than hypothesis testing, and it would be necessary to see the conclusions replicated in future trials. However, CC with active pain management seems promising in the treatment of depression when pain is present and our pain medication algorithm might provide an attractive alternative to the current WHO pain ladder. This needs further exploration in full-scale trials.http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1089; NTR number: NTR1089).This study was carried out in accordance with the recommendations of the scientific committees of the three participating institutions with written informed consent from all subjects in accordance with the Declaration of Helsinki. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the respective scientific committees of the three participating institutions, the medical ethical committee, and by the Central Commission for Human Bound Research . The trial is listed in the trial registration (EH, CF-C, and JD conceived the initial idea for the present study and all authors contributed to its planning, including defining the aims, variables of interest, and analysis strategy. Analyses were done by EH and LT, but all authors had access to the statistical outputs. EH drafted the article and all authors contributed to revisions. All authors approved the final manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.CF-C and JD received financial support and the study medication from Eli Lilly; AB reports personal fees from Lundbeck, outside the submitted work; all other authors have nothing to disclose.


The high percentage of female chiropractic students in Switzerland suggests a future sex shift in the chiropractic profession in Switzerland. Thus the purpose of this study is to determine if male and female chiropractors achieve the same treatment outcomes in neck pain patients.Included in this prospective outcomes study were 849 patients with neck pain of any duration. Prior to the first treatment, baseline demographic data, the Bournemouth Questionnaire (BQ) and the numerical rating scale (NRS) for neck and arm pain were completed. At the follow-up time points of 1 week, 1, 3, 6 and 12 months, the Patient’s Global Impression of Change (PGIC) scale to categorize the actual ‘improvement’ and the BQ and the NRS for neck pain were completed.The Chi-square test compared the proportion of patients reporting ‘improvement’ between male and female chiropractors for each time point. The unpaired Student’s t-test compared the BQ and the NRS actual and change scores between patients of male and female chiropractors at all time points. Demographic factors were compared between the sexes using the Chi-square test.p = 0.035) and significantly more pain reduction at 3 months (p = 0.040). Patients of male chiropractors presented with significant older age (p = 0.0001), higher levels of baseline neck pain (p = 0.012), a lower proportion with radiculopathy (p = 0.014) and less pain medication use (p = 0.046).Proportionally more patients of female chiropractors reported ‘improvement’ at 1 month (Female chiropractors achieve at least equally satisfying treatment results for neck pain patients compared to male chiropractors. Female chiropractors also have a higher proportion of female patients compared to male chiropractors and patients presenting with radiculopathy and using pain medications.Not applicable for this type of study. From the Swiss Job Analysis Survey 2009 it is known that there is a strong male predominance in the chiropractic profession in Switzerland . This waAs the complaint of neck pain is common in the general population and as the percentage of female chiropractors is increasing in Switzerland, the hypothesis is that there is no difference in treatment outcomes in neck pain patients based on the sex of the chiropractor. Therefore, purpose of this study was to evaluate if the outcomes of neck pain patients treated by female chiropractors are the same as the outcomes of neck pain patients treated by male chiropractors.This is a secondary analysis of data from a prospective cohort outcomes study  with folFor this study, successive new patients were recruited from numerous chiropractic practices in Switzerland. The patients were over the age of 18, suffered from neck pain of any duration and had not received any chiropractic or manual therapy in the previous 3 months. Excluded were patients with specific pathologies of the cervical spine which are contraindications to chiropractic manipulative therapy. These included acute fractures, infections, tumours, inflammatory arthropathies, Paget’s disease, anti-coagulation therapy, cervical spondylotic myelopathy, known unstable congenital anomalies and severe osteoporosis .All 260 members of the Association of Swiss Chiropractors were asked to recruit patients for this study and all examinations and treatments occurred in the participating chiropractic practices. All chiropractors received notification and instructions about this study plus the study protocol by email. Shortly before starting the data collection, details about the study were also discussed verbally at the annual mandatory post-graduate continuing education convention and any questions from the chiropractors were answered. At this information meeting as well as via email it was additionally emphasized that the participating chiropractors should not change their treatment methods, due to the fact that the purpose of this study was to evaluate outcomes as they were normally found in chiropractic practices. Therefore it was not desired to standardize neither the treatment method nor the treatment number. Nevertheless, it is known that most of the chiropractic patients in Switzerland 76–100%) are at least treated with the diversified technique [00% are aImmediately before starting the treatment, every patient had to rate the severity of their current neck pain using the numerical pain rating scale (NRS) and a separate NRS for arm pain. The NRS is a scale evaluating the intensity of pain over the past 24 h, ranging from 0 (no pain) to 10 (worst pain imaginable).Additionally, the Bournemouth Questionnaire for neck (BQN) disability, which has been validated and translated into German , was useAt the first consultation, additional information was collected by the treating chiropractor and sent via fax to the university chiropractic research assistant. This supplementary data was completed in a baseline information form and included: patient age, sex, marital status, paid employment, whether or not the onset of pain was due to trauma, whether or not the patient smokes, whether or not the patient was currently taking pain medication, number of previous episodes, duration of current complaint, whether or not the patient had signs and symptoms of cervical radiculopathy, whether or not the patient complained of additional dizziness and the patient’s general state of health. This data was used in the original predictors of outcome paper . Only paTo evaluate how much the patients ‘improved’ overall compared to their condition prior to treatment at the various outcome time points, the Patient’s Global Impression of Change (PGIC)-scale was used , 21. TheAdditional outcomes were assessed using the NRS (neck) and the BQN scores at the follow up time points and their subscale change  scores (secondary outcomes).The outcome data collection  after the start of the treatment was done by research assistants at the university hospital who were unknown to the patients. Via telephone interviews to the patients, they collected the data of the NRS neck pain, NRS arm pain, Patient Global Impression of Change (PGIC) scale and the BQN. The patients knew that they were enrolled in the outcomes study, having signed informed consents. This occurred at the point of data collection for the original outcomes study, and therefore patients were not nformed that subsequent analysis would include comparing treatment outcomes between male and female chiropractors.Baseline factors with categorical variables were compared between patients of male and female chiropractors using the Chi-square test. For continuous variables  the unpaired Student’s t-test was used. To analyze differences within patient groups for continuous variables, the paired t-test was performed. The proportion of patients reporting ‘improvement’ or ‘worsening’ was compared between the sexes of the chiropractors for each data collection time point using the Chi-square test. The NRS and BQ actual and change scores were compared between the patients of male and female chiropractors at each time point using the unpaired Student’s t-test. SPSS version 21.0  was used for the statistical analysis.Of the 260 active members of the Association of Swiss Chiropractors, 78 contributed patients to this study (30% response rate), with 46 chiropractors being male and 32 being female. As a total of 70 of the 260 Swiss chiropractors were female and 190 were male, this corresponds to a 45.7% response rate for the female chiropractors and a 24.2% response rate for the male chiropractors. Baseline data was provided for 849 neck pain patients with 450 being treated by male and 399 being treated by female chiropractors.N = 551) than men (35%) suffering from neck pain in this study. Additionally, there was a statistically significant difference in the proportion of male versus female patients treated when comparing the sexes of the chiropractors. Female chiropractors treated significantly more female (71.2%) than male (28.8%) neck pain patients compared to male chiropractors  (p = 0.0001). At baseline, neck pain patients of male chiropractors were significantly older than patients treated by female chiropractors (p = 0.0001) (Table p = 0.012)   compared to the patients of male chiropractors (11.2%) (7.3% compp = 0.02)   Table . At 1 we5) Table .Table 2CComparing reported ‘worsening’ between the two groups revealed a significant difference in worsening at 3 months. A higher proportion of patients treated by male chiropractors (4.8%) reported worsening compared to patients treated by female chiropractors 1.2%). At all the other time points, no significant difference in worsening between the two groups could be detected   Table .Table 3Cp = 0.052) (Table The change scores were used to assess how much the BQN and NRS neck scores changed from baseline to the various outcome time points between the two groups. Only the change scores of the time points in which there was a significant difference between the two groups in the NRS and BQN scores above were assessed (1 month and 3 months). By 1 month after the start of treatment, no significant difference was found in the change scores between the two groups treated by male or female chiropractors, although the BQ6 evaluating the change in work-related fear avoidance was almost significant (2) Table . At 3 moAs the purpose of this study was to compare treatment outcomes in Swiss neck pain patients treated by male versus female chiropractors, it was reassuring, both for patients and clinicians, to find that the neck pain patients treated by female chiropractors reported a significantly higher proportion of patients ‘improved’ only at the 1 month outcome time point compared to patients treated by their male colleagues. At the later data collection time points there were no significant differences in the percentage of patients reporting ‘improvement’ between male and female chiropractors, although the PGIC-result at 3 months was almost significant in favor of female chiropractors’ patients. However, there was a significant difference in the proportion of patients reporting ‘worsening’ at the 3 month time point with patients treated by male chiropractors being 4 times more likely to report ‘worsening’ (i.e. 4.8% of patients) compared to patients treated by female chiropractors (i.e. 1.2% of patients). Both of these values are very low however compared to the proportion of ‘improved’ patients for both groups of clinicians.The same supporting results were found in the BQ- and NRS neck data where patients of female chiropractors had better scores at 1 month and also at 3 months. Contributing to the significant difference in outcome of the NRS neck data at 1 and 3 months in favor of female chiropractors may be the fact that the NRS neck pain score was significantly higher in male chiropractors’ patients at baseline and also continued to be significantly higher after 1 and 3 months of treatment. This suggests that the pain reduction within male and female chiropractor’s patients over time was most likely similar considering that patients of male chiropractors presented with higher levels of pain. Indeed, the fact that the NRS change scores at 1 and 3 months did not show any significant differences between patients of male and female chiropractors supports this conclusion.As mentioned above, 4 subscales and the total score of the Bournemouth Questionnaire  also showed significantly lower scores in patients seen by female chiropractors compared to those seen by male chiropractors after 1 and 3 months. However, a look at the actual change scores of the BQ-data does not confirm significant differences between male and female chiropractors’ patients over time. Although statistically significant differences were found for several of the outcome measures between the patients of male and female chiropractors, when looking at the actual numerical differences, it could be argued that they are not clinically relevant. Other than the BQ total scores, the actual numerical differences were less than 0.6 of an NRS point. With large sample sizes such as those in this study, it is not difficult to find statistically significant differences. However, authors and readers must be cautious about implying too much clinical relevance in such cases when there is less than a 1 point difference on the NRS scale.It has been suggested that the change in pain over time may be more relevant to the patient and gives a better clinical picture than the pain level at a single point in time . This suPatient management not only consists of good manual treatments, but the communication style plays a conceivably important role as well. Doctor-patient communication may be an additional and important factor in order to get a good and satisfying result at the end of a treatment period. It has been shown that female physicians view doctor-patient communication in a more positive way, that they talk more often and longer to patients and that they set a higher value on psychosocial aspects, confidence and empathy when talking to patients , 25. ThiThe baseline data showed that consulting a chiropractor because of neck pain was more common in women than men (65% versus 35%). This result is supported by other studies which report that in general predominantly women suffer from neck pain , 25, 26.Additionally, a strong relationship between patient sex and chiropractor sex was revealed in this study. Although more females than males suffered from neck pain, female chiropractors still had a significantly higher percentage of female patients than male chiropractors. Previous studies already investigated if there is a correlation between patient and doctor sex and discovered a “gender concordance preference” in females –31. One Some studies have indicated that not only in general but also with neck pain, women report significantly higher pain and disability levels than men , 27, 33.Interestingly, the results showed that female chiropractors had significantly more patients diagnosed with radiculopathy. However, their outcomes were better in the short term. One low back pain study showed that chiropractic patients with low back pain and additional leg pain improved less than patients without leg pain , while oWhether or not neck pain is of a long or short duration has been shown to have an impact on the treatment outcome. While patients suffering from acute neck pain present with higher pain and disability levels, they improve faster and in a higher proportion than chronic neck pain sufferers, although many chronic neck pain patients improve as well , 16. ThuPain medication use in this present study was more common in patients of female chiropractors at baseline. This is explained by the findings that female chiropractors are visited more commonly by female rather than male neck pain sufferers. As stated by several studies, women use significantly more prescription and non-prescription analgesics than men –40. ThisIt is possible that the age of patients has an influence on the outcome with older patients improving less than younger patients. Female chiropractors have significantly younger patients than male chiropractors and it is possible that this would be related to the better outcome in patients of female chiropractors. However, the actual numeric age difference between patients seen by male and female chiropractors is small as the large sample size in this study may have made this significant. Thus, the age difference in this study also should not impact the outcome relevantly.It was interesting to observe that there was a higher response rate from female chiropractors compared to males contributing patients to this study. This is likely due to the fact that female Swiss chiropractors are more likely to work part time compared to their male colleagues . No infoAs this study was not a randomized controlled trial but a prospective cohort study, no control or comparison group was included. Therefore, whether the improvement that occurred in both study groups is mainly a result of the chiropractic treatment or only a consequence of the natural history of healing cannot be verified. Chiropractors from all parts of Switzerland contributed patients to this study. These patients chose their own chiropractor so randomization was not possible in this setting. Therefore, it is likely that inequalities between the two study groups additionally influenced the results. By analyzing the unbalanced baseline data and their possible impact on the results in the discussion section, possible additional sources of influence were identified, but some may have remained undetected.In this study, data collection at baseline was conducted with a paper questionnaire and the follow-up data was collected by telephone interviews. It has been shown that using telephone interviews for data collection has a slight positive effect on the results, as patients tend to report better scores when answering the questions by telephone than in a written form –43. By uAs there was no standardization of the treatment method desired in this study and as the chiropractors did not have to describe their treatment procedures, it is unknown which treatment method was used by how many chiropractors and if one procedure achieved better results than others. Whether male and female chiropractors in this study used the same or different treatment methods could therefore also not be determined. Nevertheless, from the results of the Swiss Job Analysis 2009 it can be assumed that the vast majority of the patients in this study were treated with at least the diversified technique .The participating chiropractors contributed different numbers of patients to this study, as the number of patients was not determined. Therefore, chiropractors contributing numerous patients to this study did have a higher impact on the overall outcome than chiropractors contributing only few patients to this study. Additionally, the number and frequency of treatments was not determined. This decision was left to the chiropractor, as the purpose of this study was to evaluate outcomes as they would be found routinely in chiropractic practice.Thirty percent of chiropractors (78 of 260) in Switzerland contributed patients to this present study. Whether or not these 30% truly represented the average of Swiss chiropractors remains unknown.The results showed that the sex of the chiropractor was only linked to the treatment outcomes of these chiropractic neck pain patients at the 1 month time point. Additionally, although the BQ neck pain change score at 3 months also favored the female chiropractors, the sample size was very large in this study and the actual numerical differences were comparatively small, though statistically significant. Therefore these neck pain change scores at 3 months are not likely to be clinically relevant. Nevertheless, this study has shown that with their treatment of neck pain patients, female chiropractors achieve at least equally satisfying results as their male colleagues. This suggests that the quality of the chiropractic treatment of neck pain patients in Switzerland will not change in the future despite a prospective sex shift in the chiropractic profession.


The Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH) is a valid and reliable patient-reported outcome measure (PROM). It was designed to measure physical disability and symptoms in patients with musculoskeletal disorders of the upper extremity, and is one of the most commonly used PROMs for patients with shoulder pain. The aim of this study was to examine responsiveness, the smallest detectable change (SDC) and the minimal important change (MIC) of the DASH, in line with international (COSMIN) recommendations.The study sample consisted of 50 patients with subacromial pain syndrome, undergoing physical therapy for 3–4 months. Responsiveness to change was examined by calculating area under the receiver operating characteristic curves (AUC) and testing a priori-formulated hypothesis regarding correlations with changes in other instruments that measuring the same construct. The SDC was calculated using a test re-test protocol, and the MIC was calculated by the anchor-based MIC distribution. MIC values for patients with low and high baseline scores were also calculated.DASH appeared to be responsive, as it was able to distinguish patients who reported to be improved from those unchanged (AUC 0.77). All of the hypotheses were accepted. The SDC was 11.8, and the MIC was 4.4.This study shows that the Norwegian version of the DASH has good responsiveness to change and may thus be recommended to measure outcome in patients with shoulder pain in Norway. Shoulder pain is common in the general population with a reported 1-year prevalence of 5–47% . NumerouThe DASH is a region specific PROM, and is according to Roy et al.  the mostHowever, according to the COSMIN panel inadequate methods for examining responsiveness and MIC have been applied, such as effect size (ES), standardized response mean (SRM) and distribution-based approaches . The COSTo our knowledge, responsiveness of the DASH has not previously been examined in line with the COSMIN recommendations. Hence, the purpose of this study was to assess responsiveness, and to determine and compare the SDC and MIC of the Norwegian version of the questionnaire following these guidelines.This clinimetric study included patients with subacromial pain syndrome (SPS). The patients were recruited from an outpatient clinic for physical therapy and rehabilitation at X, from December 2007 to October 2010. The patients were referred to “usual physical therapy” in primary health care, partly financed by the public health insurance service. The inclusion criteria was a diagnosis of SPS given by an orthopaedic surgeon based on clinical findings and symptoms, including anterior-lateral shoulder pain worsening during elevation of the arm and overhead activities, positive isometric abduction and positive impingement sign . ExclusiThe assessments for the present study were completed at three different time-points: T1 (baseline), T2 (1–2 weeks after baseline) and T3 (3–4 months follow-up). At T1 they completed the DASH, Shoulder Pain and Disability Index (SPADI), Short Form 36 Health Survey (SF-36), Numeric Pain Rating Scale (NPRS), and provided demographic data. Active range of motion (AROM)  was measured with a goniometer by a physiotherapist. At T2, the patients only filled out the DASH and SPADI. After completed treatment (T3) they filled out DASH, SPADI, SF-36, and NPRS, and AROM was measured. Perceived recovery was reported by the patients on a 3-level ordinal scale. Mean DASH scores of T1 and T2 were calculated as a basis for measuring change.The DASH consists of a 30-item scale that contains 21 physical function items, five symptom items and four social role items. Each item has five response options concerning the patient’s symptom severity and function of the upper extremity in activity during the previous week. The scores range from 0 to 100, where 100 reflects the most severe disability. The DASH was considered incomplete if more than 10% (missing rule) of the items scores were missing. Missing items were imputed as the average of the remaining items . A previThe Shoulder Pain and Disability Index (SPADI) measures shoulder pain and disability, and contains 13 items in two domains: pain (five items) and disability (eight items). The total score ranges from 0 to 100, lower scores indicating less pain and disability [sability . Accordisability  and satisability , but itssability . The Norsability .The Short Form 36 Health Survey (SF-36) measures health in eight domains: physical functioning (PF), role-physical (RP), bodily pain (BP), perception of general health (GH), energy and vitality (VT), social functioning (SF), role limitation due to emotional problems (RE), and mental health (MH). The results range from the worst outcome (0) to the best outcome (100). The SF-36 was used as a generic measure of health, recommended to supplement condition-specific measures in shoulder patients [patients . The scopatients . The Norpatients .Numeric Pain Rating Scale (NPRS) captures the patient’s level of pain. It is an 11-point scale that is anchored on the left with “no pain”, and on the right with “worst pain possible”. The patients were asked to rate their current pain within the last 24 h. NPRS has shown good reliability and responsiveness, with reported MIC values varying from 1.1 to 2.17 in patients with shoulder pain [der pain , 28.Perceived recovery. At the 3–4 months’ follow-up (T3) the patients were asked to rate on a 3-level ordinal scale whether their condition had improved, was unchanged or had deteriorated since baseline. The use of a change scale is common, while designs and the number of scoring alternatives may vary. In a recent review change scales were shown to be reliable and responsive [sponsive , and excsponsive , althougsponsive , 32.Both criterion and construct approaches were used to examine responsiveness . As a crThe construct approach includes a priori hypotheses of expected associations between scores of DASH and other assessment tools that measure more or less the same construct . The strength of the positive correlation coefficients were interpreted according to Munro : little,The patients did not receive any treatment between T1 and T2. These two measurement points were used to determine measurement error. Measurement error can be expressed by the standard error of measurement (SEM) and the SDC. The COSMIN-group defines SEM as the standard deviation (SD) around a single measurement , and it To explore interpretability of change scores, the SDC was compared to the MIC. To distinguish clinically important change from measurement error, the MIC should be greater than the SDC. The MIC was determined by using visual anchor-based MIC distribution based on the ROC method . The perIn recent studies the MIC of PROMs has been found to vary depending on the baseline scores , 40, andThe data was assumed to be normally distributed if there was no or minimal difference between the mean and median value, confirmed by histograms, by Q-Q plot and by the Shapiro-Wilk test. Pearson and Spearman correlation coefficients were used as appropriate depending on fulfilment of normality criteria. Floor and ceiling effects were considered to be present if the lowest or highest possible score was achieved by more than 15% of the patients . The anaNinety-four patients met the inclusion criteria, while 29 31.0%) were unwilling or unable to participate, and two were excluded because of generalized pain. Of the 63 subjects, 13 dropped out before follow-up assessment after treatment (between baseline test and 3–4 months follow-up). The final study population consisted of 22 women and 28 men, with a mean age of 54.4 years  were identified as missing. Five items were missing (0.33%) at T3. All of the completed DASH questionnaires had at least 27 of the 30 items answered (missing rule), and the missing items were imputed as the average of the remaining items.Figure Table No floor or ceiling effects were observed for baseline or follow-up scores. The score distribution of the DASH is presented in Fig. The mean time period between T1 and T2 was 7.4 days . The ICC of the DASH was found to be 0.91. The SEM was 4.3, and the SDC was found to be 11.8.Patients who reported deterioration on the perceived recovery (anchor) were excluded from the calculation of MIC. The anchor was considered appropriate since the correlation of both instruments with the anchor was higher than 0.5 Table .The MIC for the total change scores of DASH was 4.4, with a sensitivity of 0.77 and specificity of 0.69 Table . Figure MIC values for low and high baseline scores was respectively 4.4 and 7.7. The median DASH score was 26.4. Twenty-two patients  had low DASH baseline scores (i.e. DASH ≤26.4). Twenty-one patients  had high DASH baseline scores (DASH > 26.4). The MIC data are presented in Table The DASH is often used in research and clinical practice to evaluate disability and the effect of interventions for shoulder disorders. Therefore, it is important to evaluate its ability to capture change, and especially the smallest change score that patients perceive as important.n = 50–99), except for the subgroup analysis and the calculation of the MIC which was poor (n < 30). (4) A longitudinal design with three measurements was used, (5) the time interval was stated, (6) the intervention was described, and (7) the proportion of patients that changed  was described. Regarding the hypotheses testing, (8) the hypotheses were formulated a priori,  the expected direction and magnitude of correlations of the change scores were defined,  the comparator instruments and its measurement properties were described.  The design, method and statistics are considered appropriate, (15) the criterion for change (anchor) can be considered to be a reasonable gold standard according to its correlation with the DASH (>0.50), (17) both correlation between the change scores and ROC curve were calculated, and (18) sensitivity and specificity for the patients who were ‘improved’ and ‘unchanged’ was determined.The study of responsiveness was conducted following all requirements of the COSMIN-checklist : (1) RepFor evaluating the responsiveness, both a criterion and a construct approach was conducted according to the COSMIN recommendations . Using tAccording to the construct approach, a total of 6 hypotheses were a priori formulated regarding the relationships between changes on the DASH and changes on related measures. None of the hypotheses were refuted. DASH showed little to moderate correlation with impairment measures, as is consistent with findings in other studies , 47.We found a MIC value of 4.4 for the total DASH data. This implies that a change of five on the scale is likely to be considered important by individual patients. However, measurement error by SDC was found to be 11.8 which is a larger value than all calculated MIC values. This means that individual patients may considered a MIC value to be an important change. However, as it cannot be distinguished from measurement error it is not statistically significant . MeasureAdditionally, we found a higher MIC (7.7) for the patients with high baseline scores Table . This suThe SDC value found in our study is comparable with SDC values reported by others , 49, 50.n = 50). Although it is within the COSMIN recommendation for examination of responsiveness, the sample size of the unchanged subgroup (n = 13) used for the analyses was small. Third, an ordinal scale with more scoring options might have been preferred.The present study is, to our knowledge, the first study to explicitly follow the COSMIN panel recommendation regarding examination of responsiveness of the DASH. However, there are some limitations as to how the findings should be interpreted. First, the COSMIN-checklist was developed to improve the selection of measurement instruments and how to evaluate these measurement properties. However, the checklist has not yet been tested for its reliability, and according to the authors it needs further refinement . Second,In conclusion, the Norwegian version of the DASH was found to be satisfactory responsive when applied on patients with subacromial pain. Based on the SDC and MIC, a change value on the DASH must be above 11.8 to be considered as an important change that is not due to measurement error.


Cancer is an increasing public health burden for Ethiopia. Pain is among the most common symptoms in patients with cancer. Hence, we aimed to assess cancer pain prevalence, cancer pain interference, and adequacy of cancer pain treatment in the oncology ward of an Ethiopian teaching hospital. Of 83 patients, total of 76 (91.6%) cancer patients experienced pain with varying degree of severity, and 7 (8.4%) patients experienced severe pain. Of the 76 cancer patients with pain, 68 (89.2%) experienced pain interference with their daily activities. Fifty-four (65%) patients were receiving inadequate cancer pain treatment with negative Pain Management Index. Therefore, it is vital to anticipate and assess pain of the cancer patients as routine clinical practice, to optimize analgesic therapy, and to identify and overcome barriers to adequate pain management. Cancer is an increasing public health burden for Ethiopia and currently accounts for four per cent of all deaths in Ethiopia . Most caCancer pain is more common in patients with advanced or metastatic cancer , 5. NearDespite availability of several established guidelines for the management of cancer pain, many cancer patients frequently receive inadequate pain treatment and undertreatment is well documented , 4, 9. PGUH  has recently (2014) opened an oncology ward. The severity and adequacy of cancer pain management in GUH are unknown and this study will help understand the severity and adequacy of cancer pain and its interference on their daily functioning of such patients in this hospital. Hence, we aimed to assess pain interference on patients' daily functioning and associated contributing factors and adequacy of cancer pain treatment in the oncology ward of GUH.The study was conducted from February 15 to May 15, 2016, in the oncology ward of GUH, Gondar, north-west Ethiopia. GUH is a teaching and referral hospital located in the northwest Ethiopia 727 kilo meters from the capital Addis Ababa. The hospital serves an estimated 7 million people and the oncology ward is providing service with ten beds.Patients were considered eligible if they fulfill the following criteria: age 18 years and older; diagnosed with any type of cancer; and admitted to the oncology ward in the specified time period. However, patients with other medical or psychiatric problems and unable or unwilling to provide the required information were excluded from the study.Before conducting the study, ethical clearance was secured from the University of Gondar School of Pharmacy ethical review committee and permission to collect data from patients was obtained from Gondar University Hospital. Then, after explaining the anonymity of the interview, verbal informed consent was obtained from the respondents (patients) for the interview. Furthermore, the data collected from each patient was kept confidential and used strictly only for the purpose of the study. pain severity score was calculated by adding the scores for items 2, 3, 4, and 5 and then dividing by 4 [A questionnaire-based interview using Brief Pain Inventory-Short Form (BPI-sf)  and charing by 4 . This giBased on the type of analgesic medication(s) the patients were receiving, the following scores were given: 0 , 1 , 2 , and 3 . Subsequently we determined the Pain Management Index (PMI). To construct PMI, the 4 levels of analgesic drug therapy used were determined by the potency: (0) no order for analgesic, (1) nonopioid , (2) weak opioid , and (3) strong opioid . Potency of analgesic was then compared with “pain worst.” Absence of pain was scored as “0,” mild pain as “1,” moderate pain as “2,” and severe pain as “3.” The PMI is computed by subtracting the pain level from the analgesic level. It ranges in value from −3  to +3 . A negative PMI score was considered an indicator of potentially inadequate pain management by the prescriber.P value < 0.2 in a univariate analysis were included to the final model of multivariate logistic regression analysis. Multivariate analysis was performed to compute adjusted odds ratio (AOR). Statistical significance was set at a one-sided P value < 0.05 in the multivariate analysis.All statistical analysis was performed using IBM SPSS ver. 22 . Descriptive statistics were used to summarize demographic characteristics, sites of cancer, tumor stages, presence of metastases, history of cancer treatment modality, history and type of pain, number of medications prescribed, and types and number of analgesics prescribed. Association between predictive variables (demographic data of patients) and outcome of interests (pain management adequacy and pain interference on functioning) using binary logistic regression and Fisher's exact test was done to identify determinants of outcome of interest. According to Hosmer-Lemeshow assumption, variables with a A total of 83 cancer patients, meeting the inclusion criteria, were identified during the 5-month study period between January and May 2016 in Oncology Ward of Gondar University Hospital. The median age of the patients was 50 ranging from 18 to 72 years; 50.6% were male. Higher proportions of patients with cancer were admitted in the Oncology Department due to genitourinary cancer (25.3%) and gastrointestinal cancer (22.9%). Most of the cancer patients had metastasis (73.5%), with stage 4 tumor observed in 19/83 (22.9%) cancer patients . No analA total of 76 (91.6%) cancer patients experienced pain with varying degree of severity. Of 83 patients, 7 (8.4%) patients were identified to experience severe pain . The sevBased on the assessment of factors affecting the adequacy of cancer pain management, a higher proportion inadequate pain management 10/13 (76.9%) was observed in cancer patients with high school education level. Cancer pain was not adequately controlled in patients (86%) for whom no analgesics was prescribed .An assessment of factors affecting the severity of pain interference on functioning was also done. A higher proportion of moderate to severe interference of pain on functioning was observed in cancer patients with stage 3 (59.5%) and stage 4 (68.4%) as shown in Upon univariate analysis regarding the adequacy of cancer pain management, COR revealed that pain was more likely to be managed adequately in patients taking nonopioids + adjuvant , 1.48–19.55) and weak opioids + nonopioids + adjuvant . In addition, number of all medications  and number of analgesics  had a statistically significant positive association with the likelihood of adequacy of cancer pain management. Patients with comorbidity  and Hx of pain  were less likely to get their pain adequately treated . Based oMultivariate analysis regarding the adequacy of cancer pain management showed that patients who had attended college/university  and patients with metastasis  were less likely having adequate pain management. An increase in the number of analgesics prescribed was positively associated with adequacy of pain management . Pain was about 9.6 times more likely to be managed adequately in patients prescribed with weak opioids + nonopioids + adjuvant . ConsidePain is a known symptom in patients with cancer interfering on functioning and leading to poor health outcome unless adequately managed. Several studies have examined undertreatment of cancer pain in different setup and populations , 13–27. Our study revealed that total of 76 (91.6%) cancer patients experienced pain with varying degree of severity. This finding is higher than other studies: 73.3% in Qadire et al. , 34% in Fifty-four (65%) patients were receiving inadequate cancer pain treatment with negative PMI which is higher than those reported by Apolone et al. and Mercadante et al. , 27. HowLittle is known about the contributing factors of the prevalence of moderate to severe pain interference on functioning. In our study, cancer patients with tumor stage I and stage II (nonadvanced stage) and patients with adequately treated pain were less likely to experience pain interference on functioning. Patients with metastasis and those who had a history of both surgery and chemotherapy treatment and a history of pain were more likely to pose moderate to severe pain interference on functioning.We could not assess patient's barrier to cancer pain management and healthcare provider's factors such as year of experience of the prescriber as a potential factor for under analgesic treatment. The sample size obtained during the study period is also small. This is a single center study done in GUH as it is the only cancer center in Amhara region.Based on the findings of our study, a significant percentage (91.6%) of patients with cancer experience pain of which nearly two-thirds of them (65%) were receiving inadequate cancer treatment and 89.2% of them experienced pain interference with their daily activities. It is also vital to anticipate and assess pain of the cancer patients as routine clinical practice to optimize analgesic therapy through identifying and intervening barriers of adequacy of pain management, thereby improving patient health outcome and quality of life.


This retrospective study investigated the association between the Charlson comorbidity index (CCI) score and the survival of patients with stage IIIB-IV  non-small cell lung cancer (NSCLC) who also did not have gene mutations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK).The records of 165 patients  who met the above criteria and were admitted to Beijing Friendship Hospital Capital Medical University from 1 May 2010 to 1 October 2014were reviewed. Associations between baseline variables and the CCI score were assessed via univariate and multivariate logistic regression analysis. Overall survival was defined as the time from the first clinic visit to death from any cause, or to the end of follow-up. Survival curves were estimated via the Kaplan-Meier method and compared with the log-rank test.P = 0.009), smoking (P = 0.042), and male gender (P = 0.021).Logistic regression analyses indicated that smoking and performance status were independently associated with the CCI score. Smoking was associated with an increased risk of mortality (odds ratio (OR) 4.12  compared to non-smokers), as was performance status 2   compared to performance status 1). Univariate Cox’s regression analyses showed that the hazard ratios were significantly associated with the CCI score (The CCI score is an important prognostic factor for the prediction of overall survival in patients with stage IIIB-IV NSCLC who are negative for EGFR and ALK gene mutations. Non-small cell lung cancer (NSCLC) is a common malignant tumour worldwide . BecauseThe use of comorbidities for prognostic assessment has been extensively studied in many fields , 10, incThe CCI score has been positively associated with increased risk of death in patients with inoperable NSCLC treated with radiofrequency ablation  . In patiThe effects of treatment selection on outcome in both surgical and nonsurgical patients with early-stage NSCLC have been assessed . HoweverElderly patients are often excluded from clinical trials because it is believed that they are unable to tolerate aggressive chemotherapy and are more likely to suffer increased toxicity, resulting in poorer quality of life. However, it has been demonstrated that age alone is not an independent prognostic factor, and the tolerance to treatment, its toxicity and the benefits experienced by elderly patients with good performance status are similar to those of the nonelderly .The present study retrospectively investigated whether CCI scores can predict the long-term survival of patients with unresectable advanced NSCLC.The Research Ethics Board of Beijing Friendship Hospital approved this retrospective study. The study complied with the Declaration of Helsinki. All subjects gave written informed consent.All subjects in this study conformed to the following criteria: visited an oncology clinic at Beijing Friendship Hospital, Capital Medical University  between May 2010 and October 2014; aged ≥18 y; tested negative for both epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene mutations; had unresectable NSCLC, stage IIIB-IV, which was confirmed histologically or cytologically and via imaging; and underwent a chemotherapy regimen, but not radiotherapy. The date of the last follow-up was 1 May 2015. We excluded patients who had previously received radiotherapy in the lung area, or who had an Eastern Cooperative Oncology Group (ECOG) performance status of≥ 3 .th edition of the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) TNM staging system for stages I, II, III, and IV [Age, gender, histology, stage, ECOG performance status, and smoking status were obtained from the Beijing Friendship Hospital medical records Table . The fir, and IV .Table 1PThe CCI parameters and scores were assigned according to the definitions established by Charlson et al. . SpecifiWe obtained additional comorbidity data via are view of the hospital administrative databases for individual patients, from both paper and electronic medical records. For conditions that could be scored in multiple categories based on disease severity, points were only counted for the more severe condition. For advanced NSCLC patients, cancer metastasis is common, and the CCI score was usually >6. The best cut-off value for the CCI and the survival data for all patients were evaluated through receiver operating characteristic (ROC) analysis.P < 0.05. All statistical analyses were performed with SPSS 13.0 for Windows software .The outcome measure was overall survival, defined as the time from the first clinic visit date to death from any cause, or to the end of the follow-up period. Summaries of discrete variables are displayed in terms of proportion, and continuous variables are presented as means with 95% confidence intervals (95% CI). ROC analysis was used to determine the best cut-off value for the CCI and survival data for all the patients. Survival curves were estimated via the Kaplan-Meier method. Univariate and multivariate Cox’s regression analyses were used to determine the association between baseline characteristics  and clinical outcomes. The survival curves were estimated via the Kaplan-Meier method. Logistic regression and multinomial logistic regression analyses were used to test the CCI score and baseline characteristics . Significance was defined at From 1 May 2010 to 1 October 2014, 297 patients received a new diagnosis of stage IIIB-IV NSCLC. Of these, 132 patients were excluded for being positive for EGFR or ALK gene mutations, having received radiotherapy in the lung area, having a performance status level of ≥3, or being lost early during follow-up. Therefore, 165 patients were included in the analysis  were metastatic solid tumours (82%), chronic pulmonary disease (37%), mild liver disease (29%), cerebrovascular disease (23%), diabetes with end-organ damage (21%), congestive heart failure (21%), peptic ulcer disease (19%), and peripheral vascular disease (16%).P < 0.05). The result of ROC analysis showed that a CCI score of 9 was the cut-off . The median survival time was 19.3 months (95% CI 17.00–23.30). The median survival rates at 1, 2, and 3 years were 78.31%, 41.56%, and 11.53%, respectively. The survival rates of patients in the low CCI score group at 1, 2, and 3 years  were better than those of patients with high CCI scores . The median survival time of patients in the low CCI score group  exceeded that of patients in the high CCI score group  . The Cox regression analysis revealed that there were significant differences (P < 0.05) between stage, CCI score, smoking status, gender, and the probability of surviving.The logistic regression analyses showed that smoking status and performance status were independent prognostic factors for CCI scores Table . SmokingP > 0.05).Higher stages (stage IV), high CCI scores (CCI ≥ 9), smoking, and male gender were associated with higher HRs than were lower stages, lower CCI scores, not smoking, and female gender Table . PatientP < 0.05; Table P < 0.05).The multivariate analysis showed that higher CCI scores (CCI ≥ 9), smoking, and male gender were associated with higher HRs  NSCLC without gene mutations in EGFR or ALK. The results showed that higher CCI scores (CCI ≥ 9), smoking, and male gender were associated with higher HRs.Currently, the prognostic determinants of NSCLC are disease stage, performance status, male gender, age greater than 60 years, non-squamous histology, and weight loss. Grosso et al. demonstrated that intraoperative complications did not differ between young and old patients who underwent surgery for stage I-III colorectal cancer, whereas some differences were found in postoperative complications and late complications . In anotIn the present study, we evaluated whether the CCI score can be used to predict chemotherapy benefit and survival in patients with unresectable stage IIIB-IV NSCLC. As cancer metastasis is very common in these patients, the CCI score is usually >6. We adjusted the CCI groups using ROC analysis to determine the best cut-off (CCI = 9). We found that the CCI score, gender, and smoking status were prognostic factors for patients with unresectable stage IIIB-IV NSCLC without EGFR or ALK gene mutations. In the clinical setting, we usually choose cancer stage and performance status to determine the treatment strategy. Although these factors are easy to determine, their prognostic accuracy is questionable. Rather, the present study found that the CCI score, smoking status, and gender are potential prognostic factors for patients with unresectable stage IIIB-IV NSCLC. Although there is evidence that comorbidities may influence the progression of aggressive cancers, patients often die of the cancer before the comorbidity can affect survival , 33. OurTNM staging is an important factor in the prognosis of NSCLC patients. However, for advanced NSCLC patients, such as patients with stage IIIB or stage IV NSCLC, whose tumours have similar biological behaviours, the main treatment and prognosis  are very similar. In our study, tumour staging was significant in the univariate analysis of OS but not in the multivariate analysis, indicating that tumour staging is not an independent predictor of OS. For example, most of the chemotherapy drugs are hepatotoxic and nephrotoxic; the most commonly used chemotherapy drug, paclitaxel, isneurotoxic, and the new targeted drug bevacizumab has the side effect of arterial embolization. When IIIB patients cannot be effectively treated because of liver and kidney dysfunction, diabetes, peripheral neuropathy, cardiovascular and cerebrovascular events, and other comorbidities, the OS of these patients may lower than that of stage IV patients without these comorbidities or with less comorbidity. We found that the CCI score was more significantly associated with the prognosis of NSCLC patients than was tumour staging. This finding also shows that the presence of complications may have a certain impact on the treatment of the NSCLC patients, which may affect the prognosis of patients. Comorbidities in patients with aggressive cancers should not be ignored. Further research is needed to determine whether the CCI score is a strong prognostic factor in patients with other cancers and whether it is useful in choosing chemotherapeutics.This study is limited, first, by the relatively small sample size, as more cases would increase the statistical power of the results. Second, the CCI was not designed specifically for patients with cancer, and some common comorbidities (such as hypertension) have not been incorporated into the CCI. A CCI score that is applicable specifically for cancer patients should be established. Finally, we defined the cut-off CCI score as9 to predict whether patients can benefit from chemotherapy, and this should be confirmed in the future.The CCI score can be considered an independent prognostic factor for stage IIIB-IV NSCLC patients that do not have EGFR or ALK genetic mutations. Performance status attenuates the strength of the association with the CCI score, but the CCI score is still significantly associated with survival after adjusting for performance status. Smoking status and gender were also found to be independent prognostic factors in this study. More large-scale research is required to further verify whether the CCI score is an independent prognostic factor for the overall survival of patients with NSCLC and other solid tumours.


The STarT Back Tool has good predictive performance for non-specific low back pain in primary care. We therefore aimed to investigate whether a modified STarT Back Tool predicted outcome with a broader group of musculoskeletal patients, and assessed the consequences of using existing risk-group cut-points across different pain regions.Secondary analysis of prospective data from 2 cohorts: (1) outpatient musculoskeletal physiotherapy services  and (2) musculoskeletal primary–secondary care interface services (SAMBA study n=1082).Patients with back, neck, upper limb, lower limb or multisite pain with a completed modified STarT Back Tool (baseline) and 6-month physical health outcome (Short Form 36 (SF-36)).Area under the receiving operator curve (AUCs) tested discriminative abilities of the tool's baseline score for identifying poor 6-month outcome . Risk-group cut-points were tested using sensitivity and specificity for identifying poor outcome using (1) Youden's J statistic and (2) a clinically determined rule that specificity should not fall below 0.7 .In PhysioDirect and SAMBA, poor 6-month physical health was 18.5% and 28.2%, respectively. Modified STarT Back Tool score AUCs for predicting outcome in back pain were 0.72 and 0.79, neck 0.82 and 0.88, upper limb 0.79 and 0.86, lower limb 0.77 and 0.83, and multisite pain 0.83 and 0.82 in PhysioDirect and SAMBA, respectively. Differences between pain region AUCs were non-significant. Optimal cut-points to discriminate low-risk and medium-risk/high-risk groups depended on pain region and clinical services.A modified STarT Back Tool similarly predicts 6-month physical health outcome across 5 musculoskeletal pain regions. However, the use of consistent risk-group cut-points was not possible and resulted in poor sensitivity (too many with long-term disability being missed) or specificity (too many with good outcome inaccurately classified as ‘at risk’) for some pain regions. The draft tool is now being refined and validated within a new programme of research for a broader musculoskeletal population.ISRCTN55666618; Post results. First study to demonstrate that modified STarT Back Tool items are similarly predictive of 6-month physical health across different musculoskeletal pain regions.Within two large independent cohorts it was consistently shown that a modified STarT Back Tool similarly predicts 6-month physical health outcome in other musculoskeletal pain regions as well as low back pain.A limitation of the study was that the original STarT Back Tool was not included in these two data sets, so a direct comparison between the performance of the original and modified STarT Back Tool versions for patients with low back pain was not possible.The Keele STarT Back Tool is designed to stratify patients with low back pain according to their risk of future physical disability, in order that prognostic subgroups can receive matched treatment.A previous systematic review of 45 cohort studieset al).While the likely value and acceptability of extending risk stratification to patients with other common musculoskeletal pain is as yet unknown, evidence suggests that the majority of general practitioners (GPs) consider prognosis to be important in their clinical decision-making for musculoskeletal treatment.The aim of this study was therefore to investigate the performance of a modified STarT Back Tool for predicting future physical health outcome for a broader group of musculoskeletal pain patients. Specific objectives were to compare the predictive performance of a modified STarT Back Tool for patients with musculoskeletal pain in different body regions and assess the consequences  of using existing STarT Back Tool score cut-points for classifying patients as medium/high risk across different pain regions .This study involved prespecified further analysis of existing data sets from two prospective cohorts of adults with musculoskeletal conditions consulting in two different services in the National Health Service, UK. Full ethical approval for both these studies was obtained and patients provided written informed consent prior to their research participation.The PhysioDirect trial included 2249 adult musculoskeletal patients taking part in a randomised trial comparing a PhysioDirect service (telephone-based physiotherapy assessment and advice) with usual physiotherapy care.The SAMBA study was an observational cohort of adults attending an NHS musculoskeletal clinical assessment and treatment service at the primary–secondary care interface.22The original STarT Back Tool includes nine items of which five concern psychosocial factors . The PhysioDirect trial and SAMBA study included the STarT Back Tool's psychosocial items within their baseline questionnaires.Participants were asked to indicate the primary site of their musculoskeletal pain for which they had sought treatment. From this information, patients were categorised as having one of the following regional pain problems: neck, back (thoracic or lumbar), upper limb, lower limb or multisite pain (pain in more than one region).The standardised summary score for the Physical Component Score (PCS) of the Short Form 36 (SF-36) Health Survey is population normalised  and was classified by tertiles  as has been used previously27–29All analyses were conducted separately for the two data sets and a descriptive comparison of the modified baseline STarT Back Tool scores (mean and SD) and proportion with poor 6-month physical health outcome (SF-36 PCS ≤33) calculated. Descriptive statistics using means and SDs were used to examine the modified STarT Back Tool score's distribution and investigate potential floor or ceiling effects (>10% of either lowest or maximum score).30Predictive performance (discrimination) was assessed by calculating ROC curve AUCs for baseline modified STarT Back Tool total scores against 6-month poor physical health outcome (dichotomised as poor/good) for each of the five different bodily pain presentations and their equality compared using STATA's ‘roccomp’ command to establish whether AUC differences were statistically significant.To examine whether the optimal subgroup cut-point on the modified STarT Back Tool total score to discriminate low from medium/high risk for poor 6-month physical health outcome was consistent across the five different pain regions and across the two data sets, we used two methods based on sensitivity and specificity of each potential cut-point. First, we used Youden's J Statistic which is calculated as sensitivity+specificity−1 for each potential cut-point and the optimal cut-point is the tool score with the highest value.In this study, we were not able to identify optimal subgroup cut-points on the modified STarT Back Tool to distinguish between medium-risk and high-risk patients as there were no reference standards for psychological distress in the two available data sets. The original STarT Back Tool used these reference standards to identify distress ‘caseness’ at baseline, and identified the optimal cut-point to screen for these distressed ‘cases’ using a psychological subscale score. Without these reference standards for psychological distress, we were limited to determining optimal subgroup cut-points on the total scale score between low and medium/high risk alone.In the PhysioDirect trial sample (n=1887), the 8-item modified STarT Back Tool score at baseline was normally distributed with a mean (SD) of 3.35 (2.09); 8.4% had the lowest score (0) and 2.2% had the maximum score (8). The distribution of primary pain regions was reported by clinicians as: lower limb 31.1%, back 28.7%, upper limb 23.5%, neck 11.8% and multisite pain 4.8%. The 6-month SF-36 PCS mean (SD) was 43.7 (10.9) with 18.5% having a ‘poor outcome’ in their physical health at 6-month follow-up. The mean age was 48 years old and 60% were female.In the SAMBA study sample (n=1082), the 8-item modified STarT Back Tool score at baseline was not normally distributed but had roughly equal numbers of all possible scores with a mean (SD) of 3.95 (2.65); 12.6% had the lowest score (0) and 10.9% had the maximum score (8). The distribution of primary pain sites was reported by patients as: lower limb 30.8%, back 26.7%, upper limb 23.8%, multisite pain 13.4% and neck 5.4%. The 6-month SF-36 PCS mean (SD) was 38.41 (12.76) with 28.2% having a ‘poor outcome’ in their physical health at 6-month follow-up. The mean age was 51 years old and 57% were female.Predictive performance of the modified STarT Back Tool as determined by ROC curve AUCs ranged from 0.72 to 0.83 and was not found to be statistically different across different pain regions in the PhysioDirect trial (p=0.098) and SAMBA study (p=0.130)  across different musculoskeletal pain regions. Predictive performance determined by AUCs for the 8-item modified STarT Back Tool total score was in fact slightly higher for neck, upper limb, lower limb and multisite pain than for back pain, although differences were not statistically significant. The results therefore demonstrate that the prognostic factors included within the STarT Back Tool are predictive of 6-month physical health across a range of musculoskeletal pain regions, not just back pain. However, the results demonstrated that the optimal baseline STarT Back Tool score cut-point for identifying individuals with poor physical health outcome was neither consistent across different pain regions nor across clinical services ) and primary–secondary care interface services (SAMBA study). This finding was consistent regardless of method used to determine the optimal modified STarT Back Tool score cut-point . This implies that the existing original STarT Back Tool score cut-point (4 or more out of 9) used to allocate patients with low back pain to the medium-risk/high-risk subgroups cannot simply be applied to patients with other musculoskeletal pain presentations or in different clinical services. This is likely to be due to differences in patient characteristics across services such as episode duration, which is known to influence the performance of the original STarT Back Tool.The findings of this study concur with previous evidence suggesting that the same set of prognostic variables can be used to estimate prognosis of patients with different musculoskeletal pain presentations.The implications from this analysis are that, despite good predictive performance of the modified STarT Back Tool in patients with pain in different regions of the body, clinicians need to cautiously consider the choice of cut-points when using a modified STarT Back Tool for musculoskeletal pain regions other than low back pain. The results suggest that existing cut-points may lead to an inefficiency in healthcare resource use, with too many patients with a likely long-term disability being missed, or too many patients with good physical health outcome being inaccurately classified as ‘at risk’, which may result in over treatment of low-risk groups.A modified version of the STarT Back Tool has similar predictive performance when used for patients with musculoskeletal pain in different body regions. However, the cut-points used to identify patients with a poor physical health outcome at 6-month follow-up are not consistent across pain regions or clinical services. Further research is underway to refine and validate a new Keele STarT MSK Tool which will form part of a new stratified care approach to be tested in a randomised controlled trial.


TRIAL DESIGN: To compare the difference in pain score during flexible cystoscopy between patients undergoing the procedure with plain lubricating gel  only and plain gel with diclofenac suppository in a randomized control trial.METHODS:  A total of 60 male patients with an indication of flexible cystoscopy were enrolled in a prospective, randomized controlled study. Patients were randomized in two groups. In group “A”, patients received diclofenac suppository one hour prior to the procedure while group “B” did not receive diclofenac suppository. Both groups received 10 ml of intra-urethral  plain gel for lubrication during flexible cystoscopy. Pain score was recorded immediately after the procedure using the visual analogue scale (VAS). Pre- and post-procedure pulse rate and systolic blood pressure was also recorded. Statistical analyses were performed using chi-square test and student t-test. Regression analysis was performed to address the confounding variables.RESULTS: Both groups were comparable for variables including age, duration of procedure, level of operating surgeon and indication of procedure. Most common indication for flexible cystoscopy was removal of double J stent. There was a statistically significant difference in the mean pain score between two groups (p = 0.012).  The difference in post-procedure mean pulse rate in the two groups was statistically significant (p= 0.01) however there was no difference observed in mean post procedure systolic blood pressure. Regression analysis showed that none of the confounding variables were significantly affecting pain perception.CONCLUSIONS: Intra rectal diclofenac suppository is simple and effective pre-emptive analgesia. We recommend its routine use during flexible cystoscopy for better pain control. It is now one of the most commonly performed diagnostic as well as therapeutic urologic interventions2. Pain associated with cystoscopy varies from patient to patient and there is continuous effort using various methods to reduce pain during and after the procedure to improve patient compliance for flexible cystoscopy. The majority of patients require local anesthesia or lubricant solution only but some patients may require intravenous sedation3 or inhalation analgesia (nitrous oxide)4. Factors contributing to severity of pain include: lubrication, use of topical anesthesia and duration of cystoscopy7 but the available evidence for best practice in terms of treatment is continuously evolving8. The important issues regarding the correct use of intra-urethral gels are, for the most part, left to individual preference9. Effect of different intra-urethral gels, their dosage, temperature and time of instillation on pain perception has been evaluated in literature. In a randomized control trail, 2% lidocaine gel in two different doses (10 and 20 ml) and plain lubricating gels were found to be equally effective for pain control during flexible cystoscopy(p=0.406)10. Pain perception with use of lidocaine versus plain lubricating gel is less as reported in a meta-analysis by Aaronsonet al.11 while another meta-analysis by Patelet al. has reported no statistical difference among the two gels for pain control12. In a study by Komiyaet al., oral zaltoprofen has been used as pre-emptive analgesia for rigid cystoscopy and it has been proved to provide better pain control than 2% lidocaine gel alone 13. Intra-rectal diclofenac suppository administration used by Ireret al. has a proven role to reduce pain and improve patients’ tolerance of trans rectal ultrasound-guided prostate biopsy14.The earliest reported use of flexible endoscope for examination of bladder neck was by Tsuchida and Sugawara15. In the current study we have attempted to assess the use of diclofenac suppository as a pre-emptive analgesia during flexible ureteroscopy.Diclofenac is an anti-inflammatory drug with local and systemic effects; the local effects include reducing the impact of pain mediators. The diclofenac suppository in comparison to the oral has a rapid onset and a slower rate of absorption. The maximal plasma level Is reached within 2 hours, and is maintained for up to 12 hours and that forms the basis of using suppository rather than oral NSAID in our studywww.clinicaltrials.gov . This trial was conducted at the surgical day care unit from February 2013 to July 2013.The Ethical Review Committee of the Aga Khan University and the Clinical Trial Unit approved the study protocol. The study was registered atsymptoms and those for removal of double J ureteral stent. All patients undergoing the procedure had a urinalysis and culture to exclude UTI. Patients were requested to empty the bladder immediately prior to the procedure or within 30 minutes. Prior to the procedure, patients were explained the visual analog scale . Eligible patients were randomized by a computer-generated list and sealed envelopes. Patients were randomized into either Group A (those patients who received diclofenac suppository prior to procedure) or Group B (those patients who did not receive diclofenac suppository prior to procedure) using a web-based random number generator . Diclofenac suppository (100 mg) was administered rectally 1 hour prior to the procedure in the pre-operative area. Both groups received 10 ml of plain lubricating gel immediately before the procedure for the purpose of lubrication.Details of recruitment and flow of study has been demonstrated as CONSORT flow diagram. . The pri16. The investigator was blinded to the group (independent assessor). Operative time was recorded from the operating room time log. Pre- and post-procedure pulse rate and blood pressure were recorded for all participants.The procedure was performed at the surgical day care unit in supine position by a consultant urologist or senior urology resident (residency year 5 and 6) that was blinded to the randomization group. A second resident immediately following the procedure, collected data (pain score) in the operating room. The VAS consists of a straight line with the endpoints defining extreme limits such as ‘no pain at all’ and ‘pain as bad as it could be’p-value of <0.05 was considered as statistically significant.Data was analyzed using SPSS™ version 17.0. Results were described in terms of mean and standard deviation for age, duration of procedure and pain score while frequency and percentage were mentioned for categorical variables. The student t-test  was used to determine statistical significance of VAS for pain between group A and B. Confounder and effect modifiers i.e. age, level of the person performing procedure, indication for procedure and duration of procedure were analyzed using linear regression analysis.Raw data for ‘Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial’, 2016Group A: Diclofenac + Gel; Group B: Gel alone; Indication: 1= LUTS, 2= Haematuria, 3= JJ Stent removal.Click here for additional data file.Copyright: © 2016 Nadeem M and Ather MH2016Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).Seventy-three patients were evaluated for inclusion in the study. A total of sixty patients were recruited in the trial and analyzed. The mean age was 46.75 ± 16.12 years (IQR: 18–80). The most common indication for flexible cystoscopy was removal of double J Stent , others were for evaluation of hematuria  and lower urinary tract symptoms . Year 5 and 6 urology residents performed the majority of the procedures (n= 56). Mean duration of the procedure was 5.52 ± 2.13 minutes (IQR: 2–10 minutes). On the 11 point VAS the mean pain score was 3.63 with a standard deviation of 1.46 for the entire group (IQR: 0 – 7). The highest pain score was of 7 on VAS reported by only one patient from group B.p= 0.53). The pre-procedure pulse and systolic blood pressures were comparable in both groups. Mean duration of procedure in group A was 5.76 ± 2.25 minutes and in group B was 5.28 ± 2.00 minutes. This difference in duration was not statistically significant (p=0.82). Indications for the procedure and level of operating surgeon were also comparable between the groups.The mean age of the patients in groups A and group B were 48.53 ± 17.81 years and 44.97 ± 14.31 years respectively and there was no statistically significant difference (p= 0.012). None of our patients required additional analgesia in either group. The difference in post-procedure pulse rate was found to be statistically significant (p=0.01) between groups however no statistically significant difference (p=0.15) was observed in systolic blood pressure between two groups  was found to have significant impact on the outcome parameter . This meta-analysis challenged the commonly held belief among clinicians that intra urethral lidocaine gel is more efficacious than plain gel for decreasing pain during flexible cystoscopy12. In contrast to the findings of Patelet al.12, Cornelet al. observed slightly less pain  in the test group and pain perception was the same between patients with past experience of cystoscopy and initial cystoscopy17. To avoid this bias, we kept very strict inclusion criteria and excluded all the patients with previous experience of flexible cystoscopy.Randomized studies by Patela priori to detect the effect, according to Lwangaet al.18 We followed stringent criteria for enrollment of patients in this trial to eliminate confounding factors for pain. Computer generated sequences were used for randomization in order to give equal chance of being selected in either group to all recruited patients.The present study has demonstrated significant reduction in pain perception during flexible cystoscopy in male patients with use of diclofenac suppository as pre-emptive analgesia. Sample size was calculated19. Till date various techniques have been used to ameliorate the perception of pain during flexible cystoscopy. Use of NSAID as pre-emptive analgesia has been tested for various surgical procedures21. Komiya and co-workers examined the effect of anti-inflammatory drug (NSAID) zaltoprofen that inhibits the generation of prostaglandins as well as the pain induced by bradykinin during rigid cystoscopy13. The mean age of the patients in their study was 69.3+/- 8.2 (range: 41–83) while in our study we had relatively younger study subjects  who are presumably more anxious with lower pain threshold. Despite this fact, diclofenac suppository significantly improved the pain perception and proved to be effective regardless of age on regression analysis. Another matter of debate is the statistical method used in the study by Komiyaet al.13 where they used a “one sample Wilcoxon test” for comparing the two groups which is rather an inappropriate test to demonstrate the effect. The one-Sample Wilcoxon signed-rank test is a non-parametric alternative to a one-sample t-test. The test determines whether the median of the sample is equal to some specified value. Data should be distributed symmetrically about the median. In the present study we have used regression analysis, which is a more stringent method to demonstrate the effect.Flexible cystoscopy is often performed repeatedly in particular during the follow up of urothelial cancer. As repeated cystoscopy did not increase the patient's tolerability to pain associated with cystoscopy, Muezzinoglu noted the need for more effective anesthesia to improve tolerability during the procedure and maintain quality of life of the patients under long-term follow-up with repeated cystoscopies15. The efficacy of the diclofenac suppository is due to more rapid onset of effect, and a slower rate of absorption (it takes approximately 4.5 hours for complete absorption) than oral enteric-coated tablets. The maximal plasma level is attained within 2 hours, and it is maintained for up to 12 hours15. The terminal half-life of diclofenac in plasma is 1 to 2 hours. The major route of excretion is the urine (~60%) and a small percentage through bile in the feces22. Its role has proven to be effective for pain control during trans rectal ultra sound guided prostate biopsy in study by Haqet al.23. In a case control the investigators noted that it is a simple and safe method. While Ireret al.14 showed additional benefit of using lidocaine gel for pain control during the same procedure but statistical significance of this study is in question due to its smaller sample size.In our study, we used diclofenac suppository as pre-emptive analgesia. The pharmacokinetics of the suppository form is quite different from the orally administered agent. It acts as an anti-inflammatory drug both locally and systemically, by minimizing the effects of local mediators involved in the pain response. Diclofenac has been marketed internationally since 1973 and is currently available in oral, rectal, parenteral and topical preparationsIn the present study, appropriate sample size, stringent criteria for recruitment, computer generated randomization, proper statistical methods and analysis has increased the scientific rigor. This was not a placebo controlled as various per rectally medications or “dummy drugs” may have some local inflammatory effect.Intra rectal diclofenac suppository is a simple and effective method to reduce pain during flexible cystoscopy regardless of age. We recommend its routine use for better tolerability of pain and to increase patient’s compliance.The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2016 Nadeem M and Ather MHData associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).F1000Research: Dataset 1. Raw data for ‘Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial’, 2016,10.5256/f1000research.9519.d14526824 Usage of diclofenac suppository, seems to be an excellent choice, based on the results of this revelatory research, so I congratulate the authors for running a well-designed trial and obtained an acceptable scientific standard. The issue of non-anesthetists procedures, for any examination like flexible cystoscopy, is always the most common matter of concern about patients for the practicing Urologists. Worldwide there are many used local anesthetic drugs or substitutes transient analgesia, without much success in the best case or side effects to their use in the worst. However, the use of an analgesic which may be readily obtained from the patient while avoiding adverse effects associated with the gastric tolerability, for maintaining a sufficiently efficient to meet the requirements as a pain reliever during flexible cystoscopy, is not only necessary but also imperative. We will certainly take into account the fact that during both rigid and flexible cystoscopy, there is a potential of greater momentary discomfort when the stent is being pulled through the bladder neck and due to the length of the urethra. So, an effective analgesic, not only will help the patient to be well tolerated, it will give the advantage to the urologist to deal with more calm the cystoscopy. Moreover it would be interesting to know the authors’ feedback on the response of patients according to sex and age in the administration of diclofenac.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. K Das and N Buchholz: Comment on “Nadeem M and Ather MH. Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial . F1000Research 2016, 5:2834 (doi: 10.12688/f1000research.9519.1)” Firstly, I congratulate the authors for a well-chosen study topic, and running a well-designed trial. Flexible cystoscopy, being a commonly practised office procedure without the involvement of anesthetists on most occasions, the choice of appropriate analgesics always remains a dilemma to the practising urologist. A gamut of approaches ranging from local anaethetic usage, lubricant solution to usage of inhalational agents has been practiced with mixed reports. Usage of diclofenac suppository, as has been advocated in this study appears to be a simple and effective approach for conducting this procedure. The statistics supports the claim of the proponents regarding the efficacy of this drug. Considering the ease of administration it will be a good option for the practising urologist conducting office flexible cystoscopy.Was there a difference in pain perception in individuals undergoing diagnostic flexible cystoscopy and those undergoing flexible cystoscopy for stent removal as the latter often involves added pain stimulus to the patient due to additional instrumentation.Was the benefit of diclofenac suppository equally perceived in males and females - our personal observations are flexible cystoscopies are presumably easier and well tolerated in females than males.The last sentence in the introduction says- “In the current study we have attempted to assess the use of diclofenac suppository as a pre-emptive analgesia during flexible ureteroscopy” - we presume this is a typographical error and should be “flexible cystoscopy” instead of flexible ureteroscopy – this needs to be corrected if so. It would be interesting to know the authors’ feedback on the following aspects from their experience in this study-We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. No we did not find any difference in the diagnostic cystoscopy versus interventional flexicystoscopy. The subgroup analysis not shared in the data  was insignificant, however, our own experience was that there is indeed is a momentary discomfort when the stent is being pulled through the bladder neck.Again an important point as indeed due to the length of the urethra there is a potential of greater discomfort in men during flexible cystoscopy. We, however, notice no significant difference in our practice (perhaps due to routine use of low pressure irrigation during introduction of the scope to keep the urethra open.) However, in our current work we only studied men.Indeed it is a typographical error, many thanks for pointing this out.We thank Drs. Buccholz and Das for their valuable comments on the above submission. In response to the questions raised: